RESUMO
INTRODUCTION: We aimed to identify whether ST-segment abnormalities, in the admission or during in-hospital stay, are associated with survival and/or new incident myocardial infarction (MI) in 623 non-ST-elevation acute coronary syndrome participants of the Strategy of Registry of Acute Coronary Syndrome (ERICO) study. MATERIALS AND METHODS: ERICO is conducted in a community-based hospital. ST-segment analysis was based on the Minnesota Code. We built Cox regression models to study whether ECG was an independent predictor for clinical outcomes. RESULTS: Median follow-up was 3years. We found higher risk of death due to MI in individuals with ST-segment abnormalities in the final ECG (adjusted hazard ratio: 2.68; 95% confidence interval: 1.14-6.28). Individuals with ST-segment abnormalities in any tracing had a non-significant trend toward a higher risk of fatal or new non-fatal MI (p=0.088). CONCLUSIONS: ST-segment abnormalities after the initial tracing added long-term prognostic information.
Assuntos
Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Eletrocardiografia/métodos , Eletrocardiografia/estatística & dados numéricos , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio sem Supradesnível do Segmento ST/mortalidade , Síndrome Coronariana Aguda/terapia , Idoso , Algoritmos , Brasil/epidemiologia , Estudos de Coortes , Comorbidade , Diagnóstico por Computador/métodos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio sem Supradesnível do Segmento ST/terapia , Prevalência , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Medição de Risco/métodos , Sensibilidade e Especificidade , Análise de SobrevidaRESUMO
BACKGROUND AND AIMS: There are limited data on serial coronary artery calcium (CAC) assessments outside North American and European populations. We sought to investigate risk factors for CAC incidence and progression in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: We included individuals with no prior cardiovascular disease and two CAC measurements in ELSA-Brasil. Incident CAC was defined as a baseline CAC of 0 followed by CAC >0 on the second study. CAC progression was defined according to multiple published criteria. We performed logistic and linear regression to identify risk factors for CAC incidence and progression. We also examined risk factor effect modification by baseline CAC (0 vs. >0). RESULTS: A total of 2707 individuals were included (57% women, age 48.6 ± 7.7 years). Participants self-identified as white (55%), brown (24%), black (16%), Asian (4%) and Indigenous (1%). The mean period between CAC assessments was 5.1 ± 0.9 years. CAC incidence occurred in 282 (13.3%) of 2127 individuals with baseline CAC of 0. CAC progression occurred in 319 (55%) of 580 participants with baseline CAC >0. Risk factors for CAC incidence included older age, male sex, white race, hypertension, diabetes, higher BMI, smoking, lower HDL-C, higher LDL-C and triglycerides, and metabolic syndrome. Older age and elevated LDL-C were associated with CAC incidence, but not progression. Risk factors consistently associated with CAC progression were hypertension, diabetes, hypertriglyceridemia, and metabolic syndrome. On interaction testing, these four risk factors were more strongly associated with CAC progression as compared to CAC incidence. CONCLUSIONS: CAC incidence was associated with multiple traditional risk factors, whereas the only risk factors associated with progression of CAC were hypertension, diabetes, hypertriglyceridemia, and metabolic syndrome.
Assuntos
Doença da Artéria Coronariana , Calcificação Vascular , Adulto , Idoso , Brasil/epidemiologia , Cálcio , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Progressão da Doença , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/epidemiologiaRESUMO
BACKGROUND: Although elevated high-density lipoprotein cholesterol (HDL-C) is considered protective against atherosclerotic cardiovascular disease, no causal relationship has been demonstrated. HDL-C comprises a group of different subfractions that might have different effects on atherosclerosis. Our objective was to investigate the association between HDL-C subfractions with the coronary artery calcium (CAC) score. METHODS: We included 3,674 (49.8 ± 8.3 years, 54% women) participants from the ELSA-Brasil study who had no prior history of CVD and were not currently using lipid-lowering medications. We measured the fasting lipoprotein cholesterol fractions (in mmol/l) by a zonal ultracentrifugation method (VAP). We analyzed the independent predictive values of total HDL-C, HDL2-C, and HDL3-C subfractions and in the HDL2-C/HDL3-C ratio using linear regression to predict Ln(CAC+1) and logistic regression to predict the presence of CAC. RESULTS: Overall 912 (24.8%) of the participants had CAC>0, and 294 (7.7%) had CAC>100. The mean total HDL-C, HDL2-C, and HDL3-C were: 1.42 ± 0.37, 0.38 ± 0.17 and 1.03 ± 0.21 mmol/l, respectively. Individuals with CAC>0 had lower levels of total HDL-C as well as of each subfraction (p < 0.001). When adjusted for age, gender, smoking, hypertension, alcohol use, physical activity, and LDL-C, we observed an inverse association between HDL-C and its subfractions and CAC (p < 0.05). However, by adding triglycerides in the adjustment, neither total HDL-C nor its subfractions remained independently associated with the presence or extent of CAC. CONCLUSION: In this cross-sectional analysis, neither the total HDL-C nor its subfractions (HDL2-C and HDL3-C, as well as HDL2-C/HDL3-C ratio) measured by VAP are independently associated with the presence or extent of coronary calcification.
Assuntos
Aterosclerose/patologia , Cálcio/análise , HDL-Colesterol/sangue , Colesterol/sangue , Vasos Coronários/patologia , Lipoproteínas/sangue , Calcificação Vascular/patologia , Adulto , Aterosclerose/sangue , Brasil , Estudos Transversais , Jejum , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
BACKGROUND: Obstructive sleep apnea (OSA) is a very often clinical condition that can be associated with high mortality risk, particularly in coronary heart disease (CHD). The diagnosis of OSA is not always accessible via the gold-standard method polysomnography. OBJECTIVE: To evaluate long-term influence of the high risk for OSA on fatal and non-fatal outcomes after acute coronary syndrome (ACS) in the Acute Coronary Syndrome Registry Strategy (ERICO) Study using the Berlin questionnaire as a surrogate. METHODS: Berlin questionnaire, a screening questionnaire for OSA, was applied in 639 cases of ACS 30 days after the index event. Cox regression proportional-hazards model was used to calculate the hazard ratio (HR) of all-cause, cardiovascular and CHD (myocardial infarction) mortality, as well as, the combined endpoint of fatal or recurrent non-fatal CHD. RESULTS: The high-risk group for OSA had higher frequencies of previous personal/family history of CHD and diabetes, in addition to a poorer event-free survival, as compared to the low-risk group (p-log-rank=0.03). The HR for fatal or recurrent non-fatal CHD was 4.26 (95% confidence interval, 1.18 - 15.36) in patients at high risk for OSA compared to those at low risk for OSA after a 2.6-year mean follow-up. CONCLUSIONS: Using Berlin questionnaire, we were able to identify high risk for OSA as an independent predictor of non-fatal reinfarction or CHD mortality in post-ACS individuals in a long-term follow-up.
Assuntos
Síndrome Coronariana Aguda/mortalidade , Medição de Risco/métodos , Apneia Obstrutiva do Sono/mortalidade , Inquéritos e Questionários , Síndrome Coronariana Aguda/complicações , Idoso , Brasil , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Recidiva , Fatores de Risco , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Fatores Socioeconômicos , Fatores de TempoRESUMO
We aimed to study the association between fasting plasma glucose, diabetes incidence and cardiovascular burden after 10-12 years. We evaluated diabetes and cardiovascular events incidences, carotid intima-media thickness and coronary artery calcium scores in ELSA-Brasil (the Brazilian Longitudinal Study of Adult Health) baseline (2008-2010) of 1536 adults without diabetes in 1998. We used regression models to estimate association with carotid intima-media thickness (in mm), coronary artery calcium scores (in Agatston points) and cardiovascular events according to fasting plasma glucose in 1998. Adjusted diabetes incidence rate was 9.8/1000 person-years (95% confidence interval: 7.7-13.6/1000 person-years). Incident diabetes was positively associated with higher fasting plasma glucose. Fasting plasma glucose levels 110-125 mg/dL were associated with higher carotid intima-media thickness (ß = 0.028; 95% confidence interval: 0.003-0.053). Excluding those with incident diabetes, there was a borderline association between higher carotid intima-media thickness and fasting plasma glucose 110-125 mg/dL (ß = 0.030; 95% confidence interval: -0.005 to 0.065). Incident diabetes was associated with higher carotid intima-media thickness (ß = 0.034; 95% confidence interval: 0.015-0.053), coronary artery calcium scores ⩾400 (odds ratio = 2.84; 95% confidence interval: 1.17-6.91) and the combined outcome of a coronary artery calcium scores ⩾400 or incident cardiovascular event (odds ratio = 3.50; 95% confidence interval: 1.60-7.65). In conclusion, fasting plasma glucose in 1998 and incident diabetes were associated with higher cardiovascular burden.
Assuntos
Glicemia/metabolismo , Doenças das Artérias Carótidas/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus/epidemiologia , Jejum/sangue , Calcificação Vascular/epidemiologia , Adulto , Doenças Assintomáticas , Biomarcadores/sangue , Brasil/epidemiologia , Doenças das Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Distribuição de Qui-Quadrado , Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Incidência , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Razão de Chances , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Fatores de Tempo , Calcificação Vascular/diagnóstico por imagem , Adulto JovemRESUMO
BACKGROUND: Emerging data suggests that chronic inflammatory disease, such as psoriasis, may be associated to coronary artery disease (CAD). OBJECTIVE: Analyze the association between psoriasis and subclinical atherosclerosis using coronary calcium score (CAC). METHODS: We investigated 221 participants with psoriasis and 718 age- and sex-matched controls without prior known CAD. All participants completed a questionnaire and underwent laboratory tests and a CAC exam. Logistic regression models adjusted for Framingham risk score (FRS) and C-reactive protein (hs-CRP) were built. CAC was included in the models as a binary variable with different cut off values. RESULTS: Body-mass index, race, hypertension, HDL, LDL and hs-CRP were significantly associated with psoriasis presence and severity. Psoriasis severity was significantly associated with CAC (p = 0.04), particularly for very high CAC (>400) (p < 0.01). The OR for severe psoriasis and CAC >400 was 2.45 (95%CI: 1.26-4.75) in unadjusted models. In a model adjusted for the FRS, this association was no longer significant, but a trend was noted (p = 0.09). No significant changes in the association were noted after the inclusion of hs-CRP in the model. CONCLUSION: Psoriasis is associated with higher CAC values, mainly in individuals with severe psoriasis. The current findings also suggest the potential involvement of other mechanisms beyond classical cardiovascular risk factors and inflammation in this association.
Assuntos
Cálcio/metabolismo , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Psoríase/sangue , Psoríase/complicações , Aterosclerose/sangue , Aterosclerose/complicações , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Estudos Transversais , Feminino , Humanos , Hipertensão/sangue , Inflamação , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Análise Multivariada , Análise de Regressão , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Studies have demonstrated the association of severe anatomical coronary artery disease (CAD) with postprandial triglycerides (TG) concentrations. Nevertheless the relationship between less severe atherosclerosis plaque burden and postprandial TG is less established. OBJECTIVE: to study the relationship between postprandial TG and CAD detected by coronary computed tomographic angiography (CTA). MATERIAL AND METHODS: 130 patients who underwent an oral fat tolerance test were enrolled (85 with CAD detected by CTA and 45 without). Postprandial lipemia was studied by measuring TG from T0h to T6h with 2-h intervals, and analyzed the TG change over time using a longitudinal multivariable linear mixed effects model with the log normal of the TG as the primary outcome. RESULTS: The majority of individuals with CAD had non-obstructive disease (63.3%) Patients with CAD had a slower clearance of postprandial TG change from 4 h to 6 h (p<0.05) compared to patients without CAD. These results remained significant after adjustment for fasting TG and glucose, age, gender, body mass index, and waist circumference. However, those differences did not reach statistical significance after adjustment for fasting HDL-C. CONCLUSION: Patients with mild (<25% lumen obstruction) and moderate CAD (25-50% lumen obstruction) detected by coronary CTA had an impaired postprandial metabolism, with a delayed TG clearance, when compared to individuals with no CAD. This difference was partially explained by the lower HDL-C. Thus, though postprandial TG may contribute to the development of CAD, this association is partially related to low HDL-C.
Assuntos
Angiografia Coronária , Doença da Artéria Coronariana/sangue , Gorduras na Dieta , Período Pós-Prandial/fisiologia , Triglicerídeos/sangue , Adulto , Idoso , Antropometria , Glicemia/análise , Calcinose/sangue , Calcinose/diagnóstico por imagem , HDL-Colesterol/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/sangue , Estenose Coronária/diagnóstico por imagem , Gorduras na Dieta/farmacocinética , Jejum/sangue , Feminino , Humanos , Hipertensão/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Placa Aterosclerótica/sangue , Placa Aterosclerótica/diagnóstico por imagem , Fumar/sangue , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: To describe the ERICO study (Strategy of Registry of Acute Coronary Syndrome), a prospective cohort to investigate the epidemiology of acute coronary syndrome. METHODS: The ERICO study, which is being performed at a secondary general hospital in São Paulo, Brazil, is enrolling consecutive acute coronary syndrome patients who are 35 years old or older. The sociodemographic information, medical assessments, treatment data and blood samples are collected at admission. After 30 days, the medical history is updated, and additional blood and urinary samples are collected. In addition, a retinography, carotid intima-media thickness, heart rate variability and pulse-wave velocity are performed. Questionnaires about food frequency, physical activity, sleep apnea and depression are also applied. At six months and annually after an acute event, information is collected by telephone. RESULTS: From February 2009 to September 2011, 738 patients with a diagnosis of an acute coronary syndrome were enrolled. Of these, 208 (28.2%) had ST-elevation myocardial infarction (STEMI), 288 (39.0%) had non-ST-elevation myocardial infarction (NSTEMI) and 242 (32.8%) had unstable angina (UA). The mean age was 62.7 years, 58.5% were men and 77.4% had 8 years or less of education. The most common cardiovascular risk factors were hypertension (76%) and sedentarism (73.4%). Only 29.2% had a prior history of coronary heart disease. Compared with the ST-elevation myocardial infarction subgroup, the unstable angina and non-ST-elevation myocardial infarction patients had higher frequencies of hypertension, diabetes, prior coronary heart disease (p<0.001) and dyslipidemia (p = 0.03). Smoking was more frequent in the ST-elevation myocardial infarction patients (p = 0.006). CONCLUSIONS: Compared with other hospital registries, our findings revealed a higher burden of CV risk factors and less frequent prior CHD history.
Assuntos
Síndrome Coronariana Aguda/epidemiologia , Doença das Coronárias/epidemiologia , Sistema de Registros/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Métodos Epidemiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de TempoRESUMO
Abstract Background: Obstructive sleep apnea (OSA) is a very often clinical condition that can be associated with high mortality risk, particularly in coronary heart disease (CHD). The diagnosis of OSA is not always accessible via the gold-standard method polysomnography. Objective: To evaluate long-term influence of the high risk for OSA on fatal and non-fatal outcomes after acute coronary syndrome (ACS) in the Acute Coronary Syndrome Registry Strategy (ERICO) Study using the Berlin questionnaire as a surrogate. Methods: Berlin questionnaire, a screening questionnaire for OSA, was applied in 639 cases of ACS 30 days after the index event. Cox regression proportional-hazards model was used to calculate the hazard ratio (HR) of all-cause, cardiovascular and CHD (myocardial infarction) mortality, as well as, the combined endpoint of fatal or recurrent non-fatal CHD. Results: The high-risk group for OSA had higher frequencies of previous personal/family history of CHD and diabetes, in addition to a poorer event-free survival, as compared to the low-risk group (p-log-rank=0.03). The HR for fatal or recurrent non-fatal CHD was 4.26 (95% confidence interval, 1.18 - 15.36) in patients at high risk for OSA compared to those at low risk for OSA after a 2.6-year mean follow-up. Conclusions: Using Berlin questionnaire, we were able to identify high risk for OSA as an independent predictor of non-fatal reinfarction or CHD mortality in post-ACS individuals in a long-term follow-up.
Resumo Fundamento: Apneia obstrutiva do sono (AOS) é uma condição clínica muito frequente, que pode estar associada a alto risco de mortalidade, particularmente em doença arterial coronariana (DAC). Nem sempre o diagnóstico de AOS acha-se disponível por polissonografia, o método padrão-ouro. Objetivo: Avaliar, usando o Questionário de Berlim como substituto, a influência a longo prazo do alto risco para AOS nos desfechos fatal e não fatal após síndrome coronariana aguda (SCA) na Estratégia de Registro de Insuficiência Coronariana (estudo ERICO). Métodos: O Questionário de Berlim, para triagem de AOS, foi aplicado a 639 casos de SCA 30 dias após o evento índice. Usou-se o modelo de riscos proporcionais de Cox para calcular a razão de risco (HR) para mortalidade por todas as causas, por doença cardiovascular e por IAM (infarto agudo do miocárdio), assim como os desfecho combinado infarto do miocárdio fatal e recorrente não fatal. Resultados: O grupo de alto risco para AOS apresentou maior frequência de história pessoal/familiar de DAC e diabetes, assim como pior sobrevida livre de evento, quando comparado ao de baixo risco (p-log-rank = 0,03). A HR para IAM fatal e recorrente não fatal foi 4,26 (intervalo de confiança 95%: 1,18-15,36) para os pacientes de alto risco para AOS em comparação àqueles de baixo risco após seguimento médio de 2,6 anos. Conclusões: Usando o Questionário de Berlim, conseguimos identificar alto risco para AOS como fator preditivo independente de reinfarto não fatal ou mortalidade por IAM após SCA em seguimento em longo prazo.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Inquéritos e Questionários , Medição de Risco/métodos , Apneia Obstrutiva do Sono/mortalidade , Síndrome Coronariana Aguda/mortalidade , Prognóstico , Recidiva , Fatores Socioeconômicos , Fatores de Tempo , Brasil , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Seguimentos , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Estimativa de Kaplan-Meier , Síndrome Coronariana Aguda/complicaçõesRESUMO
OBJECTIVES: To describe the ERICO study (Strategy of Registry of Acute Coronary Syndrome), a prospective cohort to investigate the epidemiology of acute coronary syndrome. METHODS: The ERICO study, which is being performed at a secondary general hospital in São Paulo, Brazil, is enrolling consecutive acute coronary syndrome patients who are 35 years old or older. The sociodemographic information, medical assessments, treatment data and blood samples are collected at admission. After 30 days, the medical history is updated, and additional blood and urinary samples are collected. In addition, a retinography, carotid intima-media thickness, heart rate variability and pulse-wave velocity are performed. Questionnaires about food frequency, physical activity, sleep apnea and depression are also applied. At six months and annually after an acute event, information is collected by telephone. RESULTS: From February 2009 to September 2011, 738 patients with a diagnosis of an acute coronary syndrome were enrolled. Of these, 208 (28.2%) had ST-elevation myocardial infarction (STEMI), 288 (39.0%) had non-ST-elevation myocardial infarction (NSTEMI) and 242 (32.8%) had unstable angina (UA). The mean age was 62.7 years, 58.5% were men and 77.4% had 8 years or less of education. The most common cardiovascular risk factors were hypertension (76%) and sedentarism (73.4%). Only 29.2% had a prior history of coronary heart disease. Compared with the ST-elevation myocardial infarction subgroup, the unstable angina and non-ST-elevation myocardial infarction patients had higher frequencies of hypertension, diabetes, prior coronary heart disease (p<0.001) and dyslipidemia (p = 0.03). Smoking was more frequent in the ST-elevation myocardial infarction patients (p = 0.006). CONCLUSIONS: Compared with other hospital registries, our findings revealed a higher burden of CV risk factors and less frequent prior CHD history.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Coronariana Aguda/epidemiologia , Doença das Coronárias/epidemiologia , Sistema de Registros/normas , Brasil/epidemiologia , Métodos Epidemiológicos , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de TempoRESUMO
Os hipolipemiantes são medicamentos de eficácia comprovada no tratamento dos distúrbios do metabolismo dos lipídeos. Essas drogas reduzem a morbidade e a mortalidde em eventos cardiovasculares de forma notória. A suspeita de que esses agentes podem aumentar o risco de câncer tem sido questionada desde o início de seu uso, gerando intensos debates e reanálises de ensaios clínicos sobre o assunto. Recentemente, os resultados do estudo Sinvastatin and Ezetimibe in Aortic Stenosis (SEAS) despertaram novo interesse por esse tema, pois os pacientes submetidos a terapia hipolipemiante intensiva tiveram número aumentado de câncer em comparação com o grupo controle. Este artigo visa a revisar os estudos em busca de evidência sobre associação do uso de hipolipemiantes e baixos níveis de colesterol com incidência de câncer. Até o momento não há evidências concretas de meta-análises, seja com estatinas ou, mais recentemente, com ezetimiba, que indiquem que esses medicamentos induzam o aparecimento de neoplasias ou que elevem o risco de mortalidade pelo câncer.
The efficacy of lipid-lowering agents in the treatment of lipid metabolism disorders is well established. These drugs markedly reduce morbidity and mortality in cardiovascular events. The hypothesis that lipid-lowering drugs might increase the risk of cancer has been questioned from the very beginning of their use and has been subject of intense debate and several attempts to reanalyze clinical trial data. Recently, the results of the Simvastatin and Ezetimibe in Aortic Stenosis Study (SEAS) has sparked new interest on this issue, since patients undergoing intense lipid-lowering therapy had a higher rate of cancer than the control group. This article gives an overview of the clinical evidence on the association of lipid-lowering drugs and low cholesterol levels with the incidence of cancer. So far there are no clear evidences from metanalyses, whether with statins or more recently with ezetimibe, indicating that these drugs induce the development of cancer or increase the risk of mortality due to cancer.