PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (710850)

Clipboard (0)
None

Related Articles

1.  Are Markers of Inflammation More Strongly Associated with Risk for Fatal Than for Nonfatal Vascular Events? 
PLoS Medicine  2009;6(6):e1000099.
In a secondary analysis of a randomized trial comparing pravastatin versus placebo for the prevention of coronary and cerebral events in an elderly at-risk population, Naveed Sattar and colleagues find that inflammatory markers may be more strongly associated with risk of fatal vascular events than nonfatal vascular events.
Background
Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.
Methods and Findings
In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70–82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44–2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04–1.31), in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20).
Conclusions
In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the leading cause of death is coronary heart disease (CHD), a CVD in which narrowing of the heart's blood vessels by “atherosclerotic plaques” (fatty deposits that build up with age) slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). Other types of CVD include stroke (in which atherosclerotic plaques interrupt the brain's blood supply) and heart failure (a condition in which the heart cannot pump enough blood to the rest of the body). Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), having diabetes, and being overweight all increase a person's risk of developing CVD. Tools such as the “Framingham risk calculator” take these and other risk factors into account to assess an individual's overall risk of CVD, which can be reduced by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Inflammation (an immune response to injury) in the walls of blood vessels is thought to play a role in the development of atherosclerotic plaques. Consistent with this idea, several epidemiological studies (investigations of the causes and distribution of disease in populations) have shown that people with high circulating levels of markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen are more likely to have a stroke or a heart attack (a CVD event) than people with low levels of these markers. Although these studies have generally lumped together fatal and nonfatal CVD events, some evidence suggests that circulating inflammatory markers may be more strongly associated with fatal than with nonfatal CVD events. If this is the case, the mechanisms that lead to fatal and nonfatal CVD events may be subtly different and knowing about these differences could improve both the prevention and treatment of CVD. In this study, the researchers investigate this possibility using data collected in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER; a trial that examined pravastatin's effect on CVD development among 70–82 year olds with pre-existing CVD or an increased risk of CVD because of smoking, high blood pressure, or diabetes).
What Did the Researchers Do and Find?
The researchers used several statistical models to examine the association between baseline levels of IL-6, CRP, and fibrinogen in the trial participants and nonfatal CVD events (nonfatal heart attacks and nonfatal strokes), fatal CVD events, death from other types of CVD, and deaths from other causes during 3.2 years of follow-up. Increased levels of all three inflammatory markers were more strongly associated with fatal CVD than with nonfatal CVD after adjustment for treatment allocation and for other established CVD risk factors but this pattern was strongest for IL-6. Thus, a unit increase in the log of IL-6 levels increased the risk of fatal CVD by half but increased the risk of nonfatal CVD by significantly less. The researchers also investigated whether including these inflammatory markers in tools designed to predict an individual's CVD risk could improve the tool's ability to distinguish between individuals with a high and low risk. The addition of IL-6 to established risk factors, they report, increased this discriminatory ability for fatal CVD but not for nonfatal CVD.
What Do These Findings Mean?
These findings indicate that, at least for the elderly at-risk patients who were included in PROSPER, inflammatory markers are more strongly associated with the risk of a fatal heart attack or stroke than with nonfatal CVD events. These findings need to be confirmed in younger populations and larger studies also need to be done to discover whether the same association holds when fatal heart attacks and fatal strokes are considered separately. Nevertheless, the present findings suggest that inflammation may specifically help to promote the development of serious, potentially fatal CVD and should stimulate improved research into the use of inflammation markers to predict risk of deaths from CVD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000099.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and atherosclerosis (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
Information for patients and caregivers is provided by the American Heart Association on all aspects of cardiovascular disease, including information on inflammation and heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000099
PMCID: PMC2694359  PMID: 19554082
2.  Inflammatory Markers and Poor Outcome after Stroke: A Prospective Cohort Study and Systematic Review of Interleukin-6 
PLoS Medicine  2009;6(9):e1000145.
In a prospective cohort study of patient outcomes following stroke, William Whiteley and colleagues find that markers of inflammatory response are associated with poor outcomes. However, addition of these markers to existing prognostic models does not improve outcome prediction.
Background
The objective of this study was to determine whether: (a) markers of acute inflammation (white cell count, glucose, interleukin-6, C-reactive protein, and fibrinogen) are associated with poor outcome after stroke and (b) the addition of markers to previously validated prognostic models improves prediction of poor outcome.
Methods and Findings
We prospectively recruited patients between 2002 and 2005. Clinicians assessed patients and drew blood for inflammatory markers. Patients were followed up by postal questionnaire for poor outcome (a score of>2 on the modified Rankin Scale) and death through the General Register Office (Scotland) at 6 mo. We performed a systematic review of the literature and meta-analysis of the association between interleukin-6 and poor outcome after stroke to place our study in the context of previous research. We recruited 844 patients; mortality data were available in 844 (100%) and functional outcome in 750 (89%). After appropriate adjustment, the odds ratios for the association of markers and poor outcome (comparing the upper and the lower third) were interleukin-6, 3.1 (95% CI: 1.9–5.0); C-reactive protein, 1.9 (95% CI: 1.2–3.1); fibrinogen, 1.5 (95% CI: 1.0–2.36); white cell count, 2.1 (95% CI: 1.3–3.4); and glucose 1.3 (95% CI: 0.8–2.1). The results for interleukin-6 were similar to other studies. However, the addition of inflammatory marker levels to validated prognostic models did not materially improve model discrimination, calibration, or reclassification for prediction of poor outcome after stroke.
Conclusions
Raised levels of markers of the acute inflammatory response after stroke are associated with poor outcomes. However, the addition of these markers to a previously validated stroke prognostic model did not improve the prediction of poor outcome. Whether inflammatory markers are useful in prediction of recurrent stroke or other vascular events is a separate question, which requires further study.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people have a stroke. In the US alone, someone has a stroke every 40 seconds and someone dies from a stroke every 3–4 minutes. Stroke occurs when the blood supply to the brain is suddenly interrupted by a blood clot blocking a blood vessel in the brain (ischemic stroke, the commonest type of stroke) or by a blood vessel in the brain bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek medical assistance immediately because prompt treatment can limit the damage to the brain. Risk factors for stroke include age (three-quarters of strokes occur in people over 65 years old), high blood pressure, and heart disease.
Why Was This Study Done?
Many people are left with permanent disabilities after a stroke. An accurate way to predict the likely long-term outcome (prognosis) for individual patients would help clinicians manage their patients and help relatives and patients come to terms with their changed circumstances. Clinicians can get some idea of their patients' likely outcomes by assessing six simple clinical variables. These include the ability to lift both arms and awareness of the present situation. But could the inclusion of additional variables improve the predictive power of this simple prognostic model? There is some evidence that high levels in the blood of inflammatory markers (for example, interleukin-6 and C-reactive protein) are associated with poor outcomes after stroke—inflammation is the body's response to infection and to damage. In this prospective cohort study, the researchers investigate whether inflammatory markers are associated with poor outcome after stroke and whether the addition of these markers to the six-variable prognostic model improves its predictive power. Prospective cohort studies enroll a group of participants and follow their subsequent progress.
What Did the Researchers Do and Find?
The researchers recruited 844 patients who had had a stroke (mainly mild ischemic strokes) in Edinburgh. Each patient was assessed soon after the stroke by a clinician and blood was taken for the measurement of inflammatory markers. Six months after the stroke, the patient or their relatives completed a postal questionnaire that assessed their progress. Information about patient deaths was obtained from the General Register Office for Scotland. Dependency on others for the activities of daily life or dying was recorded as a poor outcome. In their statistical analysis of these data, the researchers found that raised levels of several inflammatory markers increased the likelihood of a poor outcome. For example, after allowing for age and other factors, individuals with interleukin-6 levels in the upper third of the measured range were three times as likely to have a poor outcome as patients with interleukin-6 levels in the bottom third of the range. A systematic search of the literature revealed that previous studies that had looked at the potential association between interleukin-6 levels and outcome after stroke had found similar results. Finally, the researchers found that the addition of inflammatory marker levels to the six-variable prognostic model did not substantially improve its ability to predict outcome after stroke for this cohort of patients.
What Do These Findings Mean?
These findings provide additional support for the idea that increased levels of inflammatory markers are associated with a poor outcome after stroke. However, because patients with infections were not excluded from the study, infection may be responsible for part of the observed association. Importantly, these findings also show that although the inclusion of inflammatory markers in the six variable prognostic model slightly improves its ability to predict outcome, the magnitude of this improvement is too small to warrant the use of these markers in routine practice. Whether the measurement of inflammatory markers might be useful in the prediction of recurrent stroke—at least a quarter of people who survive a stroke will have another one within 5 years—requires further study.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000145.
This study is further discussed in a PLoS Medicine Perspective by Len Kritharides
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); the Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation (in English and Spanish)
The Internet Stroke Center provides detailed information about stroke for patients, families and health professionals (in English and Spanish)
The UK National Health Service also provides information for patients and their families about stroke (in several languages)
MedlinePlus provides links to further resources and advice about stroke (in English and Spanish)
The six simple variable model for prediction of death or disability after stroke is available here: http://dcnapp1.dcn.ed.ac.uk/scope/
doi:10.1371/journal.pmed.1000145
PMCID: PMC2730573  PMID: 19901973
3.  Stroke Location and Association With Fatal Cardiac Outcomes 
Background and Purpose
Cardiac mortality after stroke is common, and small studies have suggested an association of short-term cardiac mortality with insular location of cerebral infarction. Few population-based studies with long-term follow-up have evaluated the effect of stroke location on the long-term risk of cardiac death or myocardial infarction (MI) after first ischemic stroke. We sought to determine the association between stroke location and cardiac death or MI in a multiethnic community-based cohort.
Methods
The Northern Manhattan Study is a population-based study designed to determine stroke incidence, risk factors, and prognosis in a multiethnic urban population. First ischemic stroke patients age 40 or older were prospectively followed up for cardiac death defined as fatal MI, fatal congestive heart failure, or sudden death/arrhythmia and for nonfatal MI. Primary brain anatomic site was determined by consensus of research neurologists. Hazard ratios (HRs) and 95% CIs were calculated by Cox proportional-hazards models and adjusted for vascular risk factors (age, sex, history of coronary disease, hypertension, diabetes, cholesterol, and smoking), stroke severity, infarct size, and stroke etiology.
Results
The study population consisted of 655 patients whose mean age was 69.7 ± 12.7 years; 44.6% were men and 51.3% were Hispanic. During a median follow-up of 4.0 years, 44 patients (6.7%) had fatal cardiac events. Of these, fatal MI occurred in 38.6%, fatal congestive heart failure in 18.2%, and sudden death in 43.2%. In multivariate models, clinical diagnosis of left parietal lobe infarction was associated with cardiac death (adjusted HR = 4.45; 95% CI, 1.83 to 10.83) and cardiac death or MI (adjusted HR = 3.30; 95% CI, 1.45 to 7.51). When analysis of anatomic location was restricted to neuroimaging (computed tomography, magnetic resonance imaging, or both [n = 447]), left parietal lobe infarction was associated with cardiac death (adjusted HR = 3.37; 95% CI, 1.26 to 8.97), and both left (adjusted HR = 3.49; 95% CI, 1.38 to 8.80) and right (adjusted HR = 3.13; 95% CI, 1.04 to 9.45) parietal lobe infarctions were associated with cardiac death or MI. We did not find an association between frontal, temporal, or insular stroke and fatal cardiac events, although the number of purely insular strokes was small.
Conclusions
Parietal lobe infarction is an independent predictor of long-term cardiac death or MI in this population. Further studies are needed to confirm whether parietal lobe infarction is an independent predictor of cardiac events and death. Surveillance for cardiac disease and implementation of cardioprotective therapies may reduce cardiac mortality in patients with parietal stroke.
doi:10.1161/STROKEAHA.107.506055
PMCID: PMC4112463  PMID: 18635863
acute stroke; cardiac arrhythmia; epidemiology; sudden death
4.  Modifiable Etiological Factors and the Burden of Stroke from the Rotterdam Study: A Population-Based Cohort Study 
PLoS Medicine  2014;11(4):e1001634.
Using data from the Rotterdam study, Michiel Bos and colleagues estimate the proportion of strokes that are attributable to established modifiable etiological factors for stroke.
Please see later in the article for the Editors' Summary
Background
Stroke prevention requires effective treatment of its causes. Many etiological factors for stroke have been identified, but the potential gain of effective intervention on these factors in terms of numbers of actually prevented strokes remains unclear because of the lack of data from cohort studies. We assessed the impact of currently known potentially modifiable etiological factors on the occurrence of stroke.
Methods and Findings
This population-based cohort study was based on 6,844 participants of the Rotterdam Study who were aged ≥55 y and free from stroke at baseline (1990–1993). We computed population attributable risks (PARs) for individual risk factors and for risk factors in combination to estimate the proportion of strokes that could theoretically be prevented by the elimination of etiological factors from the population.
The mean age at baseline was 69.4 y (standard deviation 6.3 y). During follow-up (mean follow-up 12.9 y, standard deviation 6.3 y), 1,020 strokes occurred. The age- and sex-adjusted combined PAR of prehypertension/hypertension, smoking, diabetes mellitus, atrial fibrillation, coronary disease, and overweight/obesity was 0.51 (95% CI 0.41–0.62) for any stroke; hypertension and smoking were the most important etiological factors. C-reactive protein, fruit and vegetable consumption, and carotid intima-media thickness in combination raised the total PAR by 0.06. The PAR was 0.55 (95% CI 0.41–0.68) for ischemic stroke and 0.70 (95% CI 0.45–0.87) for hemorrhagic stroke.
The main limitations of our study are that our study population comprises almost exclusively Caucasians who live in a middle and high income area, and that risk factor awareness is higher in a study cohort than in the general population.
Conclusions
About half of all strokes are attributable to established causal and modifiable factors. This finding encourages not only intervention on established etiological factors, but also further study of less well established factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people worldwide have a stroke. About 6 million of these people die within hours, and another 5 million are left disabled. Stroke occurs when the brain's blood supply is suddenly interrupted by a blood vessel in the brain being blocked by a blood clot (ischemic stroke) or bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. In the longer term, post-stroke rehabilitation can help overcome the disabilities caused by stroke, and various drugs alongside behavioral counselling can reduce the risk of a second stroke.
Why Was This Study Done?
Fifty years ago, it was discovered that treatment of high blood pressure (hypertension) reduces the risk of stroke among people with severe hypertension. This discovery led researchers to search for other potentially modifiable etiological factors for stroke (risk factors that cause stroke). The list of established etiological factors now includes smoking, diabetes, atrial fibrillation (an irregular heartbeat), heart disease, and overweight/obesity, in addition to hypertension. But how many strokes would modification of these causal risk factors prevent? In this population-based cohort study, the researchers calculate the individual and combined population attributable risks (PARs) for these established etiological factors to provide an estimate of what proportion of strokes could theoretically be prevented by optimal treatment of known etiological factors. A population-based cohort study enrolls a group of people, determines their characteristics at baseline, and follows them to see whether specific characteristics are associated with specific outcomes. A PAR of an etiological factor for a disease indicates the proportion of that disease in the population that would not occur in the absence of the risk factor.
What Did the Researchers Do and Find?
The researchers used data from 6,844 participants in the Rotterdam Study, which was designed to investigate the causes and consequences of long-term and disabling diseases in the elderly. At baseline, all of the participants were over 55 years old and free from stroke. During follow-up, 1,020 strokes occurred among the participants. Using data on exposure at baseline to various etiological factors for stroke, the researchers calculated PARs for individual factors and used a special statistical technique to calculate PARs for the factors in combination. The combined PAR of prehypertension/hypertension, smoking, diabetes, atrial fibrillation, heart disease, and overweight/obesity was 0.51 for any stroke. That is, about half of the strokes in the study population were attributable to this combination of etiological factors. Hypertension and smoking were the most important individual factors (PARs of 0.36 and 0.16, respectively). Notably, the inclusion of several less well established etiological factors (increased blood levels of C-reactive protein, low fruit and vegetable consumption, and thickening of the lining of arteries) only raised the total PAR for any stroke by 0.06.
What Do These Findings Mean?
These findings indicate that about half of the strokes in the study cohort were attributable to established modifiable etiological factors and could theoretically be prevented by eliminating these risk factors from the population. Previous studies have estimated that a larger proportion of strokes could be prevented by eliminating known etiological factors. The researchers acknowledge that some aspects of their study may have led to an underestimation of the proportion of stroke attributable to established etiological factors and note that their findings may not be generalizable to underprivileged or racially diverse populations. Nevertheless, they argue that previous studies are likely to have overestimated the PARs for stroke because they were based on case–control studies (in which exposure to etiological factors was assessed after a stroke had occurred in cases and control individuals, rather than before a stroke as in a population-based cohort study) and often did not use optimal statistical techniques to calculate the total PAR. Importantly, these new findings underscore the importance of interventions targeted at reducing smoking and hypertension and support the search for additional etiological factors for stroke.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001634.
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation including personal stories (in English and Spanish); the US National Institutes of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices website also provides information about stroke for patients and their families, including personal stories
MedlinePlus has links to additional resources about stroke (in English and Spanish)
Information about the Rotterdam Study is available
The UK not-for-profit website Healthtalkonline provides personal stories about stroke
doi:10.1371/journal.pmed.1001634
PMCID: PMC4004543  PMID: 24781247
5.  Socioeconomic Factors and All Cause and Cause-Specific Mortality among Older People in Latin America, India, and China: A Population-Based Cohort Study 
PLoS Medicine  2012;9(2):e1001179.
Cleusa Ferri and colleagues studied mortality rates in over 12,000 people aged 65 years and over in Latin America, India, and China and showed that chronic diseases are the main causes of death and that education has an important effect on mortality.
Background
Even in low and middle income countries most deaths occur in older adults. In Europe, the effects of better education and home ownership upon mortality seem to persist into old age, but these effects may not generalise to LMICs. Reliable data on causes and determinants of mortality are lacking.
Methods and Findings
The vital status of 12,373 people aged 65 y and over was determined 3–5 y after baseline survey in sites in Latin America, India, and China. We report crude and standardised mortality rates, standardized mortality ratios comparing mortality experience with that in the United States, and estimated associations with socioeconomic factors using Cox's proportional hazards regression. Cause-specific mortality fractions were estimated using the InterVA algorithm. Crude mortality rates varied from 27.3 to 70.0 per 1,000 person-years, a 3-fold variation persisting after standardisation for demographic and economic factors. Compared with the US, mortality was much higher in urban India and rural China, much lower in Peru, Venezuela, and urban Mexico, and similar in other sites. Mortality rates were higher among men, and increased with age. Adjusting for these effects, it was found that education, occupational attainment, assets, and pension receipt were all inversely associated with mortality, and food insecurity positively associated. Mutually adjusted, only education remained protective (pooled hazard ratio 0.93, 95% CI 0.89–0.98). Most deaths occurred at home, but, except in India, most individuals received medical attention during their final illness. Chronic diseases were the main causes of death, together with tuberculosis and liver disease, with stroke the leading cause in nearly all sites.
Conclusions
Education seems to have an important latent effect on mortality into late life. However, compositional differences in socioeconomic position do not explain differences in mortality between sites. Social protection for older people, and the effectiveness of health systems in preventing and treating chronic disease, may be as important as economic and human development.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, half of all deaths occur in people aged 60 or older. Yet mortality among older people is a neglected topic in global health. In high income countries, where 84% of people do not die until they are aged 65 years or older, the causes of death among older people and the factors (determinants) that affect their risk of dying are well documented. In Europe, for example, the leading causes of death among older people are heart disease, stroke, and other chronic (long-term) diseases. Moreover, as in younger age groups, having a better education and owning a house reduces the risk of death among older people. By contrast, in low and middle income countries (LMICs), where three-quarters of deaths of older people occur, reliable data on the causes and determinants of death among older people are lacking, in part because many LMICs have inadequate vital registration systems—official records of all births and deaths.
Why Was This Study Done?
In many LMICs, chronic diseases are replacing communicable (infectious) diseases as the leading causes of death and disability—health experts call this the epidemiological transition (epidemiology is the study of the distribution and causes of disease in populations)—and the average age of the population is increasing (the demographic transition). Faced with these changes, which occur when countries move from a pre-industrial to an industrial economy, policy makers in LMICs need to introduce measures to improve health and reduce deaths among older people. However, to do this, they need reliable data on the causes and determinants of death in this section of the population. In this longitudinal population-based cohort study (a type of study that follows a group of people from a defined population over time), researchers from the 10/66 Dementia Research Group, which is carrying out population-based research on dementia, aging, and non-communicable diseases in LMICs, investigate the patterns of mortality among older people living in Latin America, India, and China.
What Did the Researchers Do and Find?
Between 2003 and 2005, the researchers completed a baseline survey of people aged 65 years or older living in six Latin American LMICs, China, and India. Three to five years later, they determined the vital status of 12,373 of the study participants (that is, they determined whether the individual was alive or dead) and interviewed a key informant (usually a relative) about each death using a standardized “verbal autopsy” questionnaire that includes questions about date and place of death, and about medical help-seeking and signs and symptoms noted during the final illness. Finally, they used a tool called the InterVA algorithm to calculate the most likely causes of death from the verbal autopsies. Crude mortality rates varied from 27.3 per 1,000 person-years in urban Peru to 70.0 per 1,000 person-years in urban India, a three-fold difference in mortality rates that persisted even after allowing for differences in age, sex, education, occupational attainment, and number of assets among the study sites. Compared to the US, mortality rates were much higher in urban India and rural China; much lower in urban and rural Peru, Venezuela, and urban Mexico; but similar elsewhere. Although several socioeconomic factors were associated with mortality, only a higher education status provided consistent independent protection against death in statistical analyses. Finally, chronic diseases were the main causes of death; stroke was the leading cause of death at all the sites except those in rural Peru and Mexico.
What Do These Findings Mean?
These findings identify the main causes of death among older adults in a range of LMICs and suggest that there is an association of education with mortality that extends into later life. However, these findings may not be generalizable to other LMICs or even to other sites in the LMICs studied, and because some of the information provided by key informants may have been affected by recall error, the accuracy of the findings may be limited. Nevertheless, these findings suggest how health and mortality might be improved in elderly people in LMICs. Specifically, they suggest that efforts to ensure universal access to education should confer substantial health benefits and that interventions that target social and economic vulnerability in later life and promote access to effectively organized health care (particularly for stroke) should be considered.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001179.
The World Health Organization provides information on mortality around the world and projections of global mortality up to 2030
The 10/66 Dementia Research Group is building an evidence base to inform the development and implementation of policies for improving the health and social welfare of older people in LMICs, particularly people with dementia; its website includes background information about demographic and epidemiological aging in LMICs
Wikipedia has a page on the demographic transition (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information about the InterVA tool for interpreting verbal autopsy data is available
The US Centers for Disease Control and Prevention has information about healthy aging
doi:10.1371/journal.pmed.1001179
PMCID: PMC3289608  PMID: 22389633
6.  Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis 
PLoS Medicine  2009;6(1):e1000016.
Background
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).
Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.
Conclusions
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.
Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people.
Editors' Summary
Background.
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the single leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels slows or stops the blood supply to the heart and eventually causes a heart attack. Other types of CVD include stroke (in which narrowing of the blood vessels interrupts the brain's blood supply) and heart failure (a condition in which the heart can no longer pump enough blood to the rest of the body). Many factors increase the risk of developing CVD, including high blood pressure (hypertension), high blood cholesterol, having diabetes, smoking, and being overweight. Tools such as the “Framingham risk calculator” assess an individual's overall CVD risk by taking these and other risk factors into account. CVD risk can be minimized by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Another potential risk factor for CVD is impaired kidney (renal) function. In healthy people, the kidneys filter waste products and excess fluid out of the blood. A reduced “estimated glomerular filtration rate” (eGFR), which indicates impaired renal function, is associated with increased CVD in young and middle-aged people and increased all-cause and cardiovascular death in people who have vascular disease. But is reduced eGFR also associated with CVD and death in older people? If it is, it would be worth encouraging elderly people with reduced eGFR to avoid other CVD risk factors. In this study, the researchers determine the predictive value of eGFR for all-cause and vascular mortality (deaths caused by CVD) and for incident vascular events (a first heart attack, stroke, or heart failure) using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This clinical trial examined pravastatin's effects on CVD development among 70–82 year olds with pre-existing vascular disease or an increased risk of CVD because of smoking, hypertension, or diabetes.
What Did the Researchers Do and Find?
The trial participants were divided into four groups based on their eGFR at the start of the study. The researchers then investigated the association between baseline CVD risk factors and baseline eGFR and between baseline eGFR and vascular events and deaths that occurred during the 3-year study. Several established CVD risk factors were associated with a reduced eGFR after allowing for other risk factors. In addition, people with a low eGFR (between 20 and 40 units) were twice as likely to die from any cause as people with an eGFR above 60 units (the normal eGFR for a young person is 100 units; eGFR decreases with age) and more than three times as likely to have nonfatal coronary heart disease or heart failure. A low eGFR also increased the risk of vascular mortality, other noncancer deaths, and fatal coronary heart disease and heart failure. Finally, pravastatin treatment reduced coronary heart disease deaths and nonfatal heart attacks most effectively among participants with the greatest degree of eGFR impairment.
What Do These Findings Mean?
These findings suggest that, in elderly people, impaired renal function is associated with levels of established CVD risk factors that increase the risk of vascular disease. They also suggest that impaired kidney function increases the risk of all-cause mortality, fatal vascular events, and fatal and nonfatal coronary heat disease and heart failure. Because the study participants were carefully chosen for inclusion in PROSPER, these findings may not be generalizable to all elderly people with vascular disease or vascular disease risk factors. Nevertheless, increased efforts should probably be made to encourage elderly people with reduced eGFR and other vascular risk factors to make lifestyle changes to reduce their overall CVD risk. Finally, although the effect of statins in elderly patients with renal dysfunction needs to be examined further, these findings suggest that this group of patients should benefit at least as much from statins as elderly patients with healthy kidneys.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000016.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and heart failure (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart disease, vascular disease, and stroke (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The American Heart Association provides information on all aspects of cardiovascular disease for patients, caregivers, and professionals (in several languages)
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000016
PMCID: PMC2628400  PMID: 19166266
7.  Moving from Data on Deaths to Public Health Policy in Agincourt, South Africa: Approaches to Analysing and Understanding Verbal Autopsy Findings 
PLoS Medicine  2010;7(8):e1000325.
Peter Byass and colleagues compared two methods of assessing data from verbal autopsies, review by physicians or probabilistic modeling, and show that probabilistic modeling is the most efficient means of analyzing these data
Background
Cause of death data are an essential source for public health planning, but their availability and quality are lacking in many parts of the world. Interviewing family and friends after a death has occurred (a procedure known as verbal autopsy) provides a source of data where deaths otherwise go unregistered; but sound methods for interpreting and analysing the ensuing data are essential. Two main approaches are commonly used: either physicians review individual interview material to arrive at probable cause of death, or probabilistic models process the data into likely cause(s). Here we compare and contrast these approaches as applied to a series of 6,153 deaths which occurred in a rural South African population from 1992 to 2005. We do not attempt to validate either approach in absolute terms.
Methods and Findings
The InterVA probabilistic model was applied to a series of 6,153 deaths which had previously been reviewed by physicians. Physicians used a total of 250 cause-of-death codes, many of which occurred very rarely, while the model used 33. Cause-specific mortality fractions, overall and for population subgroups, were derived from the model's output, and the physician causes coded into comparable categories. The ten highest-ranking causes accounted for 83% and 88% of all deaths by physician interpretation and probabilistic modelling respectively, and eight of the highest ten causes were common to both approaches. Top-ranking causes of death were classified by population subgroup and period, as done previously for the physician-interpreted material. Uncertainty around the cause(s) of individual deaths was recognised as an important concept that should be reflected in overall analyses. One notably discrepant group involved pulmonary tuberculosis as a cause of death in adults aged over 65, and these cases are discussed in more detail, but the group only accounted for 3.5% of overall deaths.
Conclusions
There were no differences between physician interpretation and probabilistic modelling that might have led to substantially different public health policy conclusions at the population level. Physician interpretation was more nuanced than the model, for example in identifying cancers at particular sites, but did not capture the uncertainty associated with individual cases. Probabilistic modelling was substantially cheaper and faster, and completely internally consistent. Both approaches characterised the rise of HIV-related mortality in this population during the period observed, and reached similar findings on other major causes of mortality. For many purposes probabilistic modelling appears to be the best available means of moving from data on deaths to public health actions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Whenever someone dies in a developed country, the cause of death is determined by a doctor and entered into a “vital registration system,” a record of all the births and deaths in that country. Public-health officials and medical professionals use this detailed and complete information about causes of death to develop public-health programs and to monitor how these programs affect the nation's health. Unfortunately, in many developing countries dying people are not attended by doctors and vital registration systems are incomplete. In most African countries, for example, less than one-quarter of deaths are recorded in vital registration systems. One increasingly important way to improve knowledge about the patterns of death in developing countries is “verbal autopsy” (VA). Using a standard form, trained personnel ask relatives and caregivers about the symptoms that the deceased had before his/her death and about the circumstances surrounding the death. Physicians then review these forms and assign a specific cause of death from a shortened version of the International Classification of Diseases, a list of codes for hundreds of diseases.
Why Was This Study Done?
Physician review of VA forms is time-consuming and expensive. Consequently, computer-based, “probabilistic” models have been developed that process the VA data and provide a likely cause of death. These models are faster and cheaper than physician review of VAs and, because they do not rely on the views of local doctors about the likely causes of death, they are more internally consistent. But are physician review and probabilistic models equally sound ways of interpreting VA data? In this study, the researchers compare and contrast the interpretation of VA data by physician review and by a probabilistic model called the InterVA model by applying these two approaches to the deaths that occurred in Agincourt, a rural region of northeast South Africa, between 1992 and 2005. The Agincourt health and sociodemographic surveillance system is a member of the INDEPTH Network, a global network that is evaluating the health and demographic characteristics (for example, age, gender, and education) of populations in low- and middle-income countries over several years.
What Did the Researchers Do and Find?
The researchers applied the InterVA probabilistic model to 6,153 deaths that had been previously reviewed by physicians. They grouped the 250 cause-of-death codes used by the physicians into categories comparable with the 33 cause-of-death codes used by the InterVA model and derived cause-specific mortality fractions (the proportions of the population dying from specific causes) for the whole population and for subgroups (for example, deaths in different age groups and deaths occurring over specific periods of time) from the output of both approaches. The ten highest-ranking causes of death accounted for 83% and 88% of all deaths by physician interpretation and by probabilistic modelling, respectively. Eight of the most frequent causes of death—HIV, tuberculosis, chronic heart conditions, diarrhea, pneumonia/sepsis, transport-related accidents, homicides, and indeterminate—were common to both interpretation methods. Both methods coded about a third of all deaths as indeterminate, often because of incomplete VA data. Generally, there was close agreement between the methods for the five principal causes of death for each age group and for each period of time, although one notable discrepancy was pulmonary (lung) tuberculosis, which accounted for 6.4% and 21.3% of deaths in this age group, respectively, according to the physicians and to the model. However, these deaths accounted for only 3.5% of all the deaths.
What Do These Findings Mean?
These findings reveal no differences between the cause-specific mortality fractions determined from VA data by physician interpretation and by probabilistic modelling that might have led to substantially different public-health policy programmes being initiated in this population. Importantly, both approaches clearly chart the rise of HIV-related mortality in this South African population between 1992 and 2005 and reach similar findings on other major causes of mortality. The researchers note that, although preparing the amount of VA data considered here for entry into the probabilistic model took several days, the model itself runs very quickly and always gives consistent answers. Given these findings, the researchers conclude that in many settings probabilistic modeling represents the best means of moving from VA data to public-health actions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000325.
The importance of accurate data on death is further discussed in a perspective previously published in PLoS Medicine Perspective by Colin Mathers and Ties Boerma
The World Health Organization (WHO) provides information on the vital registration of deaths and on the International Classification of Diseases; the WHO Health Metrics Network is a global collaboration focused on improving sources of vital statistics; and the WHO Global Health Observatory brings together core health statistics for WHO member states
The INDEPTH Network is a global collaboration that is collecting health statistics from developing countries; it provides more information about the Agincourt health and socio-demographic surveillance system and access to standard VA forms
Information on the Agincourt health and sociodemographic surveillance system is available on the University of Witwatersrand Web site
The InterVA Web site provides resources for interpreting verbal autopsy data and the Umeå Centre for Global Health Reseach, where the InterVA model was developed, is found at http://www.globalhealthresearch.net
A recent PLoS Medicine Essay by Peter Byass, lead author of this study, discusses The Unequal World of Health Data
doi:10.1371/journal.pmed.1000325
PMCID: PMC2923087  PMID: 20808956
8.  Core Verbal Autopsy Procedures with Comparative Validation Results from Two Countries 
PLoS Medicine  2006;3(8):e268.
Background
Cause-specific mortality statistics remain scarce for the majority of low-income countries, where the highest disease burdens are experienced. Neither facility-based information systems nor vital registration provide adequate or representative data. The expansion of sample vital registration with verbal autopsy procedures represents the most promising interim solution for this problem. The development and validation of core verbal autopsy forms and suitable coding and tabulation procedures are an essential first step to extending the benefits of this method.
Methods and Findings
Core forms for peri- and neonatal, child, and adult deaths were developed and revised over 12 y through a project of the Tanzanian Ministry of Health and were applied to over 50,000 deaths. The contents of the core forms draw upon and are generally comparable with previously proposed verbal autopsy procedures. The core forms and coding procedures based on the International Statistical Classification of Diseases (ICD) were further adapted for use in China. These forms, the ICD tabulation list, the summary validation protocol, and the summary validation results from Tanzania and China are presented here.
Conclusions
The procedures are capable of providing reasonable mortality estimates as adjudged against stated performance criteria for several common causes of death in two countries with radically different cause structures of mortality. However, the specific causes for which the procedures perform well varied between the two settings because of differences in the underlying prevalence of the main causes of death. These differences serve to emphasize the need to undertake validation studies of verbal autopsy procedures when they are applied in new epidemiological settings.
A procedure for recording verbal autopsy information was tested in two countries and found to be capable of providing reasonable mortality data. The need to undertake validation studies was also demonstrated.
Editors' Summary
Background.
People living in developed countries take it for granted that when a loved one dies an accurate cause-of-death certificate will be issued. But for two-thirds of the deaths that occur worldwide, there are no certificates. Detailed information about what people die from is unavailable for more than 50% of countries, many of which have high death rates. This information is badly needed for public-health planning, for using scarce health resources wisely, and for monitoring the effect of new health initiatives. One way to improve knowledge about what people die from is a procedure called verbal autopsy (VA). Relatives or caregivers are interviewed about the symptoms experienced by the deceased before their death and the circumstances surrounding their death by trained personnel who use a standard form. Doctors then review the completed VA forms and assign a specific cause of death from a short version of the International Classifications of Diseases, or ICD, an internationally agreed on list of codes for hundreds of diseases.
Why Was This Study Done?
VA procedures are being developed in many countries, but each step in a VA can be affected by factors that vary from place to place, such as how long after the death the interview is done, the training that interviewers receive, how the questions are worded, and the locally common diseases, which tend to be recognized better than rare diseases. To ensure that the data collected are accurate and comparable between countries and also over time, VA procedures need to be standardized. In this study, the researchers describe their efforts to achieve this through the development and validation of core VA procedures.
What Did the Researchers Do and Find?
In 2001, the researchers refined the VA forms that were being used in Tanzania for deaths occurring around the time of birth and for deaths occurring in childhood and adulthood. They then translated the forms for use in China, adapting them slightly to allow for cultural differences in how symptoms are described. They also drew up a short list of ICD codes to use in tabulating and validating important causes of death. Then, for four years, they collected VA and medical record information for the same deceased individuals and measured how well the VA procedure agreed with the medical record information in both countries. They found that the procedure could be transferred between China and Tanzania but that it performed rather differently for different causes of death in the two countries. So, in both countries, the procedure accurately recorded tuberculosis, cerebrovascular diseases such as strokes, and transport accidents as causes of death. But some other causes of death were accurately recorded in one country only—generally the common diseases in that country—and many causes of death were inaccurately reported in both countries.
What Do These Findings Mean?
The researchers use their experience of developing VAs for use in Tanzania and China and the results of this study to make several recommendations about how to develop standardized VA procedures that will yield accurate cause of death. For example, they suggest that the VA form should contain a detailed core symptom duration checklist and only a short space for a narrative history (an open-ended description of the last illness provided by the relative or caregiver) because long narrative histories are hard to standardize. They discuss the need to adapt core VA forms when moving between countries to allow for linguistic differences and colloquial expression and also the need to consider cultural differences between countries—for example, how soon after bereavement a VA interview can occur. Most importantly, they strongly recommend that validation studies like theirs should be routinely done when VA procedures are applied in new countries or if the major cause of death in a country changes because of a new epidemic or health initiative. Provided this is done, write the researchers, although VA procedures can never be as accurate as proper medical certification at the time of death, they should provide important information about the causes of death for the many countries where this information would otherwise be completely missing.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030268.
• World Health Organization information on mortality and on the International Classification of Diseases
• The United Nations' World Mortality Report 2005
• Information on the Tanzania Ministry of Health Adult Morbidity and Mortality Project, which used the VA procedures on which this study was based
• A description of a standard VA method for investigating deaths in infants and children from the World Health Organization
• The INDEPTH Network, an organization collecting health statistics from developing countries that provides standardized VA forms
• MEASURE Evaluation, a USAID-funded project that, in collaboration with the US Census Bureau and the University of Queensland (Australia), supports countries to implement core VA procedures and sample/sentinel vital registration methods
• The Health Metrics Network, a global collaboration focused on strengthening country health information systems to generate sound data for decision-making at country and global levels, is committed to improving sources of vital statistics and cause-of-death data
doi:10.1371/journal.pmed.0030268
PMCID: PMC1502154  PMID: 16942391
9.  5-year survival and rehospitalization due to stroke recurrence among patients with hemorrhagic or ischemic strokes in Singapore 
BMC Neurology  2013;13:133.
Background
Stroke is the 4th leading cause of death and 1st leading cause of disability in Singapore. However the information on long-term post stroke outcomes for Singaporean patients was limited. This study aimed to investigate the post stroke outcomes of 5-year survival and rehospitalization due to stroke recurrence for hemorrhagic and ischemic stroke patients in Singapore. The outcomes were stratified by age, ethnic group, gender and stroke types. The causes of death and stroke recurrence were also explored in the study.
Methods
A multi-site retrospective cohort study. Patients admitted for stroke at any of the three hospitals in the National Healthcare Group of Singapore were included in the study. All study patients were followed up to 5 years. Kaplan-Meier was applied to study the time to first event, death or rehospitalization due to stroke recurrence. Cox proportional hazard model was applied to study the time to death with adjustment for stroke type, age, sex, ethnic group, and admission year. Cumulative incidence model with competing risk was applied for comparing the risks of rehospitalization due to stroke recurrence with death as the competing risk.
Results
Totally 12,559 stroke patients were included in the study. Among them, 59.3% survived for 5 years; 18.4% were rehospitalized due to stroke recurrence in 5 years. The risk of stroke recurrence and mortality increased with age in all stroke types. Gender, ethnic group and admitting year were not significantly associated with the risk of mortality or stroke recurrence in hemorrhagic stroke. Male or Malay patient had higher risk of stroke recurrence and mortality in ischemic stroke. Hemorrhagic stroke had higher early mortality while ischemic stroke had higher recurrence and late mortality. The top cause of death among died stroke patients was cerebrovascular diseases, followed by pneumonia and ischemic heart diseases. The recurrent stroke was most likely to be the same type as the initial stroke among rehospitalized stroke patients.
Conclusions
Five year post-stroke survival and rehospitalization due to stroke recurrence as well as their associations with patient demographics were studied for different stroke types in Singapore. Specific preventive strategies are needed to target the high risk groups to improve their long-term outcomes after acute stroke.
doi:10.1186/1471-2377-13-133
PMCID: PMC3850698  PMID: 24088308
Stroke; Outcomes; Recurrence; Rehospitalization; Mortality; Singapore
10.  Verifying causes of death in Thailand: rationale and methods for empirical investigation 
Background
Cause-specific mortality statistics by age and sex are primary evidence for epidemiological research and health policy. Annual mortality statistics from vital registration systems in Thailand are of limited utility because about 40% of deaths are registered with unknown or nonspecific causes. This paper reports the rationale, methods, and broad results from a comprehensive study to verify registered causes in Thailand.
Methods
A nationally representative sample of 11,984 deaths was selected using a multistage stratified cluster sampling approach, distributed across 28 districts located in nine provinces of Thailand. Registered causes were verified through medical record review for deaths in hospitals and standard verbal autopsy procedures for deaths outside hospitals, the results of which were used to measure validity and reliability of registration data. Study findings were used to develop descriptive estimates of cause-specific mortality by age and sex in Thailand.
Results
Causes of death were verified for a total of 9,644 deaths in the study sample, comprised of 3,316 deaths in hospitals and 6,328 deaths outside hospitals. Field studies yielded specific diagnoses in almost all deaths in the sample originally assigned an ill-defined cause of death at registration. Study findings suggest that the leading causes of death in Thailand among males are stroke (9.4%); transport accidents (8.1%); HIV/AIDS (7.9%); ischemic heart diseases (6.4%); and chronic obstructive lung diseases (5.7%). Among females, the leading causes are stroke (11.3%); diabetes (8%); ischemic heart disease (7.5%); HIV/AIDS (5.7%); and renal diseases (4%).
Conclusions
Empirical investigation of registered causes of death in the study sample yielded adequate information to enable estimation of cause-specific mortality patterns in Thailand. These findings will inform burden of disease estimation and economic evaluation of health policy choices in the country. The development and implementation of research methods in this study will contribute to improvements in the quality of annual mortality statistics in Thailand. Similar research is recommended for other countries where the quality of mortality statistics is poor.
doi:10.1186/1478-7954-8-11
PMCID: PMC2880956  PMID: 20482758
11.  Associations Between Renal Duplex Parameters and Adverse Cardiovascular Events in the Elderly: A Prospective Cohort Study 
Background
Atherosclerotic renovascular disease is associated with an increased risk of cardiovascular disease (CVD) events. This study examines associations between Doppler-derived parameters from the renal artery and renal parenchyma and all-cause mortality and fatal and nonfatal CVD events in a cohort of elderly Americans.
Study Design
Cohort study.
Setting
A subset of participants from the Cardiovascular Health Study (CHS). Through an ancillary study, 870 (70% recruitment) Forsyth County, NC, CHS participants consented to undergo renal duplex sonography to define the prevalence of renovascular disease in the elderly, resulting in 726 (36% men; mean age, 77 years) technically adequate complete studies included in this investigation.
Predictor
Renal duplex sonography–derived Doppler signals from the main renal arteries and renal parenchyma. Spectral analysis from Doppler-shifted frequencies and angle of insonation were used to estimate renal artery peak systolic and end diastolic velocity (both in meters per second). Color Doppler was used to identify the corticomedullary junction. Using a 3-mm Doppler sample, the parenchymal peak systolic and end diastolic frequency shift (both in kilohertz) were obtained. Resistive index was calculated as (1 – [end diastolic frequency shift/peak systolic frequency shift]) using Doppler samples from the hilar arteries of the left or right kidney with the higher main renal artery peak systolic velocity.
Outcomes & Measurements
Proportional hazard regression analysis was used to determine associations between renal duplex sonography–derived Doppler signals and CVD events and all-cause mortality adjusted for accepted cardiovascular risk factors. Index CVD outcomes were defined as coronary events (angina, myocardial infarction, and coronary artery bypass grafting/percutaneous coronary intervention), cerebrovascular events (stroke or transient ischemic attack), and any CVD event (angina, congestive heart failure, myocardial infarction, stroke, transient ischemic attack, and coronary artery bypass grafting [CABG]/percutaneous transluminal coronary intervention [PTCI]).
Results
During follow-up, 221 deaths (31%), 229 CVD events (32%), 122 coronary events (17%), and 92 cerebrovascular events (13%) were observed. Renal duplex sonography–derived Doppler signals from the renal parenchyma were associated independently with all-cause mortality and CVD outcomes. In particular, increased parenchymal end diastolic frequency shift was associated significantly with any CVD event (HR, 0.73; 95% CI, 0.62-0.87; P < 0.001). Marginally significant associations were observed between increases in parenchymal end diastolic frequency shift and decreased risk of death (HR, 0.86; 95% CI, 0.73-1.00; P = 0.06) and decreased risk of cerebrovascular events (HR, 0.78; 95% CI, 0.61-1.01; P = 0.06). Parenchymal end diastolic frequency shift was not significantly predictive of coronary events (HR, 0.84; 95% CI, 0.67-1.06; P = 0.1).
Limitations
CHS participants showed a “healthy cohort” effect that may underestimate the rate of CVD events in the general population.
Conclusion
Renal duplex sonographic Doppler signals from the renal parenchyma showed significant associations with subsequent CVD events after controlling for other significant risk factors. In particular, a standard deviation increase in parenchymal end diastolic frequency shift was associated with 27% risk reduction in any CVD event.
doi:10.1053/j.ajkd.2009.10.044
PMCID: PMC2933103  PMID: 20116688
Renovascular disease; resistive index; intrarenal Doppler; renal duplex sonography; prospective; population based; cardiovascular events; Cardiovascular Health Study (CHS)
12.  Post-mortem imaging as an alternative to autopsy in the diagnosis of adult deaths: a validation study 
Lancet  2012;379(9811):136-142.
Summary
Background
Public objection to autopsy has led to a search for minimally invasive alternatives. Imaging has potential, but its accuracy is unknown. We aimed to identify the accuracy of post-mortem CT and MRI compared with full autopsy in a large series of adult deaths.
Methods
This study was undertaken at two UK centres in Manchester and Oxford between April, 2006, and November, 2008. We used whole-body CT and MRI followed by full autopsy to investigate a series of adult deaths that were reported to the coroner. CT and MRI scans were reported independently, each by two radiologists who were masked to the autopsy findings. All four radiologists then produced a consensus report based on both techniques, recorded their confidence in cause of death, and identified whether autopsy was needed.
Findings
We assessed 182 unselected cases. The major discrepancy rate between cause of death identified by radiology and autopsy was 32% (95% CI 26–40) for CT, 43% (36–50) for MRI, and 30% (24–37) for the consensus radiology report; 10% (3–17) lower for CT than for MRI. Radiologists indicated that autopsy was not needed in 62 (34%; 95% CI 28–41) of 182 cases for CT reports, 76 (42%; 35–49) of 182 cases for MRI reports, and 88 (48%; 41–56) of 182 cases for consensus reports. Of these cases, the major discrepancy rate compared with autopsy was 16% (95% CI 9–27), 21% (13–32), and 16% (10–25), respectively, which is significantly lower (p<0·0001) than for cases with no definite cause of death. The most common imaging errors in identification of cause of death were ischaemic heart disease (n=27), pulmonary embolism (11), pneumonia (13), and intra-abdominal lesions (16).
Interpretation
We found that, compared with traditional autopsy, CT was a more accurate imaging technique than MRI for providing a cause of death. The error rate when radiologists provided a confident cause of death was similar to that for clinical death certificates, and could therefore be acceptable for medicolegal purposes. However, common causes of sudden death are frequently missed on CT and MRI, and, unless these weaknesses are addressed, systematic errors in mortality statistics would result if imaging were to replace conventional autopsy.
Funding
Policy Research Programme, Department of Health, UK.
doi:10.1016/S0140-6736(11)61483-9
PMCID: PMC3262166  PMID: 22112684
13.  Estimated causes of death in Thailand, 2005: implications for health policy 
Background
Almost 400,000 deaths are registered each year in Thailand. Their value for public health policy and planning is greatly diminished by incomplete registration of deaths and by concerns about the quality of cause-of-death information. This arises from misclassification of specified causes of death, particularly in hospitals, as well as from extensive use of ill-defined and vague codes to attribute the underlying cause of death. Detailed investigations of a sample of deaths in and out of hospital were carried out to identify misclassification of causes and thus derive a best estimate of national mortality patterns by age, sex, and cause of death.
Methods
A nationally representative sample of 11,984 deaths in 2005 was selected, and verbal autopsy interviews were conducted for almost 10,000 deaths. Verbal autopsy procedures were validated against 2,558 cases for which medical record review was possible. Misclassification matrices for leading causes of death, including ill-defined causes, were developed separately for deaths inside and outside of hospitals and proportionate mortality distributions constructed. Estimates of mortality undercount were derived from "capture-recapture" methods applied to the 2005-06 Survey of Population Change. Proportionate mortality distributions were applied to this mortality "envelope" and ill-defined causes redistributed according to Global Burden of Disease methods to yield final estimates of mortality levels and patterns in 2005.
Results
Estimated life expectancy in Thailand in 2005 was 68.5 years for males and 75.6 years for females, two years lower than vital registration data suggest. Upon correction, stroke is the leading cause of death in Thailand (10.7%), followed by ischemic heart disease (7.8%) and HIV/AIDS (7.4%). Other leading causes are road traffic accidents (males) and diabetes mellitus (females). In many cases, estimated mortality is at least twice what is estimated in vital registration. Leading causes of death have remained stable since 1999, with the exception of a large decline in HIV/AIDS mortality.
Conclusions
Field research into the accuracy of cause-of-death data can result in substantially different patterns of mortality than suggested by routine death registration. Misclassification errors are likely to have very significant implications for health policy debates. Routine incorporation of validated verbal autopsy methods could significantly improve cause-of-death data quality in Thailand.
doi:10.1186/1478-7954-8-14
PMCID: PMC2885317  PMID: 20482761
14.  Genetic Susceptibility for Ischemic Infarction and Arteriolosclerosis based on Neuropathologic Evaluations 
Cerebrovascular diseases (Basel, Switzerland)  2013;36(3):10.1159/000352054.
Background
Recent genetic studies of stroke and related risk factors have identified a growing number of susceptibility loci; however, the relationship of these alleles to ischemic stroke is unknown. The challenge in finding reproducible loci of ischemic stroke susceptibility may be in part related to the etiologic heterogeneity in clinically-defined stroke subtypes. In this study, we tested whether known single nucleotide polymorphisms (SNPs) associated with stroke or putative stroke risk factors are associated with neuropathologically-defined micro- or macroscopic infarcts and with arteriolosclerosis.
Methods
Measures of neuropathology and genotyping were available from 755 deceased participants from the Religious Orders Study and the Rush Memory and Aging Project. All donated brains were examined by a board-certified neuropathologist using standardized protocol for the presence of microscopic infarct, macroscopic infarct, and artereiolosclerosis (lipohylinosis). In primary analysis, 74 candidate SNPs previously associated (p < 5×10−8) with ischemic stroke or known risk factors, including atrial fibrillation (AF), hypertension, diabetes, low density lipoprotein (LDL) level, and carotid artery stenosis, were evaluated for association with neuropathological endpoints. We performed secondary exploratory analysis to include additional 93 SNPs associated with putative ischemic stroke risk factors including SNPS associated with high density lipoprotein (HDL), triglyceride serum levels, myocardial infarction, coronary artery disease, and cerebral white matter disease. Regression models relating SNPs to cerebrovascular neuropathology were adjusted for age at death, gender, and cohort membership.
Results
The strongest associations seen for both macroscopic and microscopic infarcts were risk variants associated with diabetes. The diabetes risk variant rs7578326 located near the IRS1 locus was associated with both macroscopic (OR=0.73, p=0.011) and microscopic (OR=0.71, p=0.009) infarct pathology. Another diabetes susceptibility locus rs12779790 located between the calcium/calmodulin-dependent protein kinase ID (CAMK1D) and cell division cycle 123 homolog (CDC123) genes is also associated with both macroscopic (OR=1.40, p=0.0292) and microscopic infarcts (OR=1.43, p=0.0285). Diabetes risk allele, rs864745, within JAZF1, was associated with arteriolosclerosis (OR=0.80, p=0.014). We observed suggestive associations with the diabetes risk alleles rs7961581 (p=0.038; between TSPAN8 and LGR5) and rs5215 (p=0.043; KCNJ11), the LDL risk variant rs11206510 (p=0.045; PCSK9), as well as the AF risk locus ZFHX3. The CDKN2A/B locus (rs2383207, 9p21), identified initially as a susceptibility allele for myocardial infarction and recently implicated in large vessel stroke, was associated with macroscopic infarct pathology in our autopsy cohort (OR=1.26, p=0.031).
Conclusion
Our results suggest replication of the candidate CDKN2A/B stroke susceptibility locus with directly measured macroscopic stroke neuropathology, and further implicate several diabetes and other risk alleles with secondary, pleiotropic associations to stroke-related pathology in our autopsy cohort. When coupled with larger sample sizes, cerebrovascular neuropathologic phenotypes will likely be powerful tools for the genetic dissection of susceptibility for ischemic stroke.
doi:10.1159/000352054
PMCID: PMC3871868  PMID: 24135527
ischemic stroke etiology; pathology; genetic risk factors of stroke; genetics of vascular pathology and stroke; diabetes mellitus; arteriolosclerosis
15.  Clinico-Pathological Discrepancies in the Diagnosis of Causes of Maternal Death in Sub-Saharan Africa: Retrospective Analysis 
PLoS Medicine  2009;6(2):e1000036.
Background
Maternal mortality is a major public-health problem in developing countries. Extreme differences in maternal mortality rates between developed and developing countries indicate that most of these deaths are preventable. Most information on the causes of maternal death in these areas is based on clinical records and verbal autopsies. Clinical diagnostic errors may play a significant role in this problem and might also have major implications for the evaluation of current estimations of causes of maternal death.
Methods and Findings
A retrospective analysis of clinico-pathologic correlation was carried out, using necropsy as the gold standard for diagnosis. All maternal autopsies (n = 139) during the period from October 2002 to December 2004 at the Maputo Central Hospital, Mozambique were included and major diagnostic discrepancies were analyzed (i.e., those involving the cause of death). Major diagnostic errors were detected in 56 (40.3%) maternal deaths. A high rate of false negative diagnoses was observed for infectious diseases, which showed sensitivities under 50%: HIV/AIDS-related conditions (33.3%), pyogenic bronchopneumonia (35.3%), pyogenic meningitis (40.0%), and puerperal septicemia (50.0%). Eclampsia, was the main source of false positive diagnoses, showing a low predictive positive value (42.9%).
Conclusions
Clinico-pathological discrepancies may have a significant impact on maternal mortality in sub-Saharan Africa and question the validity of reports based on clinical data or verbal autopsies. Increasing clinical awareness of the impact of obstetric and nonobstetric infections with their inclusion in the differential diagnosis, together with a thorough evaluation of cases clinically thought to be eclampsia, could have a significant impact on the reduction of maternal mortality.
Jaume Ordi and colleagues examine the discrepancies between clinical diagnoses of causes of maternal deaths and pathological findings by necropsy in Mozambique.
Editors' Summary
Background.
Every year, about half a million women die during pregnancy or childbirth or soon after delivery—so-called “maternal deaths.” Although nearly all these maternal deaths occur in developing countries, the situation is particularly bad in sub-Saharan Africa where more than a quarter of a million maternal deaths occur annually. The number of maternal deaths per 100,000 live births in this region is nearly 1,000, whereas in developed regions it is only nine deaths. A 15-year-old girl living in sub-Saharan Africa has a lifetime risk of dying during pregnancy or childbirth of 1 in 22, but a girl living in the developed regions of the world has a lifetime risk of only 1 in 7,300. Maternal deaths can be caused by obstetric (childbirth-related) complications such as puerperal septicemia (an infection of the blood contracted during delivery) and eclampsia (seizures associated with high blood pressure during pregnancy), and by nonobstetric conditions such as HIV/AIDS-related infections and other infections.
Why Was This Study Done?
In 2000, the United Nations made reduction of the global burden of maternal mortality one of its Millennium Development Goals (a set of targets designed to eradicate poverty by 2015), but little progress has been made toward achieving this goal. One possible explanation for this failure might be that limited access to diagnostic tests in developing countries results in more clinical diagnostic errors than in developed countries and that, consequently, mothers in developing countries don't always get the right treatment when they become ill. Unfortunately, it is difficult to test this hypothesis, because there is very little accurate information on the causes of maternal death in many developing countries. What information there is comes mainly from clinical records and verbal autopsies (asking relatives about the mother's death) rather than from examination of the body after death (a medical autopsy), the only sure way to ascertain the cause of death. In this study, the researchers retrospectively analyze discrepancies between the clinical diagnoses and autopsy diagnoses of 139 mothers who died at the Maputo Central Hospital, Mozambique, a large hospital providing specialized care for women with high-risk pregnancies.
What Did the Researchers Do and Find?
All the organs from the mothers were visually examined by a pathologist and samples of any abnormal tissues and of the internal organs were examined microscopically. Two pathologists independently established the cause of each death by considering both the clinical diagnosis and the autopsy results (the “autopsy diagnosis”). The discrepancies between the clinical and autopsy (“gold standard”) diagnoses were then analyzed. Major diagnostic errors (errors involving the cause of death) occurred in nearly half of the maternal deaths; the clinical and autopsy diagnoses completely agreed in only a third of cases. 80% of the major diagnostic errors were “class I errors.” That is, errors where a correct diagnosis would have changed patient management and prolonged survival or provided a cure. For example, 12 women were given an incorrect diagnosis of eclampsia when they had other conditions that could have been successfully treated if correctly diagnosed. Furthermore, many infections detected in the autopsies were missed in the clinical diagnoses (false-negative diagnoses), some of which could have been treated.
What Do These Findings Mean?
These findings show that clinical and autopsy diagnoses of the causes of maternal death frequently disagree in this hospital. Further studies are needed to see whether similar levels of disagreement exist in other hospitals in sub-Saharan Africa. The discrepancy reported here might, for example, be an overestimate of the general situation, because the high-risk pregnancies referred to this hospital might involve more hard-to-diagnose problems than the routine pregnancies referred to other hospitals. Nevertheless, these findings suggest that misdiagnosed conditions may affect maternal mortality rates in sub-Saharan Africa and that an increased use of autopsy in the region could reduce maternal mortality by providing more accurate information about why mothers die. In particular, these findings suggest that a more thorough evaluation of cases thought to be eclampsia and a better awareness of the involvement of infectious diseases in maternal deaths might reduce diagnostic errors and consequently reduce the incidence of maternal deaths.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000036.
UNICEF (the United Nations Children's Fund) provides information on maternal mortality and the WHO/UNICEF/UNFPA/The World Bank estimates of maternal mortality for 2005 by country
The WHO/UNICEF/UNFPA/The World Bank estimates of maternal mortality in 2005 also provides full information about global maternal mortality
The UK Department for International Development provides information about Millenium Development Goal 5: the improvement of maternal health
The Partnership for Maternal, Newborn and Child Health provides information on maternal deaths (in several languages), including information on the situation in Mozambique
doi:10.1371/journal.pmed.1000036
PMCID: PMC2646780  PMID: 19243215
16.  The Effect of Tobacco Control Measures during a Period of Rising Cardiovascular Disease Risk in India: A Mathematical Model of Myocardial Infarction and Stroke 
PLoS Medicine  2013;10(7):e1001480.
In this paper from Basu and colleagues, a simulation of tobacco control and pharmacological interventions to prevent cardiovascular disease mortality in India predicted that Smokefree laws and increased tobacco taxation are likely to be the most effective measures to avert future cardiovascular deaths in India.
Please see later in the article for the Editors' Summary
Background
We simulated tobacco control and pharmacological strategies for preventing cardiovascular deaths in India, the country that is expected to experience more cardiovascular deaths than any other over the next decade.
Methods and Findings
A microsimulation model was developed to quantify the differential effects of various tobacco control measures and pharmacological therapies on myocardial infarction and stroke deaths stratified by age, gender, and urban/rural status for 2013 to 2022. The model incorporated population-representative data from India on multiple risk factors that affect myocardial infarction and stroke mortality, including hypertension, hyperlipidemia, diabetes, coronary heart disease, and cerebrovascular disease. We also included data from India on cigarette smoking, bidi smoking, chewing tobacco, and secondhand smoke. According to the model's results, smoke-free legislation and tobacco taxation would likely be the most effective strategy among a menu of tobacco control strategies (including, as well, brief cessation advice by health care providers, mass media campaigns, and an advertising ban) for reducing myocardial infarction and stroke deaths over the next decade, while cessation advice would be expected to be the least effective strategy at the population level. In combination, these tobacco control interventions could avert 25% of myocardial infarctions and strokes (95% CI: 17%–34%) if the effects of the interventions are additive. These effects are substantially larger than would be achieved through aspirin, antihypertensive, and statin therapy under most scenarios, because of limited treatment access and adherence; nevertheless, the impacts of tobacco control policies and pharmacological interventions appear to be markedly synergistic, averting up to one-third of deaths from myocardial infarction and stroke among 20- to 79-y-olds over the next 10 y. Pharmacological therapies could also be considerably more potent with further health system improvements.
Conclusions
Smoke-free laws and substantially increased tobacco taxation appear to be markedly potent population measures to avert future cardiovascular deaths in India. Despite the rise in co-morbid cardiovascular disease risk factors like hyperlipidemia and hypertension in low- and middle-income countries, tobacco control is likely to remain a highly effective strategy to reduce cardiovascular deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cardiovascular diseases (CVDs) are conditions that affect the heart and/or the circulation. In coronary heart disease, for example, narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). Stroke, by contrast, is a CVD in which the blood supply to the brain is interrupted. CVD has been a major cause of illness and death in high-income countries for many years, but the burden of CVD is now rapidly rising in low- and middle-income countries. Indeed, worldwide, three-quarters of all deaths from heart disease and stroke occur in low- and middle-income countries. Smoking, high blood pressure (hypertension), high blood cholesterol (hyperlipidemia), diabetes, obesity, and physical inactivity all increase an individual's risk of developing CVD. Prevention strategies and treatments for CVD include lifestyle changes (for example, smoking cessation) and taking drugs that lower blood pressure (antihypertensive drugs) or blood cholesterol levels (statins) or thin the blood (aspirin).
Why Was This Study Done?
Because tobacco use is a key risk factor for CVD and for several other noncommunicable diseases, the World Health Organization has developed an international instrument for tobacco control called the Framework Convention on Tobacco Control (FCTC). Parties to the FCTC (currently 176 countries) agree to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes. But will tobacco control measures reduce the burden of CVD effectively in low- and middle-income countries as other risk factors for CVD are becoming more common? In this mathematical modeling study, the researchers investigated this question by simulating the effects of tobacco control measures and pharmacological strategies for preventing CVD on CVD deaths in India. Notably, many of the core FCTC provisions remain poorly implemented or unenforced in India even though it became a party to the convention in 2005. Moreover, experts predict that, over the next decade, this middle-income country will contribute more than any other nation to the global increase in CVD deaths.
What Did the Researchers Do and Find?
The researchers developed a microsimulation model (a computer model that operates at the level of individuals) to quantify the likely effects of various tobacco control measures and pharmacological therapies on deaths from myocardial infarction and stroke in India between 2013 and 2022. They incorporated population-representative data from India on risk factors that affect myocardial infarction and stroke mortality and on tobacco use and exposure to secondhand smoke into their model. They then simulated the effects of five tobacco control measures—smoke-free legislation, tobacco taxation, provision of brief cessation advice by health care providers, mass media campaigns, and advertising bans—and increased access to aspirin, antihypertensive drugs, and statins on deaths from myocardial infarction and stroke. Smoke-free legislation and tobacco taxation are likely to be the most effective strategies for reducing myocardial infarction and stroke deaths over the next decade, according to the model, and the effects of these strategies are likely to be substantially larger than those achieved by drug therapies under current health system conditions. If the effects of smoke-free legislation and tobacco taxation are additive, the model predicts that these two measures alone could avert about 9 million deaths, that is, a quarter of the expected deaths from myocardial infarction and stroke in India over the next 10 years, and that a combination of tobacco control policies and pharmacological interventions could avert up to a third of these deaths.
What Do These Findings Mean?
These findings suggest that the implementation of smoke-free laws and the introduction of increased tobacco taxes in India would yield substantial and rapid health benefits by averting future CVD deaths. The accuracy of these findings is likely to be affected by the many assumptions included in the mathematical model and by the quality of the data fed into it. Importantly, however, these finding suggest that, despite the rise in other CVD risk factors such as hypertension and hyperlipidemia, tobacco control is likely to be a highly effective strategy for the reduction of CVD deaths over the next decade in India and probably in other low- and middle-income countries. Policymakers in these countries should, therefore, work towards fuller and faster implementation of the core FCTC provisions to boost their efforts to reduce deaths from CVD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001480.
The American Heart Association provides information on all aspects of cardiovascular disease; its website includes personal stories about heart attacks and stroke
The US Centers for Disease Control and Prevention has information on heart disease and on stroke (in English and Spanish
The UK National Health Service Choices website provides information about cardiovascular disease and stroke
MedlinePlus provides links to other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
The World Health Organization provides information (in several languages) about the dangers of tobacco, about the Framework Convention on Tobacco Control, and about noncommunicable diseases; its Global Noncommunicable Disease Network (NCDnet) aims to help low- and middle- income countries reduce illness and death caused by CVD and other noncommunicable diseases
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, supported by the US National Cancer Institute and other US agencies, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001480
PMCID: PMC3706364  PMID: 23874160
17.  Associations between Stroke Mortality and Weekend Working by Stroke Specialist Physicians and Registered Nurses: Prospective Multicentre Cohort Study 
PLoS Medicine  2014;11(8):e1001705.
In a multicenter observational study, Benjamin Bray and colleagues evaluate whether weekend rounds by stroke specialist physicians, or the ratio of registered nurses to beds on weekends, is associated with patient mortality after stroke.
Please see later in the article for the Editors' Summary
Background
Observational studies have reported higher mortality for patients admitted on weekends. It is not known whether this “weekend effect” is modified by clinical staffing levels on weekends. We aimed to test the hypotheses that rounds by stroke specialist physicians 7 d per week and the ratio of registered nurses to beds on weekends are associated with mortality after stroke.
Methods and Findings
We conducted a prospective cohort study of 103 stroke units (SUs) in England. Data of 56,666 patients with stroke admitted between 1 June 2011 and 1 December 2012 were extracted from a national register of stroke care in England. SU characteristics and staffing levels were derived from cross-sectional survey. Cox proportional hazards models were used to estimate hazard ratios (HRs) of 30-d post-admission mortality, adjusting for case mix, organisational, staffing, and care quality variables. After adjusting for confounders, there was no significant difference in mortality risk for patients admitted to a stroke service with stroke specialist physician rounds fewer than 7 d per week (adjusted HR [aHR] 1.04, 95% CI 0.91–1.18) compared to patients admitted to a service with rounds 7 d per week. There was a dose–response relationship between weekend nurse/bed ratios and mortality risk, with the highest risk of death observed in stroke services with the lowest nurse/bed ratios. In multivariable analysis, patients admitted on a weekend to a SU with 1.5 nurses/ten beds had an estimated adjusted 30-d mortality risk of 15.2% (aHR 1.18, 95% CI 1.07–1.29) compared to 11.2% for patients admitted to a unit with 3.0 nurses/ten beds (aHR 0.85, 95% CI 0.77–0.93), equivalent to one excess death per 25 admissions. The main limitation is the risk of confounding from unmeasured characteristics of stroke services.
Conclusions
Mortality outcomes after stroke are associated with the intensity of weekend staffing by registered nurses but not 7-d/wk ward rounds by stroke specialist physicians. The findings have implications for quality improvement and resource allocation in stroke care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In a perfect world, a patient admitted to hospital on a weekend or during the night should have as good an outcome as a patient admitted during regular working hours. But several observational studies (investigations that record patient outcomes without intervening in any way; clinical trials, by contrast, test potential healthcare interventions by comparing the outcomes of patients who are deliberately given different treatments) have reported that admission on weekends is associated with a higher mortality (death) rate than admission on weekdays. This “weekend effect” has led to calls for increased medical and nursing staff to be available in hospitals during the weekend and overnight to ensure that the healthcare provided at these times is of equal quality to that provided during regular working hours. In the UK, for example, “seven-day working” has been identified as a policy and service improvement priority for the National Health Service.
Why Was This Study Done?
Few studies have actually tested the relationship between patient outcomes and weekend physician or nurse staffing levels. It could be that patients who are admitted to hospital on the weekend have poor outcomes because they are generally more ill than those admitted on weekdays. Before any health system introduces potentially expensive increases in weekend staffing levels, better evidence that this intervention will improve patient outcomes is needed. In this prospective cohort study (a study that compares the outcomes of groups of people with different baseline characteristics), the researchers ask whether mortality after stroke is associated with weekend working by stroke specialist physicians and registered nurses. Stroke occurs when the brain's blood supply is interrupted by a blood vessel in the brain bursting (hemorrhagic stroke) or being blocked by a blood clot (ischemic stroke). Swift treatment can limit the damage to the brain caused by stroke, but of the 15 million people who have a stroke every year, about 6 million die within a few hours and another 5 million are left disabled.
What Did the Researchers Do and Find?
The researchers extracted clinical data on 56,666 patients who were admitted to stroke units in England over an 18-month period from a national stroke register. They obtained information on the characteristics and staffing levels of the stroke units from a biennial survey of hospitals admitting patients with stroke, and information on deaths among patients with stroke from the national register of deaths. A quarter of the patients were admitted on a weekend, almost half the stroke units provided stroke specialist physician rounds seven days per week, and the remainder provided rounds five days per week. After adjustment for factors that might have affected outcomes (“confounders”) such as stroke severity and the level of acute stroke care available in each stroke unit, there was no significant difference in mortality risk between patients admitted to a stroke unit with rounds seven days/week and patients admitted to a unit with rounds fewer than seven days/week. However, patients admitted on a weekend to a stroke unit with 1.5 nurses/ten beds had a 30-day mortality risk of 15.2%, whereas patients admitted to a unit with 3.0 nurses/ten beds had a mortality risk of 11.2%, a mortality risk difference equivalent to one excess death per 25 admissions.
What Do These Findings Mean?
These findings show that the provision of stroke specialist physician rounds seven days/week in stroke units in England did not influence the (weak) association between weekend admission for stroke and death recorded in this study, but mortality outcomes after stroke were associated with the intensity of weekend staffing by registered nurses. The accuracy of these findings may be affected by the measure used to judge the level of acute care available in each stroke unit and by residual confounding. For example, patients admitted to units with lower nursing levels may have shared other unknown characteristics that increased their risk of dying after stroke. Moreover, this study considered the impact of staffing levels on mortality only and did not consider other relevant outcomes such as long-term disability. Despite these limitations, these findings support the provision of higher weekend ratios of registered nurses to beds in stroke units, but given the high costs of increasing weekend staffing levels, it is important that controlled trials of different models of physician and nursing staffing are undertaken as soon as possible.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001705.
This study is further discussed in a PLOS Medicine Perspective by Meeta Kerlin
Information about plans to introduce seven-day working into the National Health Service in England is available; the 2013 publication “NHS Services—Open Seven Days a Week: Every Day Counts” provides examples of how hospitals across England are working together to provide routine healthcare services seven days a week; a “Behind the Headlines” article on the UK National Health Service Choices website describes a recent observational study that investigated the association between admission to hospital on the weekend and death, and newspaper coverage of the study's results; the Choices website also provides information about stroke for patients and their families, including personal stories
A US nurses' site includes information on the association of nurse staffing with patient safety
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation, including personal stories (in English and Spanish); the US National Institute of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
doi:10.1371/journal.pmed.1001705
PMCID: PMC4138029  PMID: 25137386
18.  Markers of Dysglycaemia and Risk of Coronary Heart Disease in People without Diabetes: Reykjavik Prospective Study and Systematic Review 
PLoS Medicine  2010;7(5):e1000278.
Background
Associations between circulating markers of dysglycaemia and coronary heart disease (CHD) risk in people without diabetes have not been reliably characterised. We report new data from a prospective study and a systematic review to help quantify these associations.
Methods and Findings
Fasting and post-load glucose levels were measured in 18,569 participants in the population-based Reykjavik study, yielding 4,664 incident CHD outcomes during 23.5 y of mean follow-up. In people with no known history of diabetes at the baseline survey, the hazard ratio (HR) for CHD, adjusted for several conventional risk factors, was 2.37 (95% CI 1.79–3.14) in individuals with fasting glucose ≥7.0 mmol/l compared to those <7 mmol/l. At fasting glucose values below 7 mmol/l, adjusted HRs were 0.95 (0.89–1.01) per 1 mmol/l higher fasting glucose and 1.03 (1.01–1.05) per 1 mmol/l higher post-load glucose. HRs for CHD risk were generally modest and nonsignificant across tenths of glucose values below 7 mmol/l. We did a meta-analysis of 26 additional relevant prospective studies identified in a systematic review of Western cohort studies that recorded fasting glucose, post-load glucose, or glycated haemoglobin (HbA1c) levels. In this combined analysis, in which participants with a self-reported history of diabetes and/or fasting blood glucose ≥7 mmol/l at baseline were excluded, relative risks for CHD, adjusted for several conventional risk factors, were: 1.06 (1.00–1.12) per 1 mmol/l higher fasting glucose (23 cohorts, 10,808 cases, 255,171 participants); 1.05 (1.03–1.07) per 1 mmol/l higher post-load glucose (15 cohorts, 12,652 cases, 102,382 participants); and 1.20 (1.10–1.31) per 1% higher HbA1c (9 cohorts, 1639 cases, 49,099 participants).
Conclusions
In the Reykjavik Study and a meta-analysis of other Western prospective studies, fasting and post-load glucose levels were modestly associated with CHD risk in people without diabetes. The meta-analysis suggested a somewhat stronger association between HbA1c levels and CHD risk.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Among people diagnosed with type 2 diabetes mellitus (the commonest type of diabetes worldwide), poor management or lack of appropriate treatment can lead to long-term complications resulting from persistently high sugar levels in the blood. The long-term complications of type 2 diabetes are generally divided into two main groups: microvascular problems (such as nerve damage, kidney disease, and eye disorders), and macrovascular disease (such as heart disease, strokes, and peripheral vascular disease). A major goal of diabetes treatment is to keep glucose control as normal as possible through diet, weight control, exercise, and pharmacological treatments. However, it is unclear whether the link between high blood sugar and macrovascular disease (principally heart disease and strokes) also holds for people who have slightly higher than normal blood sugar levels, but in whom this level does not reach the diabetic threshold. Some previous research studies have suggested that a continuous relationship exists between blood sugar level and the risk of heart disease across the spectrum, i.e., below the diabetic threshold as well as above it. If such a relationship were confirmed this might have important implications for the management of high blood sugar levels even among people who would not normally meet the usual definition for a diagnosis of diabetes (the “diabetic threshold”).
Why Was This Study Done?
Studies which examine the risk of serious, but relatively common, outcomes (such as a nonfatal heart attack or fatal heart disease), often suffer from insufficient statistical power: a large number of participants need to be recruited, and followed up over a long time, to find out whether certain factors measured at baseline (e.g., fasting glucose) are indeed associated with a particular outcome (e.g., heart attack) or not during follow up. Given the inconclusive nature of some previous studies in this area, the researchers who carried out this work wanted to gather evidence from a large prospective cohort, and a reappraisal of all existing evidence, in relation to the possible link between high blood sugar and risk of heart disease in people without diabetes.
What Did the Researchers Do and Find?
In this study, the researchers report results from a prospective population-based study (in which participants are followed forward in time) from Reykjavik, Iceland. In the study, men and women without history of heart disease aged between 31 and 57 in 1966 were first invited to join the cohort, and were followed forward in time using national registries that recorded deaths (and causes of death), and incidence of heart disease. A total of 8,888 male and 9,681 female participants were recruited. At baseline, laboratory measurements were taken to record blood sugar levels using two different methods: fasting blood glucose and post-load glucose. Among the group of participants, 4,664 people were recorded as having either a nonfatal heart attack or fatal heart disease, during approximately 23 years of follow-up. In addition, the researchers attempted to identify from the published medical literature previous prospective studies conducted in Western populations that had looked at the association between blood sugar levels and risk of coronary heart disease. They requested, and obtained, re-analyses of data conducted in accordance with a common protocol for most of the identified studies and then analysed these, together with the results of the Reykjavik cohort, to produce a summary estimate (meta-analysis) of the association between blood sugar levels and risk of coronary heart disease in people without diabetes.
In the Reykjavik cohort, the researchers confirmed an increased risk of coronary heart disease among individuals with blood sugar above the diabetic threshold, as compared to those below it. However, when they looked at blood sugar in people below the diabetic threshold, they found no evidence that higher levels were strongly linked with greater risk of coronary heart disease. This held for both methods of measuring blood sugar levels (fasting and post-load).
In the meta-analysis, the researchers obtained data for 27 different studies, comprising 303,961 participants and 16,982 cases of heart disease. In this meta-analysis, very small increases in risk of heart disease were found with higher levels of blood sugar, when measured using fasting blood glucose or post-load glucose. However, studies using glycated haemoglobin (a measure of average sugar levels over the past 1–3 months or so) found this measure to be associated with a somewhat higher risk of heart disease.
What Do these Findings Mean?
In this prospective cohort and wider meta-analysis, the researchers did not find evidence of a strong or continuous association between blood sugar levels and risk of heart disease amongst people without diabetes. The prospective study, and analysis of other cohorts, was large, but only looked at participants of European decent, so it is not clear whether the findings will also hold for non-European groups.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000278.
Information is available from the US National Diabetes Information Clearinghouse about diabetes, heart disease, and stroke
Centers for Disease Control provides information for the public and professionals about diabetes on their diabetes minisite
Medline Plus encyclopedia has an entry about coronary heart disease
doi:10.1371/journal.pmed.1000278
PMCID: PMC2876150  PMID: 20520805
19.  Estimates of Outcomes Up to Ten Years after Stroke: Analysis from the Prospective South London Stroke Register 
PLoS Medicine  2011;8(5):e1001033.
Charles Wolfe and colleagues collected data from the South London Stroke Register on 3,373 first strokes registered between 1995 and 2006 and showed that between 20% and 30% of survivors have poor outcomes up to 10 years after stroke.
Background
Although stroke is acknowledged as a long-term condition, population estimates of outcomes longer term are lacking. Such estimates would be useful for planning health services and developing research that might ultimately improve outcomes. This burden of disease study provides population-based estimates of outcomes with a focus on disability, cognition, and psychological outcomes up to 10 y after initial stroke event in a multi-ethnic European population.
Methods and Findings
Data were collected from the population-based South London Stroke Register, a prospective population-based register documenting all first in a lifetime strokes since 1 January 1995 in a multi-ethnic inner city population. The outcomes assessed are reported as estimates of need and included disability (Barthel Index <15), inactivity (Frenchay Activities Index <15), cognitive impairment (Abbreviated Mental Test < 8 or Mini-Mental State Exam <24), anxiety and depression (Hospital Anxiety and Depression Scale >10), and mental and physical domain scores of the Medical Outcomes Study 12-item short form (SF-12) health survey. Estimates were stratified by age, gender, and ethnicity, and age-adjusted using the standard European population. Plots of outcome estimates over time were constructed to examine temporal trends and sociodemographic differences. Between 1995 and 2006, 3,373 first-ever strokes were registered: 20%–30% of survivors had a poor outcome over 10 y of follow-up. The highest rate of disability was observed 7 d after stroke and remained at around 110 per 1,000 stroke survivors from 3 mo to 10 y. Rates of inactivity and cognitive impairment both declined up to 1 y (280/1,000 and 180/1,000 survivors, respectively); thereafter rates of inactivity remained stable till year eight, then increased, whereas rates of cognitive impairment fluctuated till year eight, then increased. Anxiety and depression showed some fluctuation over time, with a rate of 350 and 310 per 1,000 stroke survivors, respectively. SF-12 scores showed little variation from 3 mo to 10 y after stroke. Inactivity was higher in males at all time points, and in white compared to black stroke survivors, although black survivors reported better outcomes in the SF-12 physical domain. No other major differences were observed by gender or ethnicity. Increased age was associated with higher rates of disability, inactivity, and cognitive impairment.
Conclusions
Between 20% and 30% of stroke survivors have a poor range of outcomes up to 10 y after stroke. Such epidemiological data demonstrate the sociodemographic groups that are most affected longer term and should be used to develop longer term management strategies that reduce the significant poor outcomes of this group, for whom effective interventions are currently elusive.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people have a stroke. About 5 million of these people die within a few days, and another 5 million are left disabled. Stroke occurs when the brain's blood supply is suddenly interrupted by a blood clot blocking a blood vessel in the brain (ischemic stroke, the commonest type of stroke) or by a blood vessel in the brain bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. Risk factors for stroke include age (three-quarters of strokes occur in people over 65 years old), high blood pressure, and heart disease.
Why Was This Study Done?
Post-stroke rehabilitation can help individuals overcome the physical disabilities caused by stroke, and drugs and behavioral counseling can reduce the risk of a second stroke. However, people can also have problems with cognition (thinking, awareness, attention, learning, judgment, and memory) after a stroke, and they can become depressed or anxious. These “outcomes” can persist for many years, but although stroke is acknowledged as a long-term condition, most existing data on stroke outcomes are limited to a year after the stroke and often focus on disability alone. Longer term, more extensive information is needed to help plan services and to help develop research to improve outcomes. In this burden of disease analysis, the researchers use follow-up data collected by the prospective South London Stroke Register (SLSR) to provide long-term population-based estimates of disability, cognition, and psychological outcomes after a first stroke. The SLSR has recorded and followed all patients of all ages in an inner area of South London after their first-ever stroke since 1995.
What Did the Researchers Do and Find?
Between 1995 and 2006, the SLSR recorded 3,373 first-ever strokes. Patients were examined within 48 hours of referral to SLSR, their stroke diagnosis was verified, and their sociodemographic characteristics (including age, gender, and ethnic origin) were recorded. Study nurses and fieldworkers then assessed the patients at three months and annually after the stroke for disability (using the Barthel Index, which measures the ability to, for example, eat unaided), inactivity (using the Frenchay Activities Index, which measures participation in social activities), and cognitive impairment (using the Abbreviated Mental Test or the Mini-Mental State Exam). Anxiety and depression and the patients' perceptions of their mental and physical capabilities were also assessed. Using preset cut-offs for each outcome, 20%–30% of stroke survivors had a poor outcome over ten years of follow-up. So, for example, 110 individuals per 1,000 population were judged disabled from three months to ten years, rates of inactivity remained constant from year one to year eight, at 280 affected individuals per 1,000 survivors, and rates of anxiety and depression fluctuated over time but affected about a third of the population. Notably, levels of inactivity were higher among men than women at all time points and were higher in white than in black stroke survivors. Finally, increased age was associated with higher rates of disability, inactivity, and cognitive impairment.
What Do These Findings Mean?
Although the accuracy of these findings may be affected by the loss of some patients to follow-up, these population-based estimates of outcome measures for survivors of a first-ever stroke for up to ten years after the event provide concrete evidence that stroke is a lifelong condition with ongoing poor outcomes. They also identify the sociodemographic groups of patients that are most affected in the longer term. Importantly, most of the measured outcomes remain relatively constant (and worse than outcomes in an age-matched non-stroke-affected population) after 3–12 months, a result that needs to be considered when planning services for stroke survivors. In other words, these findings highlight the need for health and social services to provide long-term, ongoing assessment and rehabilitation for patients for many years after a stroke.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001033.
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); the US National Institute of Health SeniorHealth Web site has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices Web site also provides information about stroke for patients and their families
MedlinePlus has links to additional resources about stroke (in English and Spanish)
More information about the South London Stroke Register is available
doi:10.1371/journal.pmed.1001033
PMCID: PMC3096613  PMID: 21610863
20.  Assessing the quality of evidence for verbal autopsy diagnosis of stroke in Vietnam 
Background:
Information on the leading causes of mortality will continue to rely on verbal autopsy (VA) in developing countries. The accuracy of VA methods in correctly ascertaining the cause for each individual death is crucial in order to have confidence in the data collected through the procedure. Accuracy of the VA procedure is generally established by carrying out validation studies involving a comparison of the underlying cause of death derived from the VA with a reference underlying cause from medical records. Such validation is only possible in cases for which clinical records are available, and this is clearly not the case for most deaths in developing countries. We attempt to verify the accuracy of VA evidence by reviewing the responses to specific symptom questions and other information recorded in verbal autopsy questionnaires that were assigned cerebrovascular conditions (stroke) as causes of death upon physician review in Vietnam.
Materials and Methods:
A national sample mortality surveillance activity identified deaths and causes of death that had occurred during 2008 in selected communes in 16 provinces distributed across Vietnam. All cases from the northern provinces of Hanoi, Hai Duong, Quang Ninh and Thanh Hoa with ICD codes pertaining to cerebrovascular diseases were identified. A total of 326 VA questionnaires for deaths from cerebrovascular diseases were reviewed and analysed in detail for the presence of symptoms pertaining to stroke. The respondents’ narration of the chronological disease history and the hospital diagnosis was also examined with an aim to explore supporting signs for diagnosis and to verify the quality of VA interview. Differences between responses among cases with and without hospital admission were examined using Chi-squared test of statistical significance.
Results:
Ninty percent of the cases diagnosed as stroke were found to have positive response to the key symptoms; viz., paralysis (in structured question or free text) and history of stroke. For the remaining 10% of cases, stroke was assigned as a cause-of-death based on other suggestive cardiac signs and symptoms such as hypertension, unconsciousness, or headache, etc. Community had different perspectives of “paralysis” and “stroke” which might have affected the diagnosis of stroke in some aspects. Respondents of cases with hospital admission or visit were found to have a better recall of disease symptoms than those without hospital admission.
Conclusion:
The results of this study suggest the possible utility of VA content analysis method to back up the low coverage of conventional validation studies in developing countries owing to nonavailability of medical records. The understanding of the VA content would also form the basis for improvement in the quality of interviews and collection of data to achieve better quality information in future.
doi:10.4103/0976-3147.102603
PMCID: PMC3505314  PMID: 23188975
Cause-of-death; stroke; validation; verbal autopsy
21.  Causes of death in Japanese diabetics: A questionnaire survey of 18,385 diabetics over a 10‐year period 
Abstract
We collated and analysed data from hospital records regarding the cause of death of 18,385 patients with diabetes who died in 282 medical institutions throughout Japan over the 10‐year period between 1991 and 2000. Autopsy was carried out in 1750 cases. The most frequent cause of death in all 18,385 cases was malignant neoplasia, accounting for 34.1% of cases, followed by vascular diseases (including diabetic nephropathy, ischemic heart diseases and cerebrovascular diseases) in 26.8%, infections in 14.3%, and then diabetic coma in 1.2%. The most common malignancy was liver cancer, accounting for 8.6% of all the deaths. Of the deaths from vascular diseases, diabetic nephropathy was the cause of death in 6.8% of cases, and the frequency as cause of death for ischemic heart diseases and cerebrovascular diseases were similar at 10.2% and 9.8%, respectively. Myocardial infarction accounted for almost all the deaths from ischemic heart diseases, whereas deaths from cerebral infarction were 2.2‐fold as common as those from cerebral hemorrhage. In the analyses of the relationship between age and causes of death in diabetic patients who underwent autopsy, the overall mortality rate as a result of vascular diseases increased with age, although the mortality rates from diabetic nephropathy and cerebrovascular diseases increased little from the fifth decade of life. The mortality rate from ischemic heart diseases increased with age, however, and was higher than the other forms of vascular diseases from the sixth decade of life, accounting for approximately 50% of vascular deaths in the eighth decade. Malignant neoplasia was the most frequent cause of death from the fifth decade of life, and was extremely common in the seventh decade, accounting for 46.3% of all the deaths. The mortality rate from infections varied little between age groups from the fifth decade of life. In the analyses of glycemic control and the age at the time of death, lifespans were 2.5 years shorter in males, and 1.6 years shorter in female diabetics with poor glycemic control than in those with good or fair glycemic control. This difference was greater for deaths as a result of infections and vascular diseases, particularly diabetic nephropathy, than for malignant neoplasia. Analysis of the relationship between glycemic control and the duration of diabetes and deaths as a result of vascular diseases showed no correlation between the level of glycemic control and death from diabetic nephropathy, ischemic heart diseases or cerebrovascular diseases. In diabetics with disease durations of less than 10 years, the mortality rate from macroangiopathy was higher than that as a result of diabetic nephropathy, a form of microangiopathy. Treatment for diabetes comprised of diet alone in 21.5%, oral hypoglycemic agents in 29.5%, and insulin with or without oral hypoglycemic agents in 44.2%, which was the most common. In particular, 683/1170 (58.4%) diabetics who died from diabetic nephropathy were on insulin therapy, a higher proportion than the 661/1687 (39.2%) who died from ischemic heart diseases, or the 659/1622 (40.6%) who died from cerebrovascular diseases. The average age at the time of death in the survey population was, 68 years for males and 71.6 years for females. These were 9.6 and 13 years, respectively, short of the average life expectancy for the Japanese general population. In comparison with the previous survey (1981–1990), the average age at the time of death had increased 1.5 years for males, and 3.2 years for females. The average life expectancy for the Japanese general population had also increased 1.7 and 2.7 years, respectively, over that period, showing that advances in the management and treatment of diabetes have not led to any improvement in patients’ life expectancies. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00019.x, 2010)
doi:10.1111/j.2040-1124.2010.00019.x
PMCID: PMC4020680  PMID: 24843411
Causes of death in Japanese diabetics; Average age at the time of death; Diabetic nephropathy; Ischemic heart diseases; Cerebrovascular diseases
22.  Lipoprotein(a) Concentration and the Risk of Coronary Heart Disease, Stroke, and Nonvascular Mortality 
Context
Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein–like particle, may be associated with risk of coronary heart disease (CHD) and stroke.
Objective
To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.
Study Selection
Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators.
Data Extraction
Individual records were provided for each of 126 634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22 076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline.
Data Synthesis
Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer.
Conclusion
Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.
doi:10.1001/jama.2009.1063
PMCID: PMC3272390  PMID: 19622820
23.  Analysing Recent Socioeconomic Trends in Coronary Heart Disease Mortality in England, 2000–2007: A Population Modelling Study 
PLoS Medicine  2012;9(6):e1001237.
A modeling study conducted by Madhavi Bajekal and colleagues estimates the extent to which specific risk factors and changes in uptake of treatment contributed to the declines in coronary heart disease mortality in England between 2000 and 2007, across and within socioeconomic groups.
Background
Coronary heart disease (CHD) mortality in England fell by approximately 6% every year between 2000 and 2007. However, rates fell differentially between social groups with inequalities actually widening. We sought to describe the extent to which this reduction in CHD mortality was attributable to changes in either levels of risk factors or treatment uptake, both across and within socioeconomic groups.
Methods and Findings
A widely used and replicated epidemiological model was used to synthesise estimates stratified by age, gender, and area deprivation quintiles for the English population aged 25 and older between 2000 and 2007. Mortality rates fell, with approximately 38,000 fewer CHD deaths in 2007. The model explained about 86% (95% uncertainty interval: 65%–107%) of this mortality fall. Decreases in major cardiovascular risk factors contributed approximately 34% (21%–47%) to the overall decline in CHD mortality: ranging from about 44% (31%–61%) in the most deprived to 29% (16%–42%) in the most affluent quintile. The biggest contribution came from a substantial fall in systolic blood pressure in the population not on hypertension medication (29%; 18%–40%); more so in deprived (37%) than in affluent (25%) areas. Other risk factor contributions were relatively modest across all social groups: total cholesterol (6%), smoking (3%), and physical activity (2%). Furthermore, these benefits were partly negated by mortality increases attributable to rises in body mass index and diabetes (−9%; −17% to −3%), particularly in more deprived quintiles. Treatments accounted for approximately 52% (40%–70%) of the mortality decline, equitably distributed across all social groups. Lipid reduction (14%), chronic angina treatment (13%), and secondary prevention (11%) made the largest medical contributions.
Conclusions
The model suggests that approximately half the recent CHD mortality fall in England was attributable to improved treatment uptake. This benefit occurred evenly across all social groups. However, opposing trends in major risk factors meant that their net contribution amounted to just over a third of the CHD deaths averted; these also varied substantially by socioeconomic group. Powerful and equitable evidence-based population-wide policy interventions exist; these should now be urgently implemented to effectively tackle persistent inequalities.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease is a chronic medical condition in which the blood vessels supplying the heart muscle become narrowed or even blocked by fatty deposits on the inner linings of the blood vessels—a process known as arthrosclerosis; this restricts blood flow to the heart, and if the blood vessels completely occlude, it may cause a heart attack. Lifestyle behaviors, such as unhealthy diets high in saturated fat, smoking, and physical inactivity, are the main risk factors for coronary heart disease, so efforts to reduce this condition are directed towards these factors. Global rates of coronary heart disease are increasing and the World Health Organization estimates that by 2030, it will be the biggest cause of death worldwide. However, in high-income countries, such as England, deaths due to coronary heart disease have actually fallen substantially over the past few decades with an accelerated reduction in annual death rates since 2000.
Why Was This Study Done?
Socioeconomic factors play an important role in chronic diseases such as coronary heart disease, with mortality rates almost twice as high in deprived than affluent areas. However, the potential effect of population-wide interventions on reducing inequalities in deaths from coronary heart disease remains unclear. So in this study, the researchers investigated the role of behavioral (changing lifestyle) and medical (treatments) management of coronary heart disease that contributed to the decrease in deaths in England for the period 2000–2007, within and between socioeconomic groups.
What Did the Researchers Do and Find?
The researchers used a well-known, tried and tested epidemiological model (IMPACT) but adapted it to include socioeconomic inequalities to analyze the total population of England aged 25 and older in 2000 and in 2007. The researchers included all the major risk factors for coronary heart disease plus 45 current medical and surgical treatments in their model. They used the Index of Multiple Deprivation 2007 as a proxy indicator of socioeconomic circumstances of residents in neighborhoods. Using the postal code of residence, the researchers matched deaths from, and patients treated for, coronary heart disease to the corresponding deprivation category (quintile). Changes in risk factor levels in each quintile were also calculated using the Health Survey for England. Using their model, the researchers calculated the total number of deaths prevented or postponed for each deprivation quintile by measuring the difference between observed deaths in 2007 and expected deaths based on 2000 data, if age, sex, and deprivation quintile death rates had remained the same.
The researchers found that between 2000 and 2007, death rates from coronary heart disease fell from 229 to 147 deaths per 100,000—a decrease of 36%. Both death rates and the number of deaths were lowest in the most affluent quintile and the pace of fall was also faster, decreasing by 6.7% per year compared to just 4.9% in the most deprived quintile. Furthermore, the researchers found that overall, about half of the decrease in death rates was attributable to improvements in uptake of medical and surgical treatments. The contribution of medical treatments to the deaths averted was very similar across all quintiles, ranging from 50% in the most affluent quintile to 53% in the most deprived. Risk factor changes accounted for approximately a third fewer deaths in 2007 than occurred in 2000, but were responsible for a smaller proportion of deaths prevented in the most affluent quintile compared with the most deprived (approximately 29% versus 44%, respectively). However, the benefits of improvements in blood pressure, cholesterol, smoking, and physical activity were partly negated by rises in body mass index and diabetes, particularly in more deprived quintiles.
What Do These Findings Mean?
These findings suggest that approximately half the recent substantial fall in deaths from coronary heart disease in England was attributable to improved treatment uptake across all social groups; this is consistent with equitable service delivery across the UK's National Health Service. However, opposing trends in major risk factors, which varied substantially by socioeconomic group, meant that their net contribution accounted for just a third of deaths averted. Other countries have implemented effective, evidence-based interventions to tackle lifestyle risk factors; the most powerful measures involve legislation, regulation, taxation, or subsidies, all of which tend to be equitable. Such measures should be urgently implemented in England to effectively tackle persistent inequalities in deaths due to coronary heart disease.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001237.
The World Health Organization has information about the global statistics of coronary heart disease
The National Heart Lung and Blood Institute provides a patient-friendly description of coronary heart disease
The National Heart Forum is the leading UK organization facilitating the prevention of coronary heart disease and other chronic diseases
The British Heart Foundation supports research and promotes preventative activity
Heart of Mersey is the UK's largest regional organization promoting the prevention of coronary heart disease and other chronic diseases
More information about the social determinants of health is available from WHO
doi:10.1371/journal.pmed.1001237
PMCID: PMC3373639  PMID: 22719232
24.  Agreement Between Nosologist and Cardiovascular Health Study Review of Deaths: Implications of Coding Differences 
Objectives
To compare nosologist coding of death certificate’s underlying cause of death with adjudicated cause of death for subjects age 65+ in the Cardiovascular Health Study (CHS).
Design
Observational study.
Setting
Four communities: Forsyth County North Carolina (Wake Forest University), Sacramento County California (University of California at Davis), Washington County Maryland (Johns Hopkins University), and Pittsburgh Pennsylvania (University of Pittsburgh).
Participants
Men and women ages 65 and over participating in CHS, a longitudinal study of coronary heart disease and stroke, and who died through June 2004.
Measurements
The CHS centrally adjudicated underlying cause of death for 3194 fatal events from 6/1989–6/2004 using medical records, death certificates, proxy interviews and autopsies, and results were compared with underlying cause of death assigned by a trained nosologist based on death certificate only.
Results
Comparison of 3194 CHS vs. nosologist underlying cause of death revealed moderate agreement except for cancer (kappa=0.91, 95% CI:0.89–0.93). Kappas varied by category: CHD=0.61 (95% CI:0.58–0.64), stroke=0.59 (95% CI:0.54–0.64), COPD=0.58 (95% CI:0.51–0.65), dementia=0.40 (95% CI:0.34–0.45), and pneumonia=0.35 (95% CI:0.29–0.42). Differences between CHS and nosologist coding of dementia were found especially in older ages in both sex and race categories. CHS classified 340 (10.6%) of deaths due to dementia, while nosologist coding classified only 113 (3.5%) with dementia as the underlying cause.
Conclusion
Studies that use only death certificates to determine cause of death may result in misclassification and potential bias. Changing trends in cause-specific mortality in older individuals may be a function of classification process rather than incidence and case fatality.
doi:10.1111/j.1532-5415.2008.02056.x
PMCID: PMC2631612  PMID: 19016930
death certificates; mortality; vital statistics
25.  Predicting Stroke Risk in Hypertensive Patients With Coronary Artery Disease 
Background and Purpose
Our understanding of factors influencing stroke risk among patients with coronary artery disease is incomplete. Accordingly, factors predicting stroke risk in hypertensive, clinically stable coronary artery disease patients were determined with data from the INternational VErapamil SR-trandolapril STudy (INVEST).
Methods
The effect of baseline characteristics and on-treatment blood pressure (BP) were analyzed to determine the risk of stroke (fatal or nonfatal) among the 22 576 patients enrolled. Cox proportional-hazards models (unadjusted, adjusted, and time dependent) were used to identify predictors of stroke among subgroups with these characteristics present at entry and on-treatment BP.
Results
Excellent BP control (at 24 months, >70% <140/90 mm Hg) was achieved during 61 835 patient-years of follow-up, as 377 patients had a stroke (6.1 strokes/1000 patient-years) and 28% of those patients had a fatal stroke. Increased age, black race, US residency, and history of prior myocardial infarction, smoking, stroke/transient ischemic attack, arrhythmia, diabetes, and coronary bypass surgery were associated with an increased risk of stroke. Achieving a systolic BP <140 mm Hg and a diastolic BP <90 mm Hg was associated with a decreased risk of stroke. There was no statistically significant difference in stroke risk comparing the verapamil SR–based with the atenolol-based treatment strategy (adjusted hazard ratio=0.87; 95% CI, 0.71 to 1.06; P=0.17).
Conclusions
Among hypertensive patients with chronic coronary artery disease, stroke was an important complication associated with significant mortality. Black race, US residency, and conditions associated with increased vascular disease severity and arrhythmia predicted increased stroke risk, whereas achieving a BP <140/90 mm Hg on treatment predicted a reduced stroke risk.
doi:10.1161/STROKEAHA.107.495465
PMCID: PMC2805179  PMID: 18162623
atenolol; coronary artery disease; hydrochlorothiazide; hypertension; stroke; trandolapril; verapamil SR

Results 1-25 (710850)