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1.  Future Declines of Coronary Heart Disease Mortality in England and Wales Could Counter the Burden of Population Ageing 
PLoS ONE  2014;9(6):e99482.
Background
Coronary Heart Disease (CHD) remains a major cause of mortality in the United Kingdom. Yet predictions of future CHD mortality are potentially problematic due to population ageing and increase in obesity and diabetes. Here we explore future projections of CHD mortality in England & Wales under two contrasting future trend assumptions.
Methods
In scenario A, we used the conventional counterfactual scenario that the last-observed CHD mortality rates from 2011 would persist unchanged to 2030. The future number of deaths was calculated by applying those rates to the 2012–2030 population estimates. In scenario B, we assumed that the recent falling trend in CHD mortality rates would continue. Using Lee-Carter and Bayesian Age Period Cohort (BAPC) models, we projected the linear trends up to 2030. We validate our methods using past data to predict mortality from 2002–2011. Then, we computed the error between observed and projected values.
Results
In scenario A, assuming that 2011 mortality rates stayed constant by 2030, the number of CHD deaths would increase 62% or approximately 39,600 additional deaths. In scenario B, assuming recent declines continued, the BAPC model (the model with lowest error) suggests the number of deaths will decrease by 56%, representing approximately 36,200 fewer deaths by 2030.
Conclusions
The decline in CHD mortality has been reasonably continuous since 1979, and there is little reason to believe it will soon halt. The commonly used assumption that mortality will remain constant from 2011 therefore appears slightly dubious. By contrast, using the BAPC model and assuming continuing mortality falls offers a more plausible prediction of future trends. Thus, despite population ageing, the number of CHD deaths might halve again between 2011 and 2030. This has implications for how the potential benefits of future cardiovascular strategies might best be calculated and presented.
doi:10.1371/journal.pone.0099482
PMCID: PMC4053422  PMID: 24918442
2.  Cardiovascular Health Behavior and Health Factor Changes (1988 –2008) and Projections to 2020 
Circulation  2012;125(21):2595-2602.
Background
The American Heart Association’s 2020 Strategic Impact Goals target a 20% relative improvement in overall cardiovascular health with the use of 4 health behavior (smoking, diet, physical activity, body mass) and 3 health factor (plasma glucose, cholesterol, blood pressure) metrics. We sought to define current trends and forward projections to 2020 in cardiovascular health.
Methods and Results
We included 35 059 cardiovascular disease–free adults (aged ≥20 years) from the National Health and Nutrition Examination Survey 1988–1994 and subsequent 2-year cycles during 1999–2008. We calculated population prevalence of poor, intermediate, and ideal health behaviors and factors and also computed a composite, individual-level Cardiovascular Health Score for all 7 metrics (poor=0 points; intermediate=1 point; ideal=2 points; total range, 0–14 points). Prevalence of current and former smoking, hypercholesterolemia, and hypertension declined, whereas prevalence of obesity and dysglycemia increased through 2008. Physical activity levels and low diet quality scores changed minimally. Projections to 2020 suggest that obesity and impaired fasting glucose/diabetes mellitus could increase to affect 43% and 77% of US men and 42% and 53% of US women, respectively. Overall, population-level cardiovascular health is projected to improve by 6% overall by 2020 if current trends continue. Individual-level Cardiovascular Health Score projections to 2020 (men=7.4 [95% confidence interval, 5.7–9.1]; women=8.8 [95% confidence interval, 7.6–9.9]) fall well below the level needed to achieve a 20% improvement (men=9.4; women=10.1).
Conclusions
The American Heart Association 2020 target of improving cardiovascular health by 20% by 2020 will not be reached if current trends continue.
doi:10.1161/CIRCULATIONAHA.111.070722
PMCID: PMC3914399  PMID: 22547667
cardiovascular disease risk factors; epidemiology; risk factors; trends
3.  Population Assessment of Future Trajectories in Coronary Heart Disease Mortality 
PLoS ONE  2014;9(1):e85800.
Background
Coronary heart disease (CHD) mortality rates have been decreasing in Iceland since the 1980s, largely reflecting improvements in cardiovascular risk factors. The purpose of this study was to predict future CHD mortality in Iceland based on potential risk factor trends.
Methods and findings
The previously validated IMPACT model was used to predict changes in CHD mortality between 2010 and 2040 among the projected population of Iceland aged 25–74. Calculations were based on combining: i) data on population numbers and projections (Statistics Iceland), ii) population risk factor levels and projections (Refine Reykjavik study), and iii) effectiveness of specific risk factor reductions (published meta-analyses). Projections for three contrasting scenarios were compared: 1) If the historical risk factor trends of past 30 years were to continue, the declining death rates of past decades would level off, reflecting population ageing. 2) If recent trends in risk factors (past 5 years) continue, this would result in a death rate increasing from 49 to 70 per 100,000. This would reflect a recent plateau in previously falling cholesterol levels and recent rapid increases in obesity and diabetes prevalence. 3) Assuming that in 2040 the entire population enjoys optimal risk factor levels observed in low risk cohorts, this would prevent almost all premature CHD deaths before 2040.
Conclusions
The potential increase in CHD deaths with recent trends in risk factor levels is alarming both for Iceland and probably for comparable Western populations. However, our results show considerable room for reducing CHD mortality. Achieving the best case scenario could eradicate premature CHD deaths by 2040. Public health policy interventions based on these predictions may provide a cost effective means of reducing CHD mortality in the future.
doi:10.1371/journal.pone.0085800
PMCID: PMC3897505  PMID: 24465713
4.  Continuing decrease in coronary heart disease mortality in Sweden 
Background
Deaths from coronary heart disease (CHD) have been decreasing in most Western countries over the last few decades. In contrast, a flattening of the decrease in mortality has been recently reported among younger age groups in some countries. We aimed to determine whether the decrease in CHD mortality is flattening among Swedish young adults.
Methods
We examined trends in CHD mortality in Sweden between 1987 and 2009 among persons aged 35 to 84 years using CHD mortality data from the Swedish National Register on Cause of Death. Annual percent changes in rates were examined using Joinpoint software.
Results
Overall, CHD mortality rates decreased by 67.4% in men and 65.1% in women. Among men aged 35–54 years, there was a modest early attenuation from a marked initial decrease. In the oldest women aged 75–84 years, an attenuation in the mortality decrease was observed from 1989 to 1992, followed by a decrease, as in all other age groups.
Conclusions
In Sweden, coronary heart disease deaths are still falling. We were unable to confirm a flattening of the decline in young people. Death rates continue to decline in men and women across all age groups, albeit at a slower pace in younger men since 1991. Continued careful monitoring of CHD mortality trends in Sweden is required, particularly among young adults.
doi:10.1186/1471-2261-14-9
PMCID: PMC3930358  PMID: 24447603
Myocardial ischemia; Mortality; Risk factors; Coronary heart disease
5.  A Cost Effectiveness Analysis of Salt Reduction Policies to Reduce Coronary Heart Disease in Four Eastern Mediterranean Countries 
PLoS ONE  2014;9(1):e84445.
Background
Coronary Heart Disease (CHD) is rising in middle income countries. Population based strategies to reduce specific CHD risk factors have an important role to play in reducing overall CHD mortality. Reducing dietary salt consumption is a potentially cost-effective way to reduce CHD events. This paper presents an economic evaluation of population based salt reduction policies in Tunisia, Syria, Palestine and Turkey.
Methods and Findings
Three policies to reduce dietary salt intake were evaluated: a health promotion campaign, labelling of food packaging and mandatory reformulation of salt content in processed food. These were evaluated separately and in combination. Estimates of the effectiveness of salt reduction on blood pressure were based on a literature review. The reduction in mortality was estimated using the IMPACT CHD model specific to that country. Cumulative population health effects were quantified as life years gained (LYG) over a 10 year time frame. The costs of each policy were estimated using evidence from comparable policies and expert opinion including public sector costs and costs to the food industry. Health care costs associated with CHDs were estimated using standardized unit costs. The total cost of implementing each policy was compared against the current baseline (no policy). All costs were calculated using 2010 PPP exchange rates. In all four countries most policies were cost saving compared with the baseline. The combination of all three policies (reducing salt consumption by 30%) resulted in estimated cost savings of $235,000,000 and 6455 LYG in Tunisia; $39,000,000 and 31674 LYG in Syria; $6,000,000 and 2682 LYG in Palestine and $1,3000,000,000 and 378439 LYG in Turkey.
Conclusion
Decreasing dietary salt intake will reduce coronary heart disease deaths in the four countries. A comprehensive strategy of health education and food industry actions to label and reduce salt content would save both money and lives.
doi:10.1371/journal.pone.0084445
PMCID: PMC3883693  PMID: 24409297
6.  Preventing type 2 diabetes among Palestinians: comparing five future policy scenarios 
BMJ Open  2013;3(12):e003558.
Objective
This paper aims to provide estimates of future diabetes prevalence in the West Bank, occupied Palestinian territory (oPt), and to compare five future policy scenarios for diabetes prevention.
Design
We created and refined a mathematical Markov model that integrates population, obesity and smoking trends to estimate future diabetes prevalence. Model parameters were derived from the literature. Diabetes incidence was estimated using DISMOD software. We developed the model for the Palestinian population based on data available for the period 2000–2010, and validated the model by comparing predicted diabetes prevalence to subsequent actual observed diabetes prevalence rates.
Setting
West Bank oPt.
Results
Palestinian diabetes mellitus prevalence estimated by the model (for adults aged 25 or more) was 9.7% in 2000, increasing to 15.3% by 2010. Prevalence in men increased from 9.1% to 16.9% and in women from 10.2% to 13.6%. Comparisons of the model results with the observed prevalence in the Palestinian Family Health Survey showed a close fit. The model forecasts were 20.8% for 2020 and 23.4% for 2030. A 2.8% reduction in diabetes prevalence could be achieved if obesity trends start to decline by 5% in a 5-year period. If obesity prevalence was reduced by 35% in 10 years, as suggested by the WHO, diabetes prevalence might be decreased by 20%.
Conclusions
The model estimates an increase in the prevalence of diabetes which poses a large challenge to the health system. However, if bold but reasonable action is taken, effective interventions could reduce diabetes prevalence and hence the number of patients with diabetes.
doi:10.1136/bmjopen-2013-003558
PMCID: PMC3884589  PMID: 24362011
7.  Reduction in myocardial infarction admissions in Liverpool after the smoking ban: potential socioeconomic implications for policymaking 
BMJ Open  2013;3(11):e003307.
Objectives
To analyse the trends and trend changes in myocardial infraction (MI) and coronary heart disease (CHD) admissions, to investigate the effects of the 2007 smoke-free legislation on these trends, and to consider the policy implications of any findings.
Design setting
Liverpool (city), UK.
Participants
Hospital episode statistics data on all 56 995 admissions for CHD in Liverpool between 2004 and 2012 (International Classification of Diseases codes I20–I25 coded as an admission diagnosis within the defined dates).
Primary and secondary outcome measures
Trend gradient and change points (by trend regressions analysis) in age-standardised MI admissions in Liverpool between 2004 and 2012; by sex and by socioeconomic status. Secondary analysis on CHD admissions.
Results
A significant and sustained reduction was seen in MI admissions in Liverpool beginning within 1 year of the smoking ban. Comparing 2005/2006 and 2010/2011, the age-adjusted rates for MI admissions fell by 42% (39–45%) (41.6% in men and by 42.6% in women). Trend analysis shows that this is significantly greater than the background trend of decreasing admissions. These reductions appeared consistent across all socioeconomic groups. Interestingly, admission rates for total CHD (including mild to severe angina) increased by 10% (8–12%).
Conclusions
A dramatic reduction in MI admissions in Liverpool has been observed coinciding with the smoking ban in 2007. Furthermore, the benefits were apparent across the socioeconomic spectrum. Health inequalities were not affected and may even have been reduced. The rapid effects observed with this top-down, environmental policy may further increase its value to policymakers.
doi:10.1136/bmjopen-2013-003307
PMCID: PMC3845049  PMID: 24282240
PUBLIC HEALTH; EPIDEMIOLOGY
8.  Myocardial infarction incidence and survival by ethnic group: Scottish Health and Ethnicity Linkage retrospective cohort study 
BMJ Open  2013;3(9):e003415.
Objective
Inequalities in coronary heart disease mortality by country of birth are large and poorly understood. However, these data misclassify UK-born minority ethnic groups and provide little detail on whether excess risk is due to increased incidence, poorer survival or both.
Design
Retrospective cohort study.
Setting
General resident population of Scotland.
Participants
All those residing in Scotland during the 2001 Census were eligible for inclusion: 2 972 120 people were included in the analysis. The number still residing in Scotland at the end of the study in 2008 is not known.
Primary and secondary outcome measures
As specified in the analysis plan, the primary outcome measures were first occurrence of admission or death due to myocardial infarction and time to event. There were no secondary outcome measures.
Results
Acute myocardial infarction (AMI) incidence risk ratios (95% CIs) relative to white Scottish populations (100) were highest among Pakistani men (164.1 (142.2 to 189.2)) and women (153.7 (120.5, 196.1)) and lowest for men and women of Chinese (39.5 (27.1 to 57.6) and 59.1 (38.6 to 90.7)), other white British (77 (74.2 to 79.8) and 72.2 (69.0 to 75.5)) and other white (83.1 (75.9 to 91.0) and 79.9 (71.5 to 89.3)) ethnic groups. Adjustment for educational qualification did not eliminate these differences. Cardiac intervention uptake was similar across most ethnic groups. Compared to white Scottish, 28-day survival did not differ by ethnicity, except in Pakistanis where it was better, particularly in women (0.44 (0.25 to 0.78)), a difference not removed by adjustment for education, travel time to hospital or cardiac intervention uptake.
Conclusions
Pakistanis have the highest incidence of AMI in Scotland, a country renowned for internationally high cardiovascular disease rates. In contrast, survival is similar or better in minority ethnic groups. Clinical care and policy should focus on reducing incidence among Pakistanis through more aggressive prevention.
doi:10.1136/bmjopen-2013-003415
PMCID: PMC3773657  PMID: 24038009
Epidemiology; Public Health
9.  Quantifying Policy Options for Reducing Future Coronary Heart Disease Mortality in England: A Modelling Study 
PLoS ONE  2013;8(7):e69935.
Aims
To estimate the number of coronary heart disease (CHD) deaths potentially preventable in England in 2020 comparing four risk factor change scenarios.
Methods and Results
Using 2007 as baseline, the IMPACTSEC model was extended to estimate the potential number of CHD deaths preventable in England in 2020 by age, gender and Index of Multiple Deprivation 2007 quintiles given four risk factor change scenarios: (a) assuming recent trends will continue; (b) assuming optimal but feasible levels already achieved elsewhere; (c) an intermediate point, halfway between current and optimal levels; and (d) assuming plateauing or worsening levels, the worst case scenario. These four scenarios were compared to the baseline scenario with both risk factors and CHD mortality rates remaining at 2007 levels. This would result in approximately 97,000 CHD deaths in 2020. Assuming recent trends will continue would avert approximately 22,640 deaths (95% uncertainty interval: 20,390-24,980). There would be some 39,720 (37,120-41,900) fewer deaths in 2020 with optimal risk factor levels and 22,330 fewer (19,850-24,300) in the intermediate scenario. In the worst case scenario, 16,170 additional deaths (13,880-18,420) would occur. If optimal risk factor levels were achieved, the gap in CHD rates between the most and least deprived areas would halve with falls in systolic blood pressure, physical inactivity and total cholesterol providing the largest contributions to mortality gains.
Conclusions
CHD mortality reductions of up to 45%, accompanied by significant reductions in area deprivation mortality disparities, would be possible by implementing optimal preventive policies.
doi:10.1371/journal.pone.0069935
PMCID: PMC3723729  PMID: 23936122
10.  Modelling the impact of specific food policy options on coronary heart disease and stroke deaths in Ireland 
BMJ Open  2013;3(7):e002837.
Objective
To estimate the potential reduction in cardiovascular (CVD) mortality possible by decreasing salt, trans fat and saturated fat consumption, and by increasing fruit and vegetable (F/V) consumption in Irish adults aged 25–84 years for 2010.
Design
Modelling study using the validated IMPACT Food Policy Model across two scenarios. Sensitivity analysis was undertaken. First, a conservative scenario: reductions in dietary salt by 1 g/day, trans fat by 0.5% of energy intake, saturated fat by 1% energy intake and increasing F/V intake by 1 portion/day. Second, a more substantial but politically feasible scenario: reductions in dietary salt by 3 g/day, trans fat by 1% of energy intake, saturated fat by 3% of energy intake and increasing F/V intake by 3 portions/day.
Setting
Republic of Ireland.
Outcomes
Coronary heart disease (CHD) and stroke deaths prevented.
Results
The small, conservative changes in food policy could result in approximately 395 fewer cardiovascular deaths per year; approximately 190 (minimum 155, maximum 230) fewer CHD deaths in men, 50 (minimum 40, maximum 60) fewer CHD deaths in women, 95 (minimum 75, maximum 115) fewer stroke deaths in men, and 60 (minimum 45, maximum 70) fewer stroke deaths in women. Approximately 28%, 22%, 23% and 26% of the 395 fewer deaths could be attributable to decreased consumptions in trans fat, saturated fat, dietary salt and to increased F/V consumption, respectively. The 395 fewer deaths represent an overall 10% reduction in CVD mortality. Modelling the more substantial but feasible food policy options, we estimated that CVD mortality could be reduced by up to 1070 deaths/year, representing an overall 26% decline in CVD mortality.
Conclusions
A considerable CVD burden is attributable to the excess consumption of saturated fat, trans fat, salt and insufficient fruit and vegetables. There are significant opportunities for Government and industry to reduce CVD mortality through effective, evidence-based food policies.
doi:10.1136/bmjopen-2013-002837
PMCID: PMC3703570  PMID: 23824313
Modelling; Salt; Saturated Fat; Ireland
11.  Forecasting future prevalence of type 2 diabetes mellitus in Syria 
BMC Public Health  2013;13:507.
Background
Type 2 diabetes mellitus (T2DM) is increasingly becoming a major public health problem worldwide. Estimating the future burden of diabetes is instrumental to guide the public health response to the epidemic. This study aims to project the prevalence of T2DM among adults in Syria over the period 2003–2022 by applying a modelling approach to the country’s own data.
Methods
Future prevalence of T2DM in Syria was estimated among adults aged 25 years and older for the period 2003–2022 using the IMPACT Diabetes Model (a discrete-state Markov model).
Results
According to our model, the prevalence of T2DM in Syria is projected to double in the period between 2003 and 2022 (from 10% to 21%). The projected increase in T2DM prevalence is higher in men (148%) than in women (93%). The increase in prevalence of T2DM is expected to be most marked in people younger than 55 years especially the 25–34 years age group.
Conclusions
The future projections of T2DM in Syria put it amongst countries with the highest levels of T2DM worldwide. It is estimated that by 2022 approximately a fifth of the Syrian population aged 25 years and older will have T2DM.
doi:10.1186/1471-2458-13-507
PMCID: PMC3673829  PMID: 23705638
12.  Trends in Total and Low-Density Lipoprotein Cholesterol among U.S. Adults: Contributions of Changes in Dietary Fat Intake and Use of Cholesterol-Lowering Medications 
PLoS ONE  2013;8(5):e65228.
Objective
Our aim was to examine the relative contributions of changes in dietary fat intake and use of cholesterol-lowering medications to changes in concentrations of total cholesterol among adults in the United States from 1988–1994 to 2007–2008.
Method
We used data from adults aged 20–74 years who participated in National Health and Nutrition Examination Surveys from 1988–1994 to 2007–2008. The effect of change in dietary fat intake on concentrations of total cholesterol was estimated by the use of equations developed by Keys, Hegsted, and successors.
Results
Age-adjusted mean concentrations of total cholesterol were 5.60 mmol/L (216 mg/dl) during 1988–1994 falling to 5.09 mmol/L (197 mg/dl) in 2007–2008 (P<0.001). No significant changes in the intake of total fat, saturated fat, polyunsaturated fat, and dietary cholesterol were observed from 1988–1994 to 2007–2008. However, the age-adjusted use of cholesterol-lowering medications increased from 1.6% to 12.5% (P<0.001). The various equations suggested that changes in dietary fat made minimal contributions to the observed trend in mean concentrations of total cholesterol. The increased use of cholesterol-lowering medications was estimated to account for approximately 46% of the change.
Discussion
Mean concentrations of total cholesterol among adults in the United States have declined by ∼4% since 1988–1994. The increased use of cholesterol-lowering medications has apparently accounted for about half of this small fall. Further substantial decreases in cholesterol might be potentially achievable by implementing effective and feasible public health interventions to promote the consumption of a more healthful diet by US adults.
Disclaimer
The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
doi:10.1371/journal.pone.0065228
PMCID: PMC3661527  PMID: 23717695
13.  Unequal Trends in Coronary Heart Disease Mortality by Socioeconomic Circumstances, England 1982–2006: An Analytical Study 
PLoS ONE  2013;8(3):e59608.
Background
Coronary heart disease (CHD) remains a major public health burden, causing 80,000 deaths annually in England and Wales, with major inequalities. However, there are no recent analyses of age-specific socioeconomic trends in mortality. We analysed annual trends in inequalities in age-specific CHD mortality rates in small areas in England, grouped into deprivation quintiles.
Methods
We calculated CHD mortality rates for 10-year age groups (from 35 to ≥85 years) using three year moving averages between 1982 and 2006. We used Joinpoint regression to identify significant turning points in age- sex- and deprivation-specific time trends. We also analysed trends in absolute and relative inequalities in age-standardised rates between the least and most deprived areas.
Results
Between 1982 and 2006, CHD mortality fell by 62.2% in men and 59.7% in women. Falls were largest for the most deprived areas with the highest initial level of CHD mortality. However, a social gradient in the pace of fall was apparent, being steepest in the least deprived quintile. Thus, while absolute inequalities narrowed over the period, relative inequalities increased. From 2000, declines in mortality rates slowed or levelled off in the youngest groups, notably in women aged 45–54 in the least deprived groups. In contrast, from age 55 years and older, rates of fall in CHD mortality accelerated in the 2000s, likewise falling fastest in the least deprived quintile.
Conclusions
Age-standardised CHD mortality rates have declined substantially in England, with the steepest falls in the most affluent quintiles. However, this concealed contrasting patterns in underlying age-specific rates. From 2000, mortality rates levelled off in the youngest groups but accelerated in middle aged and older groups. Mortality analyses by small areas could provide potentially valuable insights into possible drivers of inequalities, and thus inform future strategies to reduce CHD mortality across all social groups.
doi:10.1371/journal.pone.0059608
PMCID: PMC3603902  PMID: 23527228
14.  Changing patterns of cardiovascular diseases and cancer mortality in Portugal, 1980–2010 
BMC Public Health  2012;12:1126.
Background
Cardiovascular diseases and cancer are jointly responsible for more than half all deaths in Portugal. They also share some important risk factors and act as mutual competing risks. We aimed firstly to describe time trends in death rates and years of life lost due to cardiovascular diseases and cancer in the Portuguese population from 1980 to 2010; and secondly to quantify the contribution of the variation in population and age structure, and age-independent “risk” by cardiovascular or oncological causes to the change in the corresponding number of deaths.
Methods
We estimated the annual percent change in age-standardized mortality rates from cardiovascular diseases and cancer, in each sex. The specific contribution of demographic changes (due to changes in population size and in population age structure) and the variation in the age-independent “risk” of dying from the disease to the observed trends in the number of deaths was quantified using the tool RiskDiff. Years of life lost were computed using the Global Burden of Disease method.
Results
Among men, the mortality rate from all cardiovascular diseases was more than two-fold higher than cancer mortality in 1980. However, three decades later mortality from cancer surpassed cardiovascular diseases. After 2005, the years of life lost from cancer were also higher than from cardiovascular diseases. Among women, despite the decrease in death rates, cardiovascular diseases remained the leading cause of death in 2010 and their absolute burden was higher than that of cancers across the whole period, mainly due to more events in older women.
Conclusions
In Portugal, the 20th century witnessed a dramatic decrease in the cardiovascular disease mortality and YLL, and the transition towards cancer. In more recent years, the highest burdens of disease came from cancers in men and from cardiovascular diseases in women.
doi:10.1186/1471-2458-12-1126
PMCID: PMC3560231  PMID: 23273040
Cancer; Cardiovascular diseases; Mortality; Trends; Portugal
15.  Explaining the increase in coronary heart disease mortality in Syria between 1996 and 2006 
BMC Public Health  2012;12:754.
Background
Despite advances made in treating coronary heart disease (CHD), mortality due to CHD in Syria has been increasing for the past two decades. This study aims to assess CHD mortality trends in Syria between 1996 and 2006 and to investigate the main factors associated with them.
Methods
The IMPACT model was used to analyze CHD mortality trends in Syria based on numbers of CHD patients, utilization of specific treatments, trends in major cardiovascular risk factors in apparently healthy persons and CHD patients. Data sources for the IMPACT model included official statistics, published and unpublished surveys, data from neighboring countries, expert opinions, and randomized trials and meta-analyses.
Results
Between 1996 and 2006, CHD mortality rate in Syria increased by 64%, which translates into 6370 excess CHD deaths in 2006 as compared to the number expected had the 1996 baseline rate held constant. Using the IMPACT model, it was estimated that increases in cardiovascular risk factors could explain approximately 5140 (81%) of the CHD deaths, while some 2145 deaths were prevented or postponed by medical and surgical treatments for CHD.
Conclusion
Most of the recent increase in CHD mortality in Syria is attributable to increases in major cardiovascular risk factors. Treatments for CHD were able to prevent about a quarter of excess CHD deaths, despite suboptimal implementation. These findings stress the importance of population-based primary prevention strategies targeting major risk factors for CHD, as well as policies aimed at improving access and adherence to modern treatments of CHD.
doi:10.1186/1471-2458-12-754
PMCID: PMC3485167  PMID: 22958443
Coronary heart disease; Mortality; Modelling
16.  Analysing falls in coronary heart disease mortality in the West Bank between 1998 and 2009 
BMJ Open  2012;2(4):e001061.
Objectives
To analyse coronary heart disease (CHD) mortality and risk factor trends in the West Bank, occupied Palestinian territory between 1998 and 2009.
Design
Modelling study using CHD IMPACT model.
Setting
The West Bank, occupied Palestinian territory.
Participants
Data on populations, mortality, patient groups and numbers, treatments and cardiovascular risk factor trends were obtained from national and local surveys, routine national and WHO statistics, and critically appraised. Data were then integrated and analysed using a previously validated CHD model.
Primary and secondary outcome measures
CHD deaths prevented or postponed are the main outcome.
Results
CHD death rates fell by 20% in the West Bank, between 1998 and 2009. Smoking prevalence was initially high in men, 51%, but decreased to 42%. Population blood pressure levels and total cholesterol levels also decreased. Conversely, body mass index rose by 1–2 kg/m2 and diabetes increased by 2–8%. Population modelling suggested that more than two-thirds of the mortality fall was attributable to decreases in major risk factors, mainly total cholesterol, blood pressure and smoking. Approximately one-third of the CHD mortality decreases were attributable to treatments, particularly for secondary prevention and heart failure. However, the contributions from statins, surgery and angioplasty were consistently small.
Conclusions
CHD mortality fell by 20% between 1998 and 2009 in the West Bank. More than two-third of this fall was due to decreases in major risk factors, particularly total cholesterol and blood pressure. Our results clearly indicate that risk factor reductions in the general population compared save substantially more lives to specific treatments for individual patients. This emphasizes the importance of population-wide primary prevention strategies.
doi:10.1136/bmjopen-2012-001061
PMCID: PMC3432845  PMID: 22923626
Cardiology; Cardiac Epidemiology; Cardiology; Myocardial infarction; Epidemiology; Public Health; Surgery; Cardiac surgery
17.  Neighbourhood socioeconomic inequalities in incidence of acute myocardial infarction: a cohort study quantifying age- and gender-specific differences in relative and absolute terms 
BMC Public Health  2012;12:617.
Background
Socioeconomic status has a profound effect on the risk of having a first acute myocardial infarction (AMI). Information on socioeconomic inequalities in AMI incidence across age- gender-groups is lacking. Our objective was to examine socioeconomic inequalities in the incidence of AMI considering both relative and absolute measures of risk differences, with a particular focus on age and gender.
Methods
We identified all patients with a first AMI from 1997 to 2007 through linked hospital discharge and death records covering the Dutch population. Relative risks (RR) of AMI incidence were estimated by mean equivalent household income at neighbourhood-level for strata of age and gender using Poisson regression models. Socioeconomic inequalities were also shown within the stratified age-gender groups by calculating the total number of events attributable to socioeconomic disadvantage.
Results
Between 1997 and 2007, 317,564 people had a first AMI. When comparing the most deprived socioeconomic quintile with the most affluent quintile, the overall RR for AMI was 1.34 (95 % confidence interval (CI): 1.32 – 1.36) in men and 1.44 (95 % CI: 1.42 – 1.47) in women. The socioeconomic gradient decreased with age. Relative socioeconomic inequalities were most apparent in men under 35 years and in women under 65 years. The largest number of events attributable to socioeconomic inequalities was found in men aged 45–74 years and in women aged 65–84 years. The total proportion of AMIs that was attributable to socioeconomic inequalities in the Dutch population of 1997 to 2007 was 14 % in men and 18 % in women.
Conclusions
Neighbourhood socioeconomic inequalities were observed in AMI incidence in the Netherlands, but the magnitude across age-gender groups depended on whether inequality was expressed in relative or absolute terms. Relative socioeconomic inequalities were high in young persons and women, where the absolute burden of AMI was low. Absolute socioeconomic inequalities in AMI were highest in the age-gender groups of middle-aged men and elderly women, where the number of cases was largest.
doi:10.1186/1471-2458-12-617
PMCID: PMC3490806  PMID: 22870916
Coronary heart disease; Acute myocardial infarction; Incidence; Socioeconomic status; Relative; Absolute; The Netherlands
18.  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
19.  Trends in cardiovascular disease biomarkers and their socioeconomic patterning among adults in the Scottish population 1995 to 2009: cross-sectional surveys 
BMJ Open  2012;2(3):e000771.
Objectives
To examine secular and socioeconomic changes in biological cardiovascular disease risk factor and biomarker prevalences in the Scottish population. This could contribute to an understanding of why the decline in coronary heart disease mortality in Scotland has recently stalled along with persistence of associated socioeconomic inequalities.
Design
Cross-sectional surveys.
Setting
Scotland.
Participants
Scottish Health Surveys: 1995, 1998, 2003, 2008 and 2009 (6190, 6656, 5497, 4202 and 4964 respondents, respectively, aged 25–64 years).
Primary outcome measures
Gender-stratified, age-standardised prevalences of obesity, hypertension, hypercholesterolaemia and low high-density lipoprotein cholesterol blood concentration as well as elevated fibrinogen and C reactive protein concentrations according to education and social class groupings. Inequalities were assessed using the slope index of inequality, and time trends were assessed using linear regression.
Results
The prevalence of obesity, including central obesity, increased between 1995 and 2009 among men and women, irrespective of socioeconomic position. In 2009, the prevalence of obesity (defined by body mass index) was 29.8% (95% CI 27.9% to 31.7%) for men and 28.2% (26.3% to 30.2%) for women. The proportion of individuals with hypertension remained relatively unchanged between 1995 and 2008/2009, while the prevalence of hypercholesterolaemia declined in men from 79.6% (78.1% to 81.1%) to 63.8% (59.9% to 67.8%) and in women from 74.1% (72.6% to 75.7%) to 66.3% (62.6% to 70.0%). Socioeconomic inequalities persisted over time among men and women for most of the biomarkers and were particularly striking for the anthropometric measures when stratified by education.
Conclusions
If there are to be further declines in coronary heart disease mortality and reduction in associated inequalities, then there needs to be a favourable step change in the prevalence of cardiovascular disease risk factors. This may require radical population-wide interventions.
Article summary
Article focus
In Scotland, as in other developed countries, coronary heart disease mortality has substantially declined over time.
This decline may have slowed among younger ages and there are still large socioeconomic inequalities in mortality.
Examination of the secular and socioeconomic changes in biological cardiovascular disease risk factor and biomarker prevalences in the Scottish population.
Key messages
In Scotland, over a 14-year period since 1995, there has been a substantial increase in the prevalence of obesity with a persistence of large inequalities.
At the same time, the prevalence of hypertension has changed little, while that of hypercholesterolaemia has declined, albeit from a very high level. Inequalities were generally smaller and, in the case of cholesterol in men, ill defined.
Such trends can only serve to curb any further declines in coronary heart disease mortality and maintain associated inequalities.
Strengths and limitations of this study
This study utilised data from nationally representative surveys conducted over a 14-year period.
Bias may have been introduced by declining survey response levels. Differential non-response by the socioeconomically disadvantaged may lead to an underestimation of the magnitude of inequalities.
doi:10.1136/bmjopen-2011-000771
PMCID: PMC3364451  PMID: 22619264
20.  Associations between deprivation and rates of childhood overweight and obesity in England, 2007–2010: an ecological study 
BMJ Open  2012;2(2):e000463.
Objectives
To investigate the associations between deprivation and rates of childhood overweight and obesity in England, from 2007 to 2010.
Design
An ecological study using routine data from the National Child Measurement Programme and Indices of Multiple Deprivation (IMD) 2010 scores.
Setting
Local authority districts in England.
Participants
Schoolchildren in Reception year (age 4–5 years) and Year 6 (age 10–11 years) attending non-specialist maintained state schools in England.
Primary and secondary outcome measures
Prevalence of overweight in both Reception and Year 6, prevalence of obesity in both Reception and Year 6 and IMD 2010 scores for each local authority.
Results
In 2009–2010, local authority IMD 2010 scores were strongly correlated with obesity rates among schoolchildren in Reception (r=0.625, p<0.001) and Year 6 (r=0.733, p<0.001). There were no statistically significant changes in association between obesity in Reception or Year 6 and IMD from 2007–2008 to 2009–2010. In contrast, the prevalence of overweight was not statistically significantly correlated with local authority IMD scores in Reception (r=0.095, p=0.092) and only weakly correlated in Year 6 (r=0.184, p=0.001). There were no statistically significant changes in association between overweight in Reception or Year 6 and IMD from 2007–2008 to 2009–2010.
Conclusions
Childhood obesity rates in England are strongly associated with deprivation. Given the enormous public health implications of overweight and obesity in the population, these findings suggest that significant effort is required to tackle unhealthy weight in children in all local authorities and that this should be a priority in areas with high levels of deprivation.
Article summary
Article focus
Associations between local authority 2010 IMD scores and prevalence of overweight and obesity in Reception (age 4–5 years) and Year 6 (age 10–11 years) schoolchildren, 2007–2010.
Key messages
At local authority level, there is a substantial association between obesity prevalence in Reception year and Year 6 and the IMD 2010.
The associations between childhood overweight and obesity prevalence and IMD 2010 have not changed significantly from 2007 to 2010.
Primary healthcare professionals have a key role to play in delivering childhood obesity prevention messages to new parents, as part of a broad strategy to address childhood obesity.
Strengths and limitations of this study
Participation bias is likely to have resulted in some underestimation of Year 6 obesity rates for 2007–2008 and 2008–2009.
The IMD have some limitations but provide the best available means of comparing area deprivation in England.
Changes were made to local authority boundaries in 2009; however, the sensitivity analysis demonstrated that this had no meaningful impact on the results.
The strength of this study in comparison with previous analyses of the National Child Measurement Programme data is in using a more up-to-date measure of deprivation to quantify the association between local authority deprivation and childhood overweight and obesity.
doi:10.1136/bmjopen-2011-000463
PMCID: PMC3329605  PMID: 22505306
21.  Persistent socioeconomic inequalities in cardiovascular risk factors in England over 1994-2008: A time-trend analysis of repeated cross-sectional data 
BMC Public Health  2012;12:129.
Background
Our aims were to determine the pace of change in cardiovascular risk factors by age, gender and socioeconomic groups from 1994 to 2008, and quantify the magnitude, direction and change in absolute and relative inequalities.
Methods
Time trend analysis was used to measure change in absolute and relative inequalities in risk factors by gender and age (16-54, ≥ 55 years), using repeated cross-sectional data from the Health Survey for England 1994-2008. Seven risk factors were examined: smoking, obesity, diabetes, high blood pressure, raised cholesterol, consumption of five or more daily portions of fruit and vegetables, and physical activity. Socioeconomic group was measured using the Index of Multiple Deprivation 2007.
Results
Between 1994 and 2008, the prevalence of smoking, high blood pressure and raised cholesterol decreased in most deprivation quintiles. However, obesity and diabetes increased. Increasing absolute inequalities were found in obesity in older men and women (p = 0.044 and p = 0.027 respectively), diabetes in young men and older women (p = 0.036 and p = 0.019 respectively), and physical activity in older women (p = 0.025). Relative inequality increased in high blood pressure in young women (p = 0.005). The prevalence of raised cholesterol showed widening absolute and relative inverse gradients from 1998 onwards in older men (p = 0.004 and p ≤ 0.001 respectively) and women (p ≤ 0.001 and p ≤ 0.001).
Conclusions
Favourable trends in smoking, blood pressure and cholesterol are consistent with falling coronary heart disease death rates. However, adverse trends in obesity and diabetes are likely to counteract some of these gains. Furthermore, little progress over the last 15 years has been made towards reducing inequalities. Implementation of known effective population based approaches in combination with interventions targeted at individuals/subgroups with poorer cardiovascular risk profiles are therefore recommended to reduce social inequalities.
doi:10.1186/1471-2458-12-129
PMCID: PMC3342910  PMID: 22333887
22.  Why choice of metric matters in public health analyses: a case study of the attribution of credit for the decline in coronary heart disease mortality in the US and other populations 
BMC Public Health  2012;12:88.
Background
Reasons for the widespread declines in coronary heart disease (CHD) mortality in high income countries are controversial. Here we explore how the type of metric chosen for the analyses of these declines affects the answer obtained.
Methods
The analyses we reviewed were performed using IMPACT, a large Excel based model of the determinants of temporal change in mortality from CHD. Assessments of the decline in CHD mortality in the USA between 1980 and 2000 served as the central case study.
Results
Analyses based in the metric of number of deaths prevented attributed about half the decline to treatments (including preventive medications) and half to favourable shifts in risk factors. However, when mortality change was expressed in the metric of life-years-gained, the share attributed to risk factor change rose to 65%. This happened because risk factor changes were modelled as slowing disease progression, such that the hypothetical deaths averted resulted in longer average remaining lifetimes gained than the deaths averted by better treatments. This result was robust to a range of plausible assumptions on the relative effect sizes of changes in treatments and risk factors.
Conclusions
Time-based metrics (such as life years) are generally preferable because they direct attention to the changes in the natural history of disease that are produced by changes in key health determinants. The life-years attached to each death averted will also weight deaths in a way that better reflects social preferences.
doi:10.1186/1471-2458-12-88
PMCID: PMC3305465  PMID: 22284813
Comparative Effectiveness Research; Policy analysis; Determinants of Mortality; Epidemiologic Methods; Coronary Heart Disease
23.  Will Cardiovascular Disease Prevention Widen Health Inequalities? 
PLoS Medicine  2010;7(8):e1000320.
Simon Capewell and Hilary Graham review different population strategies for preventing cardiovascular disease and conclude that screening and treating high-risk individuals may be ineffective and widen social inequalities.
doi:10.1371/journal.pmed.1000320
PMCID: PMC2927551  PMID: 20811492
24.  Temporal trends in hospitalisation for stroke recurrence following incident hospitalisation for stroke in Scotland 
BMC Medicine  2010;8:23.
Background
There are few studies that have investigated temporal trends in risk of recurrent stroke. The aim of this study was to examine temporal trends in hospitalisation for stroke recurrence following incident hospitalisation for stroke in Scotland during 1986 to 2001.
Methods
Unadjusted survival analysis of time to first event, hospitalisation for recurrent stroke or death, was undertaken using the cumulative incidence method which takes into account competing risks. Regression on cumulative incidence functions was used to model the temporal trends of first recurrent stroke with adjustment for age, sex, socioeconomic status and comorbidity. Complete five year follow-up was obtained for all patients. Restricted cubic splines were used to determine the best fitting relationship between the survival events and study year.
Results
There were 128,511 incident hospitalisations for stroke in Scotland between 1986 and 2001, 57,351 (45%) in men. A total of 13,835 (10.8%) patients had a recurrent hospitalisation for stroke within five years of their incident hospitalisation. Another 74,220 (57.8%) patients died within five years of their incident hospitalisation without first having a recurrent hospitalisation for stroke. Comparing incident stroke hospitalisations in 2001 with 1986, the adjusted risk of recurrent stroke hospitalisation decreased by 27%, HR = 0.73 95% CI (0.67 to 0.78), and the adjusted risk of death being the first event decreased by 28%, HR = 0.72 (0.70 to 0.75).
Conclusions
Over the 15-year period approximately 1 in 10 patients with an incident hospitalisation for stroke in Scotland went on to have a hospitalisation for recurrent stroke within five years. Approximately 6 in 10 patients died within five years without first having a recurrent stroke hospitalisation. Using hospitalisation and death data from an entire country over a 20-year period we have been able to demonstrate not only an improvement in survival following an incident stroke, but also a reduction in the risk of a recurrent event.
doi:10.1186/1741-7015-8-23
PMCID: PMC2859404  PMID: 20380701
25.  Coronary heart disease mortality among young adults in Scotland in relation to social inequalities: time trend study 
Objective To examine recent trends and social inequalities in age specific coronary heart disease mortality.
Design Time trend analysis using joinpoint regression.
Setting Scotland, 1986-2006.
Participants Men and women aged 35 years and over.
Main outcome measures Age adjusted and age, sex, and deprivation specific coronary heart disease mortality.
Results Persistent sixfold social differentials in coronary heart disease mortality were seen between the most deprived and the most affluent groups aged 35-44 years. These differentials diminished with increasing age but equalised only above 85 years. Between 1986 and 2006, overall, age adjusted coronary heart disease mortality decreased by 61% in men and by 56% in women. Among middle aged and older adults, mortality continued to decrease fairly steadily throughout the period. However, coronary heart disease mortality levelled from 1994 onwards among young men and women aged 35-44 years. Rates in men and women aged 45-54 showed similar flattening from about 2003. Rates in women aged 55-64 may also now be flattening. The flattening of coronary heart disease mortality in younger men and women was confined to the two most deprived fifths.
Conclusions Premature death from coronary heart disease remains a major contributor to social inequalities. Furthermore, the flattening of the decline in mortality for coronary heart disease among younger adults may represent an early warning sign. The observed trends were confined to the most deprived groups. Marked deterioration in medical management of coronary heart disease seems implausible. Unfavourable trends in the major risk factors for coronary heart disease (smoking and poor diet) thus provide the most likely explanation for these inequalities.
doi:10.1136/bmj.b2613
PMCID: PMC2714675  PMID: 19602713

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