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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Alpha1-antitrypsin &#40;AAT&#41; is an acute phase protein&#44; major inhibitor of neutrophil serine proteases like elastase but also considered as a regulatory protein of broad immune and inflammatory responses&#46; Experimental data provide evidence that AAT assists host defences by neutralizing inflammation-induced molecules &#40;such as proteases&#44; cytokines and oxidants&#41;&#44; by diminishing the pro-inflammatory responses of circulating leukocytes&#44; and by forestalling endothelial activation&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The clinical importance of AAT is highlighted in individuals with inherited AAT deficiency&#44; who exhibit high risk for developing early-onset pulmonary emphysema and liver disease at any age&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> Because inherited AAT deficiency is a well-established genetic risk factor for chronic obstructive pulmonary disease &#40;COPD&#41;&#44; most of the clinical studies focus on reduced plasma levels and biological activity of AAT protein in cohorts of COPD&#46; Hitherto&#44; less attention given to the levels of plasma AAT in the general population and in COPD patients without inherited AAT deficiency&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Here we used data from the EPI-SCAN&#44; a multicentre&#44; epidemiological study conducted in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a> Our aim was to determine plasma AAT levels in a cohort of participants diagnosed with COPD&#44; having respiratory symptoms-presence of chronic cough and sputum production but no clinical diagnosis of COPD&#44; and the reference group&#44; those with normal spirometry and without respiratory symptoms&#44; considered healthy persons&#46; We also wanted to evaluate independent predictors of AAT levels including age&#44; lung function measures&#44; smoking&#44; and clinical laboratory data&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Design of the study</span><p id="par0020" class="elsevierStylePara elsevierViewall">The present study is a part of the EPI-SCAN study&#44; which was a multicentre&#44; cross-sectional&#44; population-based&#44; observational study conducted at 11 sites in 10 Spanish cities &#40;Barcelona&#44; Burgos&#44; C&#243;rdoba&#44; Huesca&#44; Madrid &#40;two areas&#41;&#44; Requena&#44; Sevilla&#44; Oviedo&#44; Vic and Vigo&#41; representing different geographic&#44; climatic and socio-economic regions&#46; The main objective of the study was to investigate the prevalence of COPD in Spain in individuals between 40 and 80 years of age&#46; The protocol of the EPI-SCAN study has been published elsewhere&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a> Fieldwork and all methods have been described previously&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> The corresponding ethics committees approved the study and all participants gave written informed consent&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study participants</span><p id="par0025" class="elsevierStylePara elsevierViewall">The final recruited population consisted of 3802 non-institutionalized participants from 40 to 80 years of age&#46; The definition of COPD was a post-bronchodilator FEV1&#47;FVC ratio &#60;0&#46;70&#46; Subjects considered not to have COPD had a post-bronchodilator FEV1&#47;FVC ratio &#8805;0&#46;70&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> The blood sample we obtained from all participants classified as having COPD&#46; To avoid excessive testing of the non-COPD population&#44; each study center collected equal number of blood samples from non-COPD subjects recruited consecutively in order to avoid selection bias&#46; Exclusion criteria included a previous diagnosis of acute myocardial infarction&#44; angina&#44; congestive heart failure&#44; cancer&#44; hepatic cirrhosis&#44; chronic renal failure&#44; rheumatoid arthritis or any other systemic inflammatory disease&#46; In addition&#44; we identified a control group of non-COPD subjects after applying the same comorbidity exclusion criteria and specific exclusion criteria of any respiratory symptoms as per the European Coal and Steel Community &#40;ECSC&#41; questionnaire and regularly prescribed medications&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> illustrates our cohort&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Procedures</span><p id="par0030" class="elsevierStylePara elsevierViewall">At each study center&#44; lung function tests were performed using the same equipment according to the current recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> Spirometry was performed before and 15&#8211;30<span class="elsevierStyleHsp" style=""></span>min after salbutamol inhalation&#46; Baseline dyspnea was assessed by the Modified Medical Research Council &#40;MMRC&#41; scale&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> and subjects completed the ECSC questionnaire of respiratory symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Blood samples were collected using standardized procedures and stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C before sending for the centralized analysis to a single laboratory &#40;Hospital Clinic&#44; Barcelona&#44; Spain&#41;&#46; Plasma levels of TNF&#945;&#44; IL-6 and IL-8 were determined in duplicate with a high sensitivity enzyme-linked immunosorbent assays &#40;Biosource&#44; Nivelles&#44; Belgium&#41;&#46; We assessed plasma levels of CRP by the latex-enhanced immunonephelometry &#40;Siemens&#44; Dublin&#44; Ireland&#41;&#44; AAT by a particle-enhanced immunonephelometry &#40;Siemens&#44; Marburg&#44; Germany&#41;&#44; albumin by the bromocresol green method &#40;Siemens&#44; Dublin&#44; Ireland&#41; and fibrinogen by using a coagulation analyzer &#40;Roche&#44; Manheim&#44; Germany&#41;&#46; Specific details about the analytic procedures described elsewhere&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Data analysis performed using R&#44; a free software environment for statistical computing and graphics&#46; Statistical significance between subject categories with regard to demographic characteristics and laboratory values was analyzed with ANOVA&#46; Specific pairwise comparisons of subject categories were assessed with the <span class="elsevierStyleItalic">t</span>-test&#46; Least squares linear regression was applied to assess the associations of the dependent variables&#44; such as AAT levels and lung function &#40;post-bronchodilator spirometry&#41;&#44; with various other clinical parameters as independent variables&#46; Modeling COPD status as a function of AAT levels and other clinical parameters was performed using logistic regression&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Characteristics of study participants</span><p id="par0045" class="elsevierStylePara elsevierViewall">Out of 3802 participants&#44; 837 &#40;22&#37;&#41; had available plasma levels of AAT&#46; Of them&#44; 303 &#40;36&#46;2&#37;&#41; had COPD diagnosis&#44; 222 &#40;26&#46;5&#37;&#41; had respiratory symptoms but not COPD&#44; and 312 &#40;37&#46;3&#37;&#41; were healthy&#44; with normal spirometry and without respiratory symptoms&#44; considered as a reference group&#46; The mean &#40;SD&#41; age of cohort was 58&#46;0 &#40;11&#46;3&#41; years&#46; The main characteristics of the participants described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">There were more men within the COPD group than in those with respiratory symptoms or healthy &#40;73&#46;6&#37; vs 53&#46;6&#37; and 44&#46;2&#37;&#44; respectively&#41;&#46; Moreover&#44; COPD group was older and had more smokers and ex-smokers relative to other groups&#46; BMI was not significantly different among the groups&#46; As expected&#44; lung function was significantly impaired in COPD individuals compared to the healthy reference group&#44; and there was a wide range of COPD severity in our cohort&#46; Although to a lesser degree&#44; lung function was also decreased in individuals with respiratory symptoms compared to the reference group&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Plasma levels of AAT and other markers of systemic inflammation</span><p id="par0055" class="elsevierStylePara elsevierViewall">In the entire cohort&#44; levels of AAT were 1&#46;51 &#40;0&#46;47&#41;<span class="elsevierStyleHsp" style=""></span>g&#47;L&#44; with no significant differences between men and women&#46; Notably&#44; a subset of cases &#40;57 or 6&#46;8&#37;&#41; exhibited particularly low levels of plasma AAT &#40;below 1<span class="elsevierStyleHsp" style=""></span>g&#47;L&#41;&#58; 20 within COPD&#44; 9 within those having respiratory symptoms and 28 within the reference group&#46; Unfortunately&#44; in this cross-sectional study&#44; genotypes of AAT were not determined and therefore the correlation between genotype and low AAT protein levels could not be analyzed&#46; Removing low-AAT cases as outliers did not affect the observations&#44; and these 57 cases were included in the final analysis&#46; When compared to reference group&#44; subjects with respiratory symptoms or COPD showed higher plasma levels of AAT &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; As illustrated in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; analysis of other plasma proteins revealed that COPD subjects had significantly higher plasma levels of CRP&#44; IL-6 and fibrinogen but lower albumin concentrations if compared to the reference group&#46; Plasma levels of TNF&#945; were higher in the COPD and respiratory symptoms groups compared to reference&#44; whereas IL-8 did not significantly differ among the groups&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Plasma AAT levels in relationship to respiratory health and laboratory measures</span><p id="par0060" class="elsevierStylePara elsevierViewall">We next examined the relationship between plasma AAT levels and clinical&#47;laboratory measures&#46; For this&#44; we applied three types of linear regression models&#58; univariate&#44; correcting for CRP&#44; and multivariate&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; plasma AAT levels were significantly affected by cohort &#40;healthy&#44; respiratory symptoms or COPD&#41;&#44; smoking status &#40;smokers but not ex-smokers&#41;&#44; lung function tests&#44; and levels of CRP&#44; IL-6&#44; IL-8&#44; fibrinogen and albumin&#44; but not by TNF&#945;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Levels of AAT were higher in individuals with COPD or with respiratory symptoms compared to the reference group&#44; an effect that persisted after age and CRP correction&#44; as well as in the multivariate model&#46; Age did not show an impact on AAT levels&#46; Plasma levels of CRP&#44; IL-6&#44; IL-8 and albumin were positively associated&#44; whereas levels of fibrinogen were negatively associated with AAT&#46; After correcting for CRP levels&#44; most parameters remained significantly associated with AAT levels with the exception of FEV1 &#40;pre and post-bronchodilators&#41;&#46; The multivariate analysis included smoking status&#59; post FEV&#47;FVC&#44; CRP&#44; IL-6&#44; IL-8&#44; fibrinogen and albumin&#46; Even when modeled jointly&#44; each of these parameters contributed significantly to the multivariate model&#46; This implies that there is an independent relationship of each of these factors to plasma AAT levels&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">The relationship between AAT levels and measures of airway obstruction</span><p id="par0070" class="elsevierStylePara elsevierViewall">We also examined whether our data above support the relationship between plasma AAT levels and lung function&#46; To do this&#44; we modeled lung function measures&#44; FEV1 and FEV1&#47;FVC&#44; as a function of AAT and other relevant analytics in both univariate and multivariate models &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; In the univariate model&#44; FEV1 was significantly and inversely associated with AAT levels&#44; but the effect was weaker relative to factors like sex&#44; BMI and smoking status&#46; When combining these terms in a multivariate model&#44; the above independent effect of AAT was diminished to non-significant level &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;32&#41;&#46; However&#44; the association between plasma AAT levels and lung function&#44; as measured by FEV1&#47;FVC ratio&#44; was more robust&#46; Here the inverse association was stronger and remained independently significant even when correcting for other associated factors such as age&#44; sex&#44; smoking status&#44; CRP&#44; TNF&#945;&#44; fibrinogen and albumin&#46; Incidental to the associations of AAT with lung function&#44; we also observe significant decreases in lung function with increased age&#44; smoking&#44; BMI&#44; and CRP&#46; Lung function &#40;FEV1&#41; was positively associated with being female and albumin&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">A number of outliers with a high AAT level and high FEV1&#47;FVC &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; allows suggesting that responders with high AAT may actually be protected from severe COPD when adjusting for smoking and age&#46; Therefore&#44; only for individuals with high AAT levels&#44; we investigated the associations between AAT and FEV1&#47;FVC&#46; We were unable to observe any indications of protection although the low numbers of cases available leaves us underpowered for any conclusive statements&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Dose response relationship between smoke and AAT level</span><p id="par0080" class="elsevierStylePara elsevierViewall">We have explored whether there is a dose response relationship between smoke and AAT level&#46; By using AAT levels and smoking status as an interaction term in the model&#44; we observed no significant interactions in this cohort&#46; However&#44; we observed for the cohort as a whole&#44; that pack-years were associated with decreased lung function in our multivariate model &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>3&#46;3 E10&#8722;7&#41;&#46; When used in an interaction term with AAT&#44; we also observed that this interaction was significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;06 for FEV1 and 0&#46;009 for FEV&#47;FVC&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">COPD as a function of plasma AAT levels&#58; binomial logistic regression analysis</span><p id="par0085" class="elsevierStylePara elsevierViewall">Based on the findings above&#44; we were interested in the association of AAT levels with COPD in the context of the other measured clinical variables&#46; To this end&#44; we modeled COPD diagnosis as a function of plasma AAT levels and other measured parameters using binomial logistic regression &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; The risk for COPD significantly increased with higher AAT levels in both the univariate and multivariate models&#44; with odds ratios of 1&#46;8 and 1&#46;5&#44; respectively&#46; The univariate model demonstrated that sex&#44; smoking status and CRP levels were associated with COPD&#46; In the multivariate model&#44; these parameters continued to be associated with COPD probability&#44; demonstrating that they act independently&#46; Similarly&#44; we looked at the AAT levels as a risk for respiratory symptoms&#46; Here&#44; we did not observe a significant association with AAT after accounting for other factors&#44; such as smoking status&#44; TNF&#945;&#44; IL-8&#44; and IL-6&#46; Herein smoking status appears to be a strongest risk factor for respiratory symptoms in a non-COPD population&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">The present study includes Spanish population-based cohort of 837 participants with measured plasma levels of AAT and their detailed characterization&#44; which allows investigating factors associated with circulating AAT&#44; as well as the association of the AAT levels with health indicators of the respiratory system&#46; Importantly&#44; based on CRP measurements we were able to control for systemic inflammation&#44; as a potential confounder&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Although determined AAT levels were within the normal reference range &#91;mean &#40;SD&#41; 1&#46;51 &#40;0&#46;47&#41;<span class="elsevierStyleHsp" style=""></span>g&#47;L&#93;&#44; participants with stable COPD or with respiratory symptoms showed 8&#46;4&#37; and 9&#46;8&#37; higher levels of plasma AAT than healthy participants &#91;1&#46;43 &#40;0&#46;47&#41;<span class="elsevierStyleHsp" style=""></span>g&#47;L&#93;&#44; a finding which was statistically significant and persisted after correction for age and CRP&#46; Results from both the univariate and multivariate models revealed that the risk for COPD was significantly associated with higher circulating levels of AAT&#46; This relationship remained significant even after correction for other factors associated with COPD&#44; such as age&#44; sex&#44; smoking status&#44; CRP&#44; TNF&#945;&#44; fibrinogen and albumin&#46; In fact&#44; we did not observe a significant association between plasma levels of AAT and respiratory symptoms&#46; Herein&#44; smoking status appears to be the strongest risk factor for respiratory symptoms in non-COPD subjects&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Our present findings are in line with those of a Copenhagen General Population study demonstrating that elevated plasma AAT levels were associated with COPD and increased risk of exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> Similarly the epidemiologic study published by Thomsen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a> found higher plasma levels of AAT in never smokers with COPD than in never smokers without COPD&#46; Furthermore&#44; in small cohorts&#44; others and ourselves previously reported higher serum levels of AAT in COPD patients than in controls&#44; independent of genetic AAT-variant&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14&#44;15</span></a> Altogether&#44; previous and our current results provide evidence that higher levels of AAT are associated with COPD&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">It is important to point out that in the population-based Swiss SAPALDIA cohort&#44; circulating AAT levels were inversely correlated with FEV1&#44; but only in the absence of CRP adjustment&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> Accordingly&#44; in our study FEV1 was also significantly and inversely associated with AAT levels&#44; but only without adjustment for other factors like CRP&#44; sex&#44; BMI&#44; and smoking status&#46; However&#44; the negative association between plasma AAT levels and lung function&#44; as measured by FEV1&#47;FVC ratio&#44; was stronger and remained independently significant after adjusting for other associated factors&#44; such as sex&#44; smoking status&#44; CRP&#44; TNF&#945;&#44; fibrinogen and albumin&#46; The ratio of FEV1&#47;FVC is the major determinant of airflow obstruction and the diagnosis of COPD&#46; Therefore&#44; we think that the association between plasma levels of AAT and lung function may depend on the tests performed and used for data analysis&#46; Further studies are required to confirm our suggestion&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">COPD is chronic inflammatory disease&#46; Several studies proposed that elevated circulating inflammatory markers&#44; such as CRP&#44; fibrinogen and inflammatory cytokines &#40;TNF&#945;&#44; IL-6&#44; and IL-8&#41; predict morbidity and mortality of patients with COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">17&#44;18</span></a> Specifically CRP&#44; a clinical indicator of inflammation&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a> has repeatedly been recommended as a useful predictor of clinical outcomes in patients with COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">20&#8211;22</span></a> Large prospective studies following healthy people for up to 20 years found that a chronically elevated CRP is associated with a progressive loss of lung function and a greater risk of COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">23&#44;24</span></a> A recent study by Bradford et al&#46; found a strong association between IL-6 and COPD status&#44; airflow limitation and emphysema progression&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">25</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">By using the univariate and multivariate models&#44; we found that the risk for COPD significantly increased with higher levels of AAT&#46; In the multivariate model&#44; we also found that sex&#44; smoking status and CRP levels were associated with having COPD&#44; suggesting that they act independently&#46; Similar to CRP or other acute phase proteins&#44; the synthesis of AAT regulated through the action of pro-inflammatory cytokines&#44; specifically IL-6&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a> Therefore&#44; in parallel to increased IL-6 and CRP levels&#59; the low-grade upregulation of AAT in stable COPD may also be useful as a long-term predictor of future outcomes&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The above-mentioned results emphasize that COPD is associated with low-grade systemic inflammation and that circulating cytokines and acute-phase proteins function adversely by maintaining activation of innate immune hyper-responsiveness in the circulation as well as in the lungs&#46; The systemic inflammation in COPD may also explain&#44; at least in part&#44; extra-pulmonary manifestations&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Our study has some strengths and limitation&#46; The strengths include the sample size&#44; population-based design&#44; and the detailed characterization of the participants&#44; which allowed us to investigate factors associated with circulating AAT levels as well as the association of the AAT with lung function and COPD&#46; The limitations to be considered are that &#40;i&#41; biomarkers were assessed at only a single time point and thus we could not assess their fluctuation during the course of the disease&#44; &#40;ii&#41; the genotypes of AAT were not determined&#44; and &#40;iii&#41; although significant&#44; the differences in AAT levels between groups were of small magnitude&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">We believe that combining information from AAT levels and other acute phase reactants may improve the prediction of risk and&#47;or progression in COPD&#46; It may also help to explain controversies as to whether -systemic inflammation in COPD represents &#8216;spill over&#8217; from the lung inflammation or is a chronic systemic process&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> According to recently reported mouse model&#44; the liver may amplify innate immune responsiveness in the lungs after bacterial infection&#46; This latter seems to depend on increased release of IL-6 by alveolar macrophages along with other acute-phase proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> The liver is a main organ producing and releasing into the circulation acute phase proteins&#44; including AAT and CRP&#46; Different studies demonstrated that activated lung epithelial cells&#44; alveolar macrophages and granulocytes also contribute to the pool of circulating AAT&#46; Whether higher plasma levels of AAT in patients with COPD mirror &#8216;spill over&#8217; from the lungs or increased release by the liver&#44; we cannot yet answer&#46; Inflammatory process initiated in the lung or elsewhere&#44; may lead to the injury in the alveolar space&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a> In support&#44; results from a Norwegian general population study revealed that increased levels of AAT were associated with a decrease in lung diffusion capacity&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a> Further studies would be necessary to confirm our results and elucidate the source of increased plasma AAT in COPD&#46; Finally&#44; the interest in AAT as a prognostic marker may help to increase the determinations of this protein in COPD and eventually reduce the under diagnosis of the AAT deficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conclusion</span><p id="par0135" class="elsevierStylePara elsevierViewall">There is a considerable inter-individual variation in the circulating levels of AAT&#44; and there is no doubt that this plays an important role during health and diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> Nevertheless&#44; the variability of plasma AAT levels in population-based studies and the possible incorporation of this variability in disease risk assessment remain largely unexplored&#46; A large body of evidence shows that the degree of risk for COPD inversely relates to the plasma level of AAT according to the AAT genotypes&#58; NullNull<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>ZZ<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>SZ<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>MZ&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">33&#44;34</span></a> Our study confirms that increased circulating levels of AAT&#44; similarly to CRP&#44; IL-6 and other putative markers of systemic inflammation&#44; is an important feature of COPD&#46; Hence&#44; determination of AAT concentrations can be an important diagnostic and&#47;or monitoring test not only for people with suspected inherited AAT deficiency&#44; but also for a general population with and- without COPD&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflicts of interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">Miriam Barrecheguren has received speaker fees from Grifols&#44; Menarini&#44; and consulting fees from Novartis and Gebro Pharma&#44; unrelated to this manuscript&#46; Marc Miravitlles has received speaker or consulting fees from AstraZeneca&#44; Bial&#44; Boehringer Ingelheim&#44; Chiesi&#44; Cipla&#44; CSL Behring&#44; Laboratorios Esteve&#44; Ferrer&#44; Gebro Pharma&#44; GlaxoSmithKline&#44; Grifols&#44; Menarini&#44; Mereo Biopharma&#44; Novartis&#44; pH Pharma&#44; Rovi&#44; TEVA&#44; Verona Pharma and Zambon&#44; and research grants from GlaxoSmithKline and Grifols&#44; unrelated to this manuscript&#46;</p></span></span>"
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          "titulo" => "Methods"
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              "identificador" => "sec0015"
              "titulo" => "Design of the study"
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            1 => array:2 [
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              "titulo" => "Study participants"
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              "titulo" => "Statistical analysis"
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          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Characteristics of study participants"
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            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Plasma levels of AAT and other markers of systemic inflammation"
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            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Plasma AAT levels in relationship to respiratory health and laboratory measures"
            ]
            3 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "The relationship between AAT levels and measures of airway obstruction"
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              "identificador" => "sec0060"
              "titulo" => "Dose response relationship between smoke and AAT level"
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              "identificador" => "sec0065"
              "titulo" => "COPD as a function of plasma AAT levels&#58; binomial logistic regression analysis"
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          "titulo" => "Conflicts of interest"
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          "titulo" => "Acknowledgments"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2018-12-10"
    "fechaAceptado" => "2019-03-02"
    "PalabrasClave" => array:2 [
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          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "Alpha1-antitrypin"
            1 => "Acute phase reactants"
            2 => "COPD"
            3 => "Lung function"
            4 => "Respiratory symptoms"
          ]
        ]
      ]
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          "palabras" => array:5 [
            0 => "Alfa-1 antitripsina"
            1 => "Reactantes de fase aguda"
            2 => "EPOC"
            3 => "Funci&#243;n pulmonar"
            4 => "S&#237;ntomas respiratorios"
          ]
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    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Background</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Low plasma level of alpha1-antitrypsin &#40;AAT&#41; is an established risk factor for early-onset chronic obstructive lung disease &#40;COPD&#41;&#46; However&#44; less attention is given to the levels of AAT in the general population&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">This is a part of a multicentre&#44; population-based study conducted at 11 sites throughout Spain&#46; Plasma levels of AAT were available for 837 persons with a mean &#40;SD&#41; age of 58&#46;05 &#40;11&#46;3&#41; years&#58; 328-smokers&#44; 272-ex-smokers and 237 non-smokers&#46; Out of 837&#44; 303 &#40;36&#46;2&#37;&#41; had a diagnosis of COPD&#44; 222 &#40;26&#46;5&#37;&#41; had respiratory symptoms but no COPD&#44; and 312 &#40;37&#46;3&#37;&#41; were healthy controls&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In the whole cohort&#44; the mean level of plasma AAT was 1&#46;51 &#40;0&#46;47&#41;<span class="elsevierStyleHsp" style=""></span>g&#47;L&#46; Levels were higher in COPD patients &#91;1&#46;55 &#40;0&#46;45&#41;<span class="elsevierStyleHsp" style=""></span>g&#47;L&#93; and individuals with respiratory symptoms &#91;1&#46;57 &#40;0&#46;47&#41;<span class="elsevierStyleHsp" style=""></span>g&#47;L&#93; than in controls &#91;1&#46;43 &#40;0&#46;47&#41;<span class="elsevierStyleHsp" style=""></span>g&#47;L&#93;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; a finding which persisted after correction for age and CRP&#46; Plasma AAT levels were negatively associated with FEV1&#47;FVC ratio&#44; after adjustment for age&#44; sex&#44; smoking status&#44; CRP&#44; TNF&#945;&#44; fibrinogen and albumin&#46; The risk for COPD was significantly associated with higher AAT levels in univariate and multivariate models&#44; with odds ratios of 1&#46;8 and 1&#46;5&#44; respectively&#46; In the univariate and multivariate models smoking status&#44; gender&#44; and CRP levels were also associated with COPD probability&#44; demonstrating that they act independently&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Increased circulating levels of AAT&#44; similarly to CRP and other markers of systemic inflammation&#44; is an important feature of COPD&#46; Our results highlight a complex interrelationship between levels of AAT and health of respiratory system&#46;</p></span>"
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            "titulo" => "Background"
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            "titulo" => "Methods"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Los niveles plasm&#225;ticos bajos de alfa-1 antitripsina &#40;AAT&#41; constituyen un factor de riesgo para el desarrollo temprano de la enfermedad pulmonar obstructiva cr&#243;nica &#40;EPOC&#41;&#46; Sin embargo&#44; se ha prestado una menor atenci&#243;n a los niveles de AAT en la poblaci&#243;n general&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">M&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Este trabajo forma parte de un estudio poblacional multic&#233;ntrico llevado a cabo en 11 centros espa&#241;oles&#46; Se incluyeron niveles de AAT de 837 personas con una edad media &#40;DE&#41; de 58&#44;05 &#40;11&#44;3&#41; a&#241;os&#58; 328 fumadores&#44; 272 exfumadores y 237 no fumadores&#46; De los 837&#44; a 303 &#40;36&#44;2&#37;&#41; se les diagnostic&#243; EPOC&#44; 222 &#40;36&#44;5&#37;&#41; presentaron s&#237;ntomas respiratorios pero no EPOC y 312 &#40;37&#44;3&#37;&#41; eran controles sanos&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">En la cohorte total&#44; los niveles plasm&#225;ticos medios de AAT fueron 1&#44;51 &#40;0&#44;47&#41;<span class="elsevierStyleHsp" style=""></span>g&#47;l&#46; Los pacientes con EPOC y los individuos con s&#237;ntomas respiratorios presentaron niveles m&#225;s elevados &#40;1&#46;55 &#91;0&#46;45&#93;<span class="elsevierStyleHsp" style=""></span>g&#47;l y 1&#46;57 &#91;0&#46;47&#93;<span class="elsevierStyleHsp" style=""></span>g&#47;l respectivamente&#41; que los sujetos control &#40;1&#46;43 &#91;0&#46;47&#93;<span class="elsevierStyleHsp" style=""></span>g&#47;l&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Este resultado se mantuvo tras la correcci&#243;n por edad y niveles de prote&#237;na C reactiva &#40;PCR&#41;&#46; Los niveles plasm&#225;ticos de AAT se asociaron negativamente con la relaci&#243;n FEV<span class="elsevierStyleInf">1</span>&#47;FVC tras el ajuste por edad&#44; sexo&#44; h&#225;bito tab&#225;quico&#44; niveles de PCR&#44; TNF&#945;&#44; fibrin&#243;geno y alb&#250;mina&#46; El riesgo de EPOC se asoci&#243; significativamente con niveles m&#225;s elevados de AAT tanto en el modelo univariante como el multivariante&#44; con <span class="elsevierStyleItalic">odds ratios</span> de 1&#44;8 y 1&#46;5 respectivamente&#46; En los modelos univariantes y multivariantes&#44; el h&#225;bito tab&#225;quico&#44; el sexo&#44; y los niveles de PCR tambi&#233;n se asociaron con la probabilidad de sufrir EPOC&#44; lo cual demostr&#243; que se trataba de variables independientes&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusi&#243;n</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Un aumento de los niveles circulantes de AAT&#44; al igual que los niveles de PCR y otros marcadores de inflamaci&#243;n sist&#233;mica&#44; son caracter&#237;sticas importantes de la EPOC&#46; Nuestros resultados evidencian la compleja interrelaci&#243;n existente entre los niveles de AAT y la salud del aparato respiratorio&#46;</p></span>"
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            "titulo" => "Introducci&#243;n"
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            "titulo" => "M&#233;todos"
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            "titulo" => "Resultados"
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            "titulo" => "Conclusi&#243;n"
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            "apendice" => "<p id="par0150" class="elsevierStylePara elsevierViewall">The organization of the EPI-Scan study was as follows&#58;</p> <p id="par0155" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Scientific Committee</span>&#58; Julio Ancochea&#46; Hospital La Princesa &#40;Madrid&#41;&#44; Carlos Badiola and Guadalupe S&#225;nchez&#44; GlaxoSmithkline &#40;Madrid&#41;&#44; Enric Duran&#46; Institut Municipal d&#8217;Investigaci&#243; M&#232;dica &#40;IMIM&#41; &#40;Barcelona&#41;&#44; Francisco Garc&#237;a R&#237;o&#46; Hospital La Paz &#40;Madrid&#41;&#44; Marc Miravitlles&#46; Hospital Universitari Vall d&#8217;Hebron &#40;Barcelona&#41;&#44; Luis Mu&#241;oz&#46; Hospital Reina Sof&#237;a &#40;C&#243;rdoba&#41;&#44; V&#237;ctor Sobradillo&#46; Hospital de Cruces &#40;Bilbao&#41;&#44; Joan B Soriano&#46; Fundaci&#243; Caubet-CIMERA &#40;Bunyola&#44; Illes Balears&#41;&#46; <span class="elsevierStyleItalic">Participating sites and coordinators</span>&#58; Julio Ancochea&#46; Hospital La Princesa &#40;Madrid&#41;&#44; Luis Borderias&#46; Hospital San Jorge &#40;Huesca&#41;&#44; Francisco Garc&#237;a R&#237;o&#46; Hospital La Paz &#40;Madrid&#41;&#44; Jaime Mart&#237;nez&#46; Hospital Central de Asturias &#40;Oviedo&#41;&#44; Teodoro Montemayor&#46; Hospital Virgen de la Macarena &#40;Sevilla&#41;&#44; Luis Mu&#241;oz&#46; Hospital Reina Sof&#237;a &#40;C&#243;rdoba&#41;&#44; Luis Pi&#241;eiro&#46; Hospital Xeral Cies &#40;Vigo&#41;&#44; Joan Serra&#46; Hospital General de Vic &#40;Vic&#44; Barcelona&#41;&#44; Juan Jos&#233; Soler-Catalu&#241;a&#46; Hospital General de Requena &#40;Requena&#44; Valencia&#41;&#44; Antoni Torres&#46; Hospital Cl&#237;nic &#40;Barcelona&#41;&#44; Jos&#233; Luis Viejo&#46; Hospital General Yag&#252;e &#40;Burgos&#41;&#46;</p>"
            "etiqueta" => "Appendix A"
            "titulo" => "<span class="elsevierStyleBold">Annex</span>"
            "identificador" => "sec0085"
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            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0095"
          ]
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      ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1615
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            "Tamanyo" => 123129
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of total number of patients included in and excluded from the EPI-SCAN study and patients with available data on plasma AAT levels&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 3173
            "Ancho" => 2500
            "Tamanyo" => 422835
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">The multivariate relationship between AAT levels and clinical measures &#40;graphical presentation of the data analysis presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p>"
        ]
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">a&#58; vs reference&#59; b&#58; vs respiratory symptoms&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variables&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">All subjects<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>837&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Respiratory symptoms&#44; <span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>312&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">138&#47;174&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pack years&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">BMI &#40;kg&#47;m</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Pulmonary function</span><a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a></td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>FVC &#40;&#37; pred&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>FEV1 &#40;&#37; pred&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>FEV1&#47;FVC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>TNF &#40;pg&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0&#46;010&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;095&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Ex-smokers&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;0017&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;043&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">FVC &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8722;0&#46;00068&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;56&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;00047&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">FEV1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8722;0&#46;0017&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8722;0&#46;0008&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">FEV1&#47;FVC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8722;0&#46;0046&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;017&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8722;0&#46;0037&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Post FVC &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8722;0&#46;00074&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;56&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Post FEV1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;018&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8722;0&#46;0017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8722;0&#46;00067&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Post FEV1&#47;FVC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;0040&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;0044&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;028&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;0032&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CRP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&#46;50E&#8722;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">na&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">na&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;0E&#8722;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TNF&#945;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8722;0&#46;043&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;13&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;0023&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&#46;60E&#8722;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;0078&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;0056&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;0047&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;0025&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;0049&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">5&#46;70E&#8722;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;0061&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;40E&#8722;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;0051&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">2&#46;2E&#8722;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;0050&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibrinogen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  """
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;0016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Ex-smokers&nbsp;\t\t\t\t\t\t\n
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                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2343793.png"
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Lung function tests as a function of AAT and other parameters&#46;</p>"
        ]
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      5 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
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                0 => """
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">COPD</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Respiratory symptoms</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Univariate model</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Multivariate model</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Univariate model</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">multivariate model</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-Value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Odds ratio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-Value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Odds ratio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-Value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Odds ratio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-Value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Odds ratio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AAT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0020&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;038&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;55&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;045&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;9E&#8722;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;6E&#8722;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;049&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;048&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ex-smokers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;8E&#8722;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;6E&#8722;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;3E&#8722;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;7E&#8722;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smokers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;1E&#8722;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;8E&#8722;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;8E&#8722;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0E&#8722;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CRP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0049&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;065&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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