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      Seropositivity to Cytomegalovirus, Inflammation, All-Cause and Cardiovascular Disease-Related Mortality in the United States


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          Studies have suggested that CMV infection may influence cardiovascular disease (CVD) risk and mortality. However, there have been no large-scale examinations of these relationships among demographically diverse populations. The inflammatory marker C-reactive protein (CRP) is also linked with CVD outcomes and mortality and may play an important role in the pathway between CMV and mortality. We utilized a U.S. nationally representative study to examine whether CMV infection is associated with all-cause and CVD-related mortality. We also assessed whether CRP level mediated or modified these relationships.

          Methodology/Principal Findings

          Data come from subjects ≥25 years of age who were tested for CMV and CRP level and were eligible for mortality follow-up on December 31 st, 2006 (N = 14153) in the National Health and Nutrition Examination Survey (NHANES) III (1988–1994). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and CVD-related mortality by CMV serostatus. After adjusting for multiple confounders, CMV seropositivity remained statistically significantly associated with all-cause mortality (HR 1.19, 95% CI: 1.01, 1.41). The association between CMV and CVD-related mortality did not achieve statistical significance after confounder adjustment. CRP did not mediate these associations. However, CMV seropositive individuals with high CRP levels showed a 30.1% higher risk for all-cause mortality and 29.5% higher risk for CVD-related mortality compared to CMV seropositive individuals with low CRP levels.


          CMV was associated with a significant increased risk for all-cause mortality and CMV seropositive subjects who also had high CRP levels were at substantially higher risk for both for all-cause and CVD-related mortality than subjects with low CRP levels. Future work should target the mechanisms by which CMV infection and low-level inflammation interact to yield significant impact on mortality.

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          Most cited references61

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          Measurement of socioeconomic status in health disparities research.

          Socioeconomic status (SES) is frequently implicated as a contributor to the disparate health observed among racial/ ethnic minorities, women and elderly populations. Findings from studies that examine the role of SES and health disparities, however, have provided inconsistent results. This is due in part to the: 1) lack of precision and reliability of measures; 2) difficulty with the collection of individual SES data; 3) the dynamic nature of SES over a lifetime; 4) the classification of women, children, retired and unemployed persons; 5) lack of or poor correlation between individual SES measures; and 6) and inaccurate or misleading interpretation of study results. Choosing the best variable or approach for measuring SES is dependent in part on its relevance to the population and outcomes under study. Many of the commonly used compositional and contextual SES measures are limited in terms of their usefulness for examining the effect of SES on outcomes in analyses of data that include population subgroups known to experience health disparities. This article describes SES measures, strengths and limitations of specific approaches and methodological issues related to the analysis and interpretation of studies that examine SES and health disparities.
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            Seroprevalence of cytomegalovirus infection in the United States, 1988-1994.

            Cytomegalovirus (CMV) is a leading cause of congenital illness and disability, including hearing loss and mental retardation. However, there are no nationwide estimates of CMV seroprevalence among pregnant women or the overall population of the United States. To determine CMV prevalence in a representative sample of the US population, we tested serum samples for CMV-specific immunoglobulin G from participants aged > or =6 years (n=21,639) in the third National Health and Nutrition Examination Survey (1988-1994). The prevalence of CMV infection was 58.9% in individuals > or =6 years old. CMV seroprevalence increased gradually with age, from 36.3% in 6-11-year-olds to 90.8% in those aged > or =80 years. CMV seroprevalence differed by race and/or ethnicity as follows: 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans. Racial and/or ethnic differences in CMV seroprevalence persisted when controlling for household income level, education, marital status, area of residence, census region, family size, country of birth, and type of medical insurance. Among women, racial and/or ethnic differences were especially significant; between ages 10-14 years and 20-24 years, seroprevalence increased 38% for non-Hispanic black persons, 7% for non-Hispanic white persons, and <1% for Mexican Americans. On the basis of these results, we estimate that each year in the United States approximately 340,000 non-Hispanic white persons, 130,000 non-Hispanic black persons, and 50,000 Mexican American women of childbearing age experience a primary CMV infection. Given the number of women at risk and the significance of congenital disease, development of programs for the prevention of CMV infection, such as vaccination or education, is of considerable public health importance.
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              Inflammatory mediators in the elderly.

              Ageing is accompanied by 2-4-fold increases in plasma/serum levels of inflammatory mediators such as cytokines and acute phase proteins. A wide range of factors seems to contribute to this low-grade inflammation, including an increased amount of fat tissue, decreased production of sex steroids, smoking, subclinical infections (e.g. asymptomatic bacteriuria), and chronic disorders such as cardiovascular diseases and Alzheimer's disease. Furthermore, there is some evidence that ageing is associated with a dysregulated cytokine response following stimulation. Several inflammatory mediators such as tumour necrosis factor-alpha and interleukin-6 have the potential to induce/aggravate risk factors in age-associated pathology, providing a positive feedback mechanism. Thus, it is possible that inflammatory mediators constitute a link between life style factors, infections and physiological changes in the process of ageing on the one hand and risk factors for age-associated diseases on the other. Consistent with this, inflammatory mediators are strong predictors of mortality independently of other known risk factors and co-morbidity in elderly cohorts. A direct pathogenetic role of inflammatory mediators would be highly likely if longevity was shown to be associated with cytokine polymorphisms regulating cytokine production. Several studies support indeed this hypothesis but, unfortunately, findings in this area are conflicting, which probably reflects the complexity of the effect of cytokine polymorphisms and their interaction with the lifestyle and sex.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                17 February 2011
                : 6
                : 2
                : e16103
                [1 ]Department of Epidemiology, Center for Social Epidemiology and Population Health, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
                [2 ]Epidemiology and Biostatistics, School of Public Health, Hunter College, City University of New York (CUNY), CUNY Institute for Demographic Research, New York, New York, United States of America
                [3 ]Second Department of Internal Medicine, Center for Medical Research, ZMF, University of Tuebingen Medical School, Tuebingen, Germany
                [4 ]Epidemiology and Public Health Group, Peninsula Medical School, Exeter, United Kingdom
                Lerner Research Institute, Cleveland Clinic, United States of America
                Author notes

                Conceived and designed the experiments: AMS JBD AEA. Analyzed the data: AMS AEA. Wrote the paper: AMS JBD GP DM AD AEA.

                Simanek et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                : 2 August 2010
                : 10 December 2010
                Page count
                Pages: 10
                Research Article
                Clinical Immunology
                Biomarker Epidemiology
                Cardiovascular Disease Epidemiology
                Epidemiology of Aging
                Infectious Disease Epidemiology
                Lifecourse Epidemiology
                Social Epidemiology
                Infectious Diseases
                Viral Diseases
                Cytomegalovirus Infection
                Public Health
                Behavioral and Social Aspects of Health
                Socioeconomic Aspects of Health



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