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The effects of cholesterol-lowering treatment with statins on mortality and risk of cancer beyond the usual 5–6-year trial periods are unknown. We extended post-trial follow-up of participants in the Scandinavian Simvastatin Survival Study (4S) to investigate cause-specific mortality and incidence of cancer 5 years after closure of the trial. 4S was a randomised double-blind trial of simvastatin or placebo in patients with coronary heart disease, serum total cholesterol 5·5–8·0 mmol/L, and serum triglycerides 2·5 mmol/L or lower. The double-blind period lasted for a median of 5·4 years (range for survivors 4·9–6·3) and ended in 1994. After the trial, most patients in both groups received open-label lipid-lowering treatment. National registers were used to assess mortality and causes of death and cancer incidence in the original treatment groups for a median total follow-up time of 10·4 years (range for survivors 9·9–11·3). Analysis was by intention to treat. 414 patients originally allocated simvastatin and 468 assigned placebo died during the 10·4-year follow-up (relative risk 0·85 [95% CI 0·74–0·97], p=0·02), a difference largely attributable to lower coronary mortality in the simvastatin group (238 vs 300 deaths; 0·76 [0·64–0.90], p=0·0018). 85 cancer deaths arose in the simvastatin group versus 100 in the placebo group (0·81 [0·60–1·08], p=0·14), and 227 incident cancers were reported in the simvastin group versus 248 in the placebo group (0·88 [0·73–1·05], p=0·15). Incidence of any specific type of cancer did not rise in the simvastatin group. Simvastatin treatment for 5 years in a placebo-controlled trial, followed by open-label statin therapy, was associated with survival benefit over 10 years of follow-up compared with open-label statin therapy for the past 5 years only. No difference was noted in mortality from and incidence of cancer between the original simvastatin group and placebo group.

Background The link between type 2 diabetes and hypertension is well established and the conditions often coexist. High normal blood pressure, defined by WHO-ISH as systolic blood pressure (SBP) 130–139 mm Hg or diastolic blood pressure (DBP) 85–89 mm Hg, has been found to be an independent predictor for type 2 diabetes in studies, although with relatively limited follow-up periods of approximately 10 years. The aim of this study was to investigate whether hypertension, including mildly elevated blood pressure within the normal range, predicted subsequent development of type 2 diabetes in men over an extended follow-up of 35 years. Methods Data were derived from the Gothenburg Primary Prevention Study where a random sample of 7 494 men aged 47–55 years underwent a baseline screening investigation in the period 1970–1973. A total of 7 333 men were free from previous history of diabetes at baseline. During a 35-year follow-up diabetes was identified through the Swedish hospital discharge and death registries. The cumulative risk of diabetes adjusted for age and competing risk of death was calculated. Using Cox proportional hazard models we calculated the multiple adjusted hazard ratios (HR) (95% confidence interval (CI)) for diabetes at different blood pressure levels. Results During a 35-year follow-up, 956 men (13%) were identified with diabetes. The 35-year cumulative risk of diabetes after adjusting for age and competing risk of death in men with SBP levels <130 mm Hg, 130–139 mm Hg, 140–159 mm Hg and ≥160 mm Hg were 19%, 30%, 31% and 49%, respectively. The HR for diabetes adjusted for age, body mass index (BMI), cholesterol, antihypertensive treatment, smoking, physical activity and occupation were 1.43 (95% CI 1.12-1.84), 1.43 (95% CI 1.14-1.79) and 1.95 (95% CI 1.55-2.46) for men with SBP 130–139 mm Hg, 140–159 mm Hg, and ≥ 160 mm Hg, respectively (reference; SBP<130 mm Hg). Conclusion In this population, at mid-life, even high-normal SBP levels were shown to be a significant predictor of type 2 diabetes, independently of BMI and other conventional type 2 diabetes risk factors over an extended follow-up.

Analysis of insulin-like growth factor I in serum (S-IGF-I) is an integral component in the diagnosis of GH-related disorders and is going to be of interest in the diagnosis and follow-up of many disorders. The objective of the present study was to develop cross-sectional reference values for S-IGF-I measured by an automated chemiluminescence immunoassay (Nichols Advantage). The study included samples from 3,961 healthy subjects (2,201 males, 1,760 females) aged 1 month to 88 years. Six laboratories were involved in this study and the samples were analyzed by one of seven automated immunoassay systems run in these laboratories. For data analysis, polynomial age and sex-specific models were fitted after transformation of S-IGF-I values. The results show the well-known age dependency of S-IGF-I levels. At ages <20, higher S-IGF-I levels were seen in girls with an estimated mean peak of 410 microg/l at age 14 and an estimated mean peak of 382 microg/l at age 16 in boys. Thereafter, a rapid decrease was seen to approximately 25 years of age, followed by a slow age-dependent decrease. In adulthood, S-IGF-I in males were slightly, but significantly higher than in females. It could be shown that the mean values of some reference sample subgroups differed significantly from the total mean. However, the multicenter approach used in this study reduces the impact of systematic population, sample handling and laboratory differences on the calculated reference mean. The present study establishes age- and sex-specific reference values for a fully automated immunoassay system based on a large population of healthy subjects. The established reference values may be used for this immunoassay system in different laboratories provided that the systematic difference between systems is low.

This study examined variations in stroke incidence across occupational classes over a 35-year follow-up period. We analyzed a random population-based sample of 6,994 men aged 47–56 years at baseline without prior history of stroke. Standardized incidence rates, subdistribution hazard ratios (SHRs) from competing risk regressions and cumulative incidence were calculated, after accounting for risk of death attributed to causes other than stroke. A total of 1,442 strokes were identified over the 35-year period with crude incidences of 5.50 (ischemic) and 1.16 (hemorrhagic) per 1,000 person-years. In the whole group, occupational class was not associated with either ischemic or hemorrhagic stroke. However, older men (≥51 years at baseline) with unskilled manual occupations had a significantly lower risk of ischemic stroke than those with high officials (referent). No association between occupation and stroke of either type was detected for men younger than 51 years. There was an inverse and graded risk of death from causes other than stroke; men in high official positions had the lowest cumulative risk and unskilled manual workers had the highest risk ( P  < 0.0001). The association between occupation and ischemic stroke in older men persisted after accounting for competing risks of death (SHR 0.62; 95 % CI 0.46–0.84). In conclusion, low socioeconomic status was not associated with an increased risk of incident hemorrhagic or ischemic stroke. Older men with the lowest occupational status i.e. unskilled manual had a significantly lower risk of ischemic stroke, even after controlling for other risk factors and competing risks of death.

Low social class is associated with higher mortality from cancer at several sites and in patients with cancer low social class is known to be associated with a poorer chance of survival. Social differences in cancer incidence are less consistent. The present study was undertaken to assess the relation between occupational class and cancer incidence, mortality and survival from cancer in a large population of 7001 men aged 51-59, free of diagnosed cancer at baseline in 1970-1972. The main outcome measures were cancer incidence and cancer mortality until 1992 according to the Swedish national cancer and cause-specific death registries. Cancer survival was analysed in a subgroup of 904 men diagnosed with cancer before 1990. There were 1329 incident cases of cancer including 620 deaths from cancer. Overall cancer incidence during follow-up did not vary significantly by occupational class, but respiratory cancers were significantly more common among men with manual occupations; p = 0.0004. This was not be explained by differences in tobacco smoking, which were minor at the start of the study and did not increase much during follow-up. Overall mortality from cancer was significantly higher among men with manual occupations. Among professionals and higher officials 336 per 100,000 observation years died from cancer, compared to 391 among intermediate officials, 509 among lower officials, 474 among skilled and 548 among non-skilled workers; p for trend = 0.0003. This difference was mainly due to mortality from respiratory cancer, with a threefold difference between manual workers and professionals; this did not change after adjustment for smoking. Among the 904 men diagnosed before 1990 with cancer at any site (except non-melanoma skin cancer) the adjusted relative risk of dying from cancer was 1.75 (95% confidence interval 1.22-2.50) in unskilled workers compared to higher officials (p for trend 0.015).

Insulin-like growth factor I (IGF-I) levels mainly reflect secretion of growth hormone (GH) in the body. The aims of this study were to compare different IGF-I assay methods in healthy individuals, test the reliability of the methods and discuss the utility of IGF-I measurement in adults. The Nichols Institute Diagnostics radioimmunoassay was used to evaluate IGF-I in two random population samples of men and women (aged 25-64 years, n = 392) taken 10 years apart, in 1985 and 1995. This method for IGF-I testing was also compared with an immunoradiometric assay (IRMA) method in 387 men and women participating in the World Health Organization MONICA (MONItoring of trends and determinants for CArdiovascular diseases) Project, Goteborg, Sweden, in 1995. Serum IGF-I decreased with increasing age in both men and women. IGF-I was higher in young women compared with young men in both cohorts, while the opposite was found in the highest age group. Age-adjusted significant correlations were found between IGF-I and smoking, fibrinogen, coffee consumption, lipoprotein (a), osteocalcin and IGF-binding protein 3. The two cohorts showed similar mean IGF-I concentrations irrespective of method. The correlation between the Nichols and the IRMA methods was high: r = 0.93 (p < 0.0001). Based on this and previous studies, population-based IGF-I measurements are robust irrespective of which commercially available method of assay is used. IGF-I levels can be used in diagnosing acromegaly as well as providing target values. IGF-I assay can be used as a complement to stimulation testing in the diagnosis of GH deficiency, and as a tool for GH dose titration.

Summary Risk factors for hip fracture were studied in 7,495 randomly selected men during 30 years; 451 men had a hip fracture. High degree of leisure-time, but not work-related, physical activity, high occupational class, and high body mass index (BMI) protected against hip fracture. Smoking, tall stature, interim stroke, and dementia increased the risk. Purpose The purpose was to prospectively study risk factors for hip fracture in men. Methods We studied midlife determinants of future hip fractures in 7,495 randomly selected men aged 46-56 years in Gothenburg, Sweden. The subjects were investigated in 1970-1973 and followed for over 30 years. Questionnaires were used regarding lifestyle factors, psychological stress, occupational class, and previous myocardial infarction, stroke, and diabetes mellitus. Alcohol problems were assessed with the aid of registers. Using the Swedish hospital discharge register, data were collected on intercurrent stroke and dementia diagnoses and on first hip fractures (X-ray-verified). Results Four hundred fifty-one men (6%) had a hip fracture. Age, tall stature, low occupational class, tobacco smoking, alcoholic intemperance, and interim stroke or dementia were independently associated with the risk of hip fracture. There were inverse associations with leisure-time physical activity, BMI, and coffee consumption. The gradient of risk for one standard deviation of multivariable risk decreased with time since measurement yet was a good alternative to dual energy X-ray absorptiometry measurements. Conclusions High degree of leisure-time physical activity, high occupational class, and high BMI protected against hip fracture. However, work-related physical activity was not protective. Smoking, tall stature, and interim stroke or dementia increased the risk.

Summary Risk factors for osteoporotic fractures were evaluated in 1,396 men and women for a period of 20 years. Serum total cholesterol was found to be an independent osteoporotic fracture risk factor whose predictive power improves with time. Introduction The purpose of this study was to evaluate long-term risk factors for osteoporotic fracture. Methods A population random sample of men and women aged 25–64 years (the Gothenburg WHO MONICA project, N  = 1,396, 53% women) was studied prospectively. The 1985 baseline examination recorded physical activity at work and during leisure time, psychological stress, smoking habits, coffee consumption, BMI, waist/hip ratio, blood pressure, total, HDL and LDL cholesterol, triglycerides, and fibrinogen. Osteoporotic fractures over a period of 20 years were retrieved from the Gothenburg hospital registers. Poisson regression was used to analyze the predictive power for osteoporotic fracture of each risk factor. Results A total number of 258 osteoporotic fractures occurred in 143 participants (10.2%). As expected, we found that previous fracture, smoking, coffee consumption, and lower BMI each increase the risk for osteoporotic fracture independently of age and sex. More unexpectedly, we found that the gradient of risk of serum total cholesterol to predict osteoporotic fracture significantly increases over time ( p  = 0.0377). Conclusions Serum total cholesterol is an independent osteoporotic fracture risk factor whose predictive power improves with time. High serum total cholesterol is a long-term cause of osteoporotic fracture.

Background Simple global self-ratings of health (SRH) have become increasingly used in national and international public health monitoring, and in recent decades recommended as a standard part of health surveys. Monitoring developments in population health requires identification and use of health measures, valid in relation to targets for population health. The aim of the present study was to investigate associations between SRH and sick leave, disability pension, hospital admissions, and mortality, adjusted for effects of significant covariates, in a large population-based cohort. Methods The analyses were based on screening data from eight population-based cohorts in southern and central Sweden, and on official register data regarding sick-leave, disability pension, hospital admissions, and death, with little or no data loss. Sampling was performed 1973–2003. The study population consisted of 11,880 women and men, age 25–99 years, providing 14,470 observations. Information on SRH, socio-demographic data, lifestyle variables and somatic and psychological symptoms were obtained from questionnaires. Results There was a significant negative association between SRH and sick leave (Beta −13.2, p<0.0001, and −9.5, p<0.01, in women and men, respectively), disability pension (Hazard ratio 0.77, p<0.0001 and 0.76, p<0.0001, in women and men, respectively), and mortality, adjusted for covariates. SRH was also significantly associated with hospital admissions in men (Hazard ratio 0.87, p<0.0001), but not in women (Hazard ratio 0.96, p0.20). Associations between SRH on the one hand, and sick leave, disability pension, hospital admission, and mortality, on the other, were robust during the follow-up period. Conclusions SRH had strong predictive validity in relation to use of social insurance facilities and health care services, and to mortality. Associations were strong and robust during follow-up.

Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess whether candesartan could reduce the incidence and progression of retinopathy in type 1 diabetes. Two randomised, double-blind, parallel-design, placebo-controlled trials were done in 309 centres worldwide. Participants with normotensive, normoalbuminuric type 1 diabetes without retinopathy were recruited to the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned to candesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators and participants were unaware of the treatment allocation status. The primary endpoints were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbers NCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1. 1421 participants (aged 18–50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) in DIRECT-Prevent 1, and 1905 (aged 18–55 years) to candesartan (n=951) or to placebo (n=954) in DIRECT-Protect 1. Incidence of retinopathy was seen in 178 (25%) participants in the candesartan group versus 217 (31%) in the placebo group. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in the placebo group. Hazard ratio (HR for candesartan vs placebo) was 0·82 (95% CI 0·67–1·00, p=0·0508) for incidence of retinopathy and 1·02 (0·80–1·31, p=0·85) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0·65 (0·48–0·87, p=0·0034), which was attenuated but still significant after adjustment for baseline characteristics (0·71, 0·53–0·95, p=0·046). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1·16, 95% CI 1·05–1·30, p=0·0048) and DIRECT-Protect 1 (1·12, 95% CI 1·01–1·25, p=0·0264). Adverse events did not differ between the treatment groups. Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression. AstraZeneca and Takeda.