Effectiveness of community-based DOTS strategy on tuberculosis treatment success rates in Namibia.

DOTS is a key pillar of the global strategy to end tuberculosis (TB). To assess the effectiveness of community-based compared with facility-based DOTS on TB treatment success rates in Namibia. Annual TB treatment success, cure, completion and case notification rates were compared between 1996 and 2015 using interrupted time series analysis. The intervention was the upgrading by the Namibian government of the TB treatment strategy from facility-based to community-based DOTS in 2005. The mean annual treatment success rate during the pre-intervention period was 58.9% (range 46-66) and increased significantly to 81.3% (range 69-87) during the post-intervention period. Before the intervention, there was a non-significant increase (0.3%/year) in the annual treatment success rate. After the intervention, the annual treatment success rate increased abruptly by 12.9% (P < 0.001) and continued to increase by 1.1%/year thereafter. The treatment success rate seemed to have stagnated at ∼85% at the end of the observation period. Expanding facility-based DOTS to community-based DOTS increased annual treatment success rates significantly. However, the treatment success rate at the end of the observation period had stagnated below the targeted 95% success rate. .

The prevention of neonatal group B streptococcal disease: a report by a working group of the Medical Screening Society.

Streptococcus agalactiae, or Lancefield group B streptococcus (GBS), is the most frequent cause of serious bacterial sepsis, including neonatal meningitis, in UK neonates. Early-onset neonatal GBS infection, but not late-onset, can be prevented by screening to identify high-risk pregnancies and administering penicillin during delivery. A vaccine has been developed as an alternative means of prevention but it is awaiting a randomized trial before being available for general use. In this review we examine the published literature to assess the morbidity and mortality attributable to neonatal GBS infection, quantify the screening performance of the two alternative modes of screening (microbiological and risk factor based), review the evidence on the efficacy of the vaccine, and estimate the numbers of deaths and cases of serious disability that each strategy in turn might prevent in the UK, in order to assess the most effective means of prevention for the UK.

Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention.

BACKGROUND: Results from prospective studies of serum homocysteine levels and ischemic heart disease (IHD) are inconclusive. We carried out a further prospective study to help clarify the position. METHODS: In the British United Provident Association (BUPA) prospective study of 21,520 men aged 35 to 64 years, we measured homocysteine levels in stored serum samples and analyzed data from 229 men without a history of IHD at study entry who subsequently died of IHD and 1126 age-matched control subjects (nested case-control design). RESULTS: Serum homocysteine levels were significantly higher in men who died of IHD than in men who did not (mean, 13.1 vs 11.8 micromol/L; P<.001). The risk of IHD among men in the highest quartile of serum homocysteine levels was 3.7 times (or 2.9 times after adjusting for other risk factors) the risk among men in the lowest quartile (95% confidence interval [CI], 1.8-4.7). There was a continuous dose-response relationship, with risk increasing by 41% (95% CI, 20%-65%) for each 5-micromol/L increase in the serum homocysteine level. After adjustment for apolipoprotein B levels and blood pressure, this estimate was 33% (95% CI, 22%-59%). In a meta-analysis of the retrospective studies of homocysteine level and myocardial infarction, the age-adjusted association was stronger: an 84% (95% CI, 52%-123%) increase in risk for a 5-micromol/L increase in the homocysteine level, possibly because the participants were younger; the relationship between serum homocysteine level and IHD seems to be stronger in younger persons than in older persons. CONCLUSIONS: Our positive results help resolve the uncertainty that resulted from previous prospective studies. The epidemiological, genetic, and animal evidence together indicate that the association between serum homocysteine level and IHD is likely to be causal. A general increase in consumption of the vitamin folic acid (which reduces serum homocysteine levels) would, therefore, be expected to reduce mortality from IHD.

Serum cholesterol and ischaemic heart disease.

A systematic examination of the evidence on the relationship between serum cholesterol and ischaemic heart disease shows conclusively that serum cholesterol reduction in populations with high rates of heart disease is an effective and safe method of reducing ischaemic heart disease rates. The relative protective effect is greater at younger ages (50% reduction at age 40 for a 0.6 mmol/l reduction in serum cholesterol declining to about 20% at age 70 or more). The absolute protective effect is greater if the disease is common because the effect of a give serum cholesterol reduction is proportional to the prevailing heart disease rate. The full effect of a serum cholesterol reduction is evident after about 5 years. The use of drugs of the 'statin' type can lower serum cholesterol by about 1.8 mmol/l, yielding a reduction in risk of about 60% at age 60. A diet typical in Japan would lower serum cholesterol by about 1.2 mmol/l and lead to a halving of the risk. Only modest serum cholesterol reductions (about 0.3 mmol/l) are generally achievable by individuals altering their diet independently of others and this is expected to lead to a 15% reduction in the risk of ischaemic heart disease at age 60. Larger reductions (about 0.6 mmol/l) require collective action over the supply and preparation of food which could reduce the risk by about 30%. Achieving the full impact of serum cholesterol reduction in a population will require a national nutritional policy. It is not something that can be effectively left to individual action.

Serum albumin and mortality in the BUPA study. British United Provident Association.

In the British United Provident Association (BUPA) study, a prospective observational study of 21,520 men, the serum albumin of 877 men who died during 10 years of follow-up was compared with that of 877 controls, each matched to a case by age (within 1 year) and date of attendance (within 3 months). There was little overall difference (mean case-control difference = -0.11 milligram, P > 0.2) despite the fact that other studies have reported a long-term association between low serum albumin and increased mortality. Cause-specific mortality data showed no association of low albumin with ischaemic heart disease or other circulatory diseases. An inverse association with cancer was confined to the first few years of follow-up and so attributable to pre-clinical cancer lowering both serum albumin itself and serum cholesterol, with which albumin was associated. There was an association of chronic respiratory, neurological, renal, liver and gut diseases with low serum albumin (case-control difference = -1.19 milligram, P < 0.001) consistent with the effect of pre-clinical disease lowering serum albumin. Other causes of death showed no association with albumin. Our data do not support a cause and effect association of low serum albumin and mortality.

Serum triglyceride: a possible risk factor for ruptured abdominal aortic aneurysm.

BACKGROUND: We aimed to determine the relationship between ruptured abdominal aortic aneurysm (AAA) and serum concentrations of lipids and apolipoproteins. METHODS: A cohort of 21 520 men, aged 35-64 years, was recruited from men attending the British United Provident Association (BUPA) clinic in London for a routine medical examination in 1975-1982. Smoking habits, weight, height and blood pressure were recorded at entry. Lipids and apolipoproteins were measured in stored serum samples from the 30 men who subsequently died of ruptured AAA and 150 matched controls. RESULTS: Triglyceride was strongly related to risk of ruptured AAA. In univariate analyses the risk in men on the 90th centile of the distribution relative to the risk in men on the 10th (RO10-90) was 12 (95% confidence interval [CI] : 3.8-37) for triglyceride, 5.5 (95% CI: 1.8-17) for apolipoprotein B (apoB) (the protein component of low density lipoprotein [LDL]), 0.15 (95% CI : 0.04-0.56) for apo A1 (the protein component of high density lipoprotein [HDL]), 3.7 (95% CI: 1.4-9.4) for body mass index and 3.0 (95% CI: 1.1-8.5) for systolic blood pressure. Lipoprotein (a) (Lp(a)) was not a significant risk factor (RO10-90 = 1.6, 95% CI: 0.6-3.0). In multivariate analysis triglyceride retained its strong association. CONCLUSION: Triglyceride appears to be a strong risk factor for ruptured AAA, although further studies are required to clarify this. If this and other associations are cause and effect, then changing the distribution of risk factors in the population (by many people stopping smoking and adopting a lower saturated fat diet and by lowering blood pressure) could achieve an important reduction in mortality from ruptured AAA.

Why is mortality higher in poorer areas and in more northern areas of England and Wales?

STUDY OBJECTIVE: To identify and quantify the factors responsible for the differences in mortality between affluent and deprived areas, the north and the south, and urban and rural areas in England and Wales. DESIGN: A multiple Poisson regression analysis of cause specific mortality in the 403 local authority districts, each classified by deprivation (using the Jarman Index), latitude (from 50 degrees to 55 degrees north) and urbanisation, adjusting for age, sex, and proportion of ethnic minorities. SETTING: England and Wales 1992. MAIN RESULTS: All cause mortality was 15% higher in the districts comprising the most compared with the least deprived tenth of the population, 23% higher in the most northern (55 degrees) than in the most southern (50 degrees) districts, and 4% higher in metropolitan (within large cities) than rural districts. Nationally these differences were associated with 40,000, 65,000, and 15,000 excess deaths respectively. More than two thirds of the overall excess mortality with deprivation, latitude, and urbanisation was from three diseases--ischaemic heart disease, lung cancer, and chronic bronchitis and emphysema. The excess mortality from these and other diseases closely matched that predicted from differences according to deprivation and latitude in smoking, heavy alcohol consumption, Helicobacter pylori infection, and temperature, and thus could be attributed to these causes. About 85% of the overall excess mortality with deprivation was attributable to heavier smoking and 6% to heavier alcohol consumption, but diet varied little. Deaths more directly related to deprivation (such as those caused by H pylori infection, drug misuse, psychoses) accounted for an estimated 12% of the excess deaths, but variation in provision and uptake of healthcare services only 1%. The direct effects of deprivation are more strongly related to morbidity than mortality. Of the difference in mortality with latitude, about 45% was attributable to differences in smoking, and 25% to climate (mainly the association of cardiovascular and respiratory disease with cold). The differences with urbanisation were mainly because of smoking. CONCLUSIONS: Differences in the prevalence of smoking account for much of the variation in mortality between areas. Alcohol accounts for some, diet little. The more direct material effect of deprivation contributes to the variation in mortality but is particularly important with respect to differences in morbidity.

An ecological study of serum cholesterol and ischaemic heart disease between 1950 and 1990.

OBJECTIVE: (i) To carry out a quantitative analysis of the average serum cholesterol levels in different countries in relationship to the ischaemic heart disease (IHD) mortality in these countries. (ii) To examine changes in serum cholesterol levels over time in different countries. DESIGN: Analysis of published surveys measuring average serum cholesterol in specified communities in different countries. SETTING: The original cholesterol surveys were mainly in occupational and residential settings. RESULTS: Survey data allowed estimation of average serum cholesterol levels during specified time periods for 17 countries; estimates in men aged 40-59 years varied from 3.8 mmol/l (rural China) to 7.0 mmol/l (Finland). Variation in serum cholesterol accounted for 80% of the tenfold range in risk of IHD across countries. A difference in total (or LDL) cholesterol of 0.6 mmol/l between countries was associated with an average difference in IHD mortality of 37% at age 55-64 years. Repeat surveys showed that serum cholesterol reductions of the order of 0.6 mmol/l have occurred in some communities over about 5-10 years. CONCLUSIONS: Variation in serum cholesterol explains four-fifths of the geographical variation in IHD mortality. Reductions in cholesterol of about 0.6 mmol/l (10%) have been achieved in some Western communities or countries over periods of a few years, a change that is associated with a decrease in IHD mortality of over one-third.

By how much does fruit and vegetable consumption reduce the risk of ischaemic heart disease?

OBJECTIVE: To quantify the relationship between fruit and vegetable consumption and the incidence of ischaemic heart disease. DESIGN: A meta-analysis of cohort studies of the relationship between ischaemic heart disease and markers of fruit and vegetable consumption, namely dietary intake of fruit, vegetables, carotenoids, vitamin C, fruit fibre and vegetable fibre, and serum concentration of carotenoids and vitamin C, adjusted for other risk factors. MAIN OUTCOME MEASURES: Risk of ischaemic heart disease at the 90th centile of consumption relative to that at the 10th, equivalent to about a four-fold difference in fruit consumption and a doubling of vegetable consumption. RESULTS: The association with ischaemic heart disease was of similar magnitude for all six dietary markers of fruit and vegetable consumption. The median of the six estimates was that risk was 15% (range 12-19%) lower at the 90th centile of consumption than at the 10th. The estimates were generally adjusted for the possible confounding effect of other heart disease risk factors. The serum studies of vitamin C were consistent with this; those of carotenoids suggested a larger difference (43%) but were not adjusted for the important confounding effect of smoking. The substances in fruit and vegetables responsible for the protective effect on heart disease are uncertain but the effect is commensurate with the estimated protective effects of the potassium and folate in fruit and vegetables. Beta-carotene or vitamin E are not likely to be important because randomised trials of these vitamins in large doses have shown no reduction in heart disease mortality. CONCLUSIONS: The risk of ischaemic heart disease is about 15% lower at the 90th than the 1Oth centile of fruit and vegetable consumption.

The performance of blood pressure and other cardiovascular risk factors as screening tests for ischaemic heart disease and stroke.

This paper summarises the main evidence and conclusions relating to using blood pressure measurement as a screening test to identify people who will develop ischaemic heart disease (IHD) or stroke, as recently published in a Health Technology Assessment report. While blood pressure is recognised as an important cause of stroke and IHD, and lowering blood pressure can substantially lower the risk of these diseases, the measurement of blood pressure is a poor screening test. It is not good in distinguishing those who will and will not develop these diseases. The poor screening performance is illustrated by the findings that in the largest cohort study, persons in the top 10% of the distribution of systolic blood pressure experienced only 21% of all IHD events and 28% of all strokes at a given age. Using several cardiovascular risk factors in combination does not add materially to the poor screening performance of blood pressure alone. Among persons in a specified age group, the 5% at highest risk experience 17% of all heart disease deaths with risk computation based on blood pressure alone, 22% when based on blood pressure and apolipoprotein B (or LDL cholesterol) in combination, and only 28% using these two, smoking and three other cardiovascular risk factors all in combination. Identifying patients at the time of hospital discharge following myocardial infarction or stroke is the most effective screening test to identify those who will die of cardiovascular disease. In patients with a history of myocardial infarction or stroke the cardiovascular death rate in the absence of treatment is about 5% per year, a risk that persists for at least 15 years. In the absence of treatment, about half of all deaths from heart disease in a population occur after hospital discharge following the first infarct. Among persons with no history of cardiovascular disease, age is a better screening test than the reversible risk factors, and the best policy is to offer treatment to all persons above a specified age such as 55 years.

The importance of age in screening for cancer.

OBJECTIVE: To derive a rational method of selecting the age range over which screening tests for cancer should be offered (that is, over which they would be most effective in saving life). MAIN OUTCOME MEASURE: The number of person-years of life that are lost through deaths occurring at each year of age from each of six cancers. RESULTS: For each cancer the number of years of life lost to age 80, plotted against age at death, showed a rise followed by a fall. The peak indicates the age at which deaths from the cancer result in most years of life lost. Special screening tests, such as mammography for breast cancer, will be most effective in saving life shortly before that age. The peak (as a five year age span) occurs at age 55-59 for breast cancer (189 years of life lost per 10,000 women per year), 70-74 for prostate cancer (114), 65-69 for colorectal cancer (96), 55-59 for ovarian cancer (61), 50-54 for cervical cancer (47), and 45-50 for melanoma (8). The precise interval by which special screening tests should precede the peak age is not critical; five years would be appropriate. Given current evidence on the efficacy of cancer screening, if it were stipulated that screening could only be performed when at least 50 years of life were to be gained per 10,000 persons screened, only mammography for breast cancer would be conducted, between the ages of 50 and 59. If the stipulation was 25 or more years of life gained mammography would be offered to women aged 40-69 and cervical smears to women aged 35-59. With only 10 or more years of life gained (unlikely to be worthwhile) mammography would be extended to women aged 30-74, cervical smears to 25-69, and faecal occult blood testing for colorectal cancer offered to those aged 45-74. Extending cervical cancer screening to age 69 would save more years of life than the present policy of screening women aged 20-29. Extending breast cancer screening to the age of 74 would be more effective than cervical screening at any age. CONCLUSIONS: Determining the number of years of life lost through deaths from a particular cancer at each age is useful in public health screening policy, both in selecting the age range over which special screening tests of proven efficacy should be offered and in quantitatively comparing the value of screening for different cancers.

A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect.

OBJECTIVE: To determine the magnitude and importance of the relation between smoking, bone mineral density, and risk of hip fracture according to age. DESIGN: Meta-analysis of 29 published cross sectional studies reporting the difference in bone density in 2156 smokers and 9705 non-smokers according to age, and of 19 cohort and case-control studies recording 3889 hip fractures reporting risk in smokers relative to non-smokers. RESULTS: In premenopausal women bone density was similar in smokers and non-smokers. Postmenopausal bone loss was greater in current smokers than non-smokers, bone density diminishing by about an additional 2% for every 10 year increase in age, with a difference of 6% at age 80. In current smokers relative to non-smokers the risk of hip fracture was similar at age 50 but greater thereafter by an estimated 17% at age 60, 41% at 70, 71% at 80, and 108% at 90. These estimates of relative risk by age, derived directly from a regression analysis of the studies of smoking and hip fracture, were close to estimates using the difference in bone density between smokers and non-smokers and the association between bone density and risk of hip fracture. The estimated cumulative risk of hip fracture in women in England was 19% in smokers and 12% in non-smokers to age 85; 37% and 22% to age 90. Among all women, one hip fracture in eight is attributable to smoking. Limited data in men suggest a similar proportionate effect of smoking as in women. The association was not explained by smokers being thinner, younger at menopause, and exercising less nor by actions of smoking on oestrogen, but smoking may have a direct action on bone. CONCLUSIONS: Hip fracture in old age is a major adverse effect of smoking after the menopause. The cumulative excess bone loss over decades is substantial, increasing the lifetime risk of hip fracture by about half.

By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?

OBJECTIVE: To estimate by how much and how quickly a given reduction in serum cholesterol concentration will reduce the risk of ischaemic heart disease. DESIGN: Data on the incidence of ischaemic heart disease and serum cholesterol concentration were analysed from 10 prospective (cohort) studies, three international studies in different communities, and 28 randomised controlled trials (with mortality data analysed according to allocated treatment to ensure the avoidance of bias). MAIN OUTCOME MEASURE: Decrease in incidence of ischaemic heart disease or mortality for a 0.6 mmol/l (about 10%) decrease in serum cholesterol concentration. RESULTS: For men results from the cohort studies showed that a decrease of serum cholesterol concentration of 0.6 mmol/l (about 10%) was associated with a decrease in incidence of ischaemic heart disease of 54% at age 40 years, 39% at age 50, 27% at 60, 20% at 70, and 19% at 80. The combined estimate from the three international studies (for ages 55-64 years) was 38% (95% confidence interval 33% to 42%), somewhat greater than the cohort study estimate of 27%. The reductions in incidence of ischaemic heart disease in the randomised trials (for ages 55-64 years) were 7% (0 to 14%) in the first two years, 22% (15% to 28%) from 2.1-5 years, and 25% (15% to 35%) after five years, the last estimate being close to the estimate of 27% for the long term reduction from the cohort studies. The data for women are limited but indicate a similar effect. CONCLUSIONS: The results from the cohort studies, international comparisons, and clinical trials are remarkably consistent. The cohort studies, based on half a million men and 18,000 ischaemic heart disease events, estimate that a long term reduction in serum cholesterol concentration of 0.6 mmol/l (10%), which can be achieved by moderate dietary change, lowers the risk of ischaemic heart disease by 50% at age 40, falling to 20% at age 70. The randomised trials, based on 45,000 men and 4000 ischaemic heart disease events show that the full effect of the reduction in risk is achieved by five years.

By how much does dietary salt reduction lower blood pressure? III--Analysis of data from trials of salt reduction.

OBJECTIVE: To determine whether the reduction in blood pressure achieved in trials of dietary salt reduction is quantitatively consistent with estimates derived from blood pressure and sodium intake in different populations, and, if so, to estimate the impact of reducing dietary salt on mortality from stroke and ischaemic heart disease. DESIGN: Analysis of the results of 68 crossover trials and 10 randomised controlled trials of dietary salt reduction. MAIN OUTCOME MEASURE: Comparison of observed reductions in systolic blood pressure for each trial with predicted values calculated from between population analysis. RESULTS: In the 45 trials in which salt reduction lasted four weeks or less the observed reductions in blood pressure were less than those predicted, with the difference between observed and predicted reductions being greatest in the trials of shortest duration. In the 33 trials lasting five weeks or longer the predicted reductions in individual trials closely matched a wide range of observed reductions. This applied for all age groups and for people with both high and normal levels of blood pressure. In people aged 50-59 years a reduction in daily sodium intake of 50 mmol (about 3 g of salt), attainable by moderate dietary salt reduction would, after a few weeks, lower systolic blood pressure by an average of 5 mm Hg, and by 7 mm Hg in those with high blood pressure (170 mm Hg); diastolic blood pressure would be lowered by about half as much. It is estimated that such a reduction in salt intake by a whole Western population would reduce the incidence of stroke by 22% and of ischaemic heart disease by 16% [corrected]. CONCLUSIONS: The results from the trials support the estimates from the observational data in the accompanying two papers. The effect of universal moderate dietary salt reduction on mortality from stroke and ischaemic heart disease would be substantial--larger, indeed, than could be achieved by fully implementing recommended policy for treating high blood pressure with drugs. However, reduction also in the amount of salt added to processed foods would lower blood pressure by at least twice as much and prevent some 75,000 [corrected] deaths a year in Britain as well as much disability.

By how much does dietary salt reduction lower blood pressure? I--Analysis of observational data among populations.

OBJECTIVE: To estimate the quantitative relation between blood pressure and sodium intake. DESIGN: Data were analysed from published reports of blood pressure and sodium intake for 24 different communities (47 000 people) throughout the world. MAIN OUTCOME MEASURE: Difference in blood pressure for a 100 mmol/24 h difference in sodium intake. Allowance was made for differences in blood pressure between economically developed and undeveloped communities to minimise overestimation of the association through confounding with other determinants of blood pressure. RESULTS: Blood pressure was higher on average in the developed communities, but the association with sodium intake was similar in both types of community. A difference in sodium intake of 100 mmol/24 h was associated with an average difference in systolic blood pressure that ranged from 5 mm Hg at age 15-19 years to 10 mm Hg at age 60-69. The differences in diastolic blood pressure were about half as great. The standard deviation of blood pressure increased with sodium intake implying that the association of blood pressure with sodium intake in individuals was related to the initial blood pressure--the higher the blood pressure the greater the expected reduction in blood pressure for the same reduction in sodium intake. For example, at age 60-69 the estimated systolic blood pressure reduction in response to a 100 mmol/24 h reduction in sodium intake was on average 10 mm Hg but varied from 6 mm Hg for those on the fifth blood pressure centile to 15 mm Hg for those on the 95th centile. CONCLUSIONS: The association of blood pressure with sodium intake is substantially larger than is generally appreciated and increases with age and initial blood pressure.

By how much does dietary salt reduction lower blood pressure? II--Analysis of observational data within populations.

OBJECTIVE: To determine whether the estimates of the size of the association between blood pressure and sodium intake derived from studies of individuals within populations can be quantitatively reconciled with our estimates derived from comparisons of the average blood pressure and sodium intake between different populations. DESIGN: Examination of data from 14 published studies that correlated blood pressure recordings in individuals against measurements of their 24 hour sodium intake (within population studies). MAIN OUTCOME MEASURE: Comparison of observed differences in blood pressure per 100 mmol/24 h difference in sodium intake in each within population study with predicted differences calculated from the between population data, after allowing for the underestimation of the true association of blood pressure with sodium intake caused by the large day to day variation in 24 hour sodium intake within individuals. RESULTS: The underestimation bias inherent in the within populations studies reduced the regression slope of blood pressure on single measures of 24 hour sodium intake to between a half and a quarter of the true value (for example, in one study from 6.0 to 2.4 mm Hg/100 mmol/24 h). Estimates from between population comparisons of the regression slope of blood pressure on sodium intake, after adjustment to take this underestimation bias into account, were similar to the values actually observed in the within population studies. CONCLUSION: The within population studies confirm our estimates from between population comparisons of the magnitude of the association between blood pressure and sodium intake.

Assessing possible hazards of reducing serum cholesterol.

OBJECTIVE: To assess whether low serum cholesterol concentration increases mortality from any cause. DESIGN: Systematic review of published data on mortality from causes other than ischaemic heart disease derived from the 10 largest cohort studies, two international studies, and 28 randomised trials, supplemented by unpublished data on causes of death obtained when necessary. MAIN OUTCOME MEASURES: Excess cause specific mortality associated with low or lowered serum cholesterol concentration. RESULTS: The only cause of death attributable to low serum cholesterol concentration was haemorrhagic stroke. The excess risk was associated only with concentrations below about 5 mmol/l (relative risk 1.9, 95% confidence interval 1.4 to 2.5), affecting about 6% of people in Western populations. For noncirculatory causes of death there was a pronounced difference between cohort studies of employed men, likely to be healthy at recruitment, and cohort studies of subjects in community settings, necessarily including some with existing disease. The employed cohorts showed no excess mortality. The community cohorts showed associations between low cholesterol concentration and lung cancer, haemopoietic cancers, suicide, chronic bronchitis, and chronic liver and bowel disease; these were most satisfactorily explained by early disease or by factors that cause the disease lowering serum cholesterol concentration (depression causes suicide and lowers cholesterol concentration, for example). In the randomised trials nine deaths (from a total of 687 deaths not due to ischaemic heart disease in treated subjects) were attributed to known adverse effects of the specific treatments, but otherwise there was no evidence of an increased mortality from any cause arising from reduction in cholesterol concentration. CONCLUSIONS: There is no evidence that low or reduced serum cholesterol concentration increases mortality from any cause other than haemorrhagic stroke. This risk affects only those people with a very low concentration and even in these will be outweighed by the benefits from the low risk of ischaemic heart disease.

Environmental tobacco smoke exposure and ischaemic heart disease: an evaluation of the evidence.

OBJECTIVES: To estimate the risk of ischaemic heart disease caused by exposure to environmental tobacco smoke and to explain why the associated excess risk is almost half that of smoking 20 cigarettes per day when the exposure is only about 1% that of smoking. DESIGN: Meta-analysis of all 19 acceptable published studies of risk of ischaemic heart disease in lifelong non-smokers who live with a smoker and in those who live with a non-smoker, five large prospective studies of smoking and ischaemic heart disease, and studies of platelet aggregation and studies of diet according to exposure to tobacco smoke. RESULTS: The relative risk of ischaemic heart disease associated with exposure to environmental tobacco smoke was 1.30 (95% confidence interval 1.22 to 1.38) at age 65. At the same age the estimated relative risk associated with smoking one cigarette per day was similar (1.39 (1.18 to 1.64)), while for 20 per day it was 1.78 (1.31 to 2.44). Two separate analyses indicated that non-smokers who live with smokers eat a diet that places them at a 6% higher risk of ischaemic heart disease, so the direct effect of environmental tobacco smoke is to increase risk by 23% (14% to 33%), since 1.30/1.06 = 1.23. Platelet aggregation provides a plausible and quantitatively consistent mechanism for the low dose effect. The increase in platelet aggregation produced experimentally by exposure to environmental tobacco smoke would be expected to have acute effects increasing the risk of ischaemic heart disease by 34%. CONCLUSION: Breathing other people's smoke is an important and avoidable cause of ischaemic heart disease, increasing a person's risk by a quarter.

The accumulated evidence on lung cancer and environmental tobacco smoke.

OBJECTIVE: To estimate the risk of lung cancer in lifelong non-smokers exposed to environmental tobacco smoke. DESIGN: Analysis of 37 published epidemiological studies of the risk of lung cancer (4626 cases) in non-smokers who did and did not live with a smoker. The risk estimate was compared with that from linear extrapolation of the risk in smokers using seven studies of biochemical markers of tobacco smoke intake. MAIN OUTCOME MEASURE: Relative risk of lung cancer in lifelong non-smokers according to whether the spouse currently smoked or had never smoked. RESULTS: The excess risk of lung cancer was 24% (95% confidence interval 13% to 36%) in non-smokers who lived with a smoker (P < 0.001). Adjustment for the effects of bias (positive and negative) and dietary confounding had little overall effect; the adjusted excess risk was 26% (7% to 47%). The dose-response relation of the risk of lung cancer with both the number of cigarettes smoked by the spouse and the duration of exposure was significant. The excess risk derived by linear extrapolation from that in smokers was 19%, similar to the direct estimate of 26%. CONCLUSION: The epidemiological and biochemical evidence on exposure to environmental tobacco smoke, with the supporting evidence of tobacco specific carcinogens in the blood and urine of non-smokers exposed to environmental tobacco smoke, provides compelling confirmation that breathing other people's tobacco smoke is a cause of lung cancer.