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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The global burden of tuberculosis &#40;TB&#41; is currently still very high&#46; It represents one of the major causes of infectious disease mortality despite the availability of curative treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a> Moreover&#44; latent tuberculosis infection &#40;LTBI&#41; affects over a third of the worldwide population posing a high risk for later reactivation of the disease&#46; Therefore&#44; TB chemotherapy is essential as an intention-to-cure measure and also as a public health policy to prevent <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> transmission&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Portugal remains the only country in Western Europe with an intermediary-prevalence of tuberculosis&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a> In 2012 alone&#44; a total of 2399 new cases of TB were reported&#44; for an estimated 22&#46;8 cases per 100&#44;000 inhabitants&#44; while 157 patients died of TB while on treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">TB disease is treated with multiple effective drugs combined for a long period of time that extends for a minimum of 6 months&#44; but in special circumstances there is demand for longer treatments&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">3&#44;4</span></a> Treatment completion&#44; defined by the number of doses taken over a period of time&#44; is vital to prevent treatment failure&#44; relapse and development of resistance&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Four drugs form the core of treatment regimens for drug-susceptible organisms&#58; PZA&#44; isoniazid &#40;INH&#41;&#44; rifampicin &#40;RIF&#41; and ethambutol &#40;EMB&#41;&#46; All of these first-line drugs can induce mild to severe adverse drug reactions &#40;ADR&#41;&#44; including&#58; hepatotoxicity associated to INH&#44; RIF and PZA&#59; cutaneous reactions associated to INH&#44; PZA and EMB&#59; gastrointestinal intolerance to RIF&#59; and retrobulbar neuritis related to EMB&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">5&#8211;7</span></a> Since streptomycin &#40;SM&#41; was no longer considered a first-line drug there was a diminished incidence of ototoxicity&#44; its main side effect&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">8</span></a> Regarding latent tuberculosis infection &#40;LTBI&#41;&#44; standard regimens as&#44; for example&#44; short-courses of INH plus RIF are associated with an increased risk for ADR such as hepatotoxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">7&#44;9&#44;10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">When an ADR occurs&#44; especially when severe&#44; one or more drugs may have to be discontinued or treatment interrupted&#44; which has multiple implications&#44; particularly extended treatment time and an increased risk for drug resistance&#44; treatment failure and relapse&#46; In addition&#44; use of alternative regimens are also related to important side effects and pose compliance issues&#46; All patients must be closely monitored to immediately recognize major ADR and activate proper therapeutic measures&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Patient selection and follow-up</span><p id="par0030" class="elsevierStylePara elsevierViewall">Between 2004 and 2013&#44; all patients who experienced major ADR due to first-line antituberculosis drugs provided on ambulatory basis by our Pulmonology Diagnostic Centre &#40;PDC&#41; were identified and all demographic and clinical data were retrospectively collected&#46; Data from a group control consisting of a matched population by sex&#44; age and year of initiation of treatment were also assembled for comorbid conditions analysis&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Inclusion criteria were as follows&#58; age of 17 years or older&#59; established diagnosis of active TB&#44; either pulmonary or extrapulmonary&#44; or proven LTBI&#59; treatment regimen with first-line antituberculosis drugs&#59; confirmed ADR to at least one of the antituberculosis drugs&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">TB was defined as a clinically compatible illness confirmed by microbiological analysis or&#44; when negative&#44; a case with compatible clinical&#44; radiologic&#44; and&#47;or histologic findings&#44; and exhibiting positive response to treatment&#46; LTBI was defined by the absence of clinical features suggestive of TB&#44; normal chest radiographic examination and a positive tuberculin skin test &#40;TST&#41; induration&#46; Since 2008&#44; after the acquisition of laboratory means to perform the interferon gamma release assay &#40;IGRA&#41; using the ELISA method &#40;Quantiferon-TB<span class="elsevierStyleSup">&#174;</span> Gold In-tube&#41;&#44; this highly specific test was implemented as an active screening routine to confirm all positive TST reactions from patients suspected of having TB infection and support treatment decision&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Once having started antituberculosis treatment&#44; all patients were closely monitored for surveillance of possible ADR and other disease-related complications&#46; The first appointment occurred 15 days after beginning treatment&#44; the second appointment at 1-month of treatment and the following ensued at monthly intervals&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Blood tests including complete blood count &#40;CBC&#41;&#44; liver transaminases&#44; bilirubin &#40;total and partial&#41; and creatinine&#44; were routinely checked at 15&#44; 30 and 60 days of treatment and&#44; afterwards&#44; once each 2 months until the treatment was completed&#46; Viral serology for hepatitis and HIV were routinely assessed&#44; mostly before starting antituberculosis treatment&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Whenever necessary&#44; as in the event of a serious side effect or complication&#44; the patient was consulted or serum analyses were done beyond the usual routine&#46; Also&#44; if required&#44; other complementary studies were added to the standard evaluation&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">From patient&#39;s clinical records and national registration forms&#44; information was collected regarding sex&#44; age&#44; nationality&#44; residency&#44; career occupation&#44; symptoms&#44; risk factors such as intravenous drug abuse&#44; alcoholism or residence in a social support community&#44; comorbidities&#44; site of disease&#44; diagnostic tests&#44; initial treatment&#44; adverse effects and outcomes&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Major ADR were defined as those that required discontinuation of one or more drugs&#44; shift to second-line drugs or hospital admission&#46; When all drugs were suspended&#44; they were restarted after clinical and&#47;or laboratory complete resolution&#44; in a sequential way to possibly isolate the drug that caused the toxicity&#46; A second-line treatment was initiated when a slow resolution was anticipated or treatment interruption was not desirable&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Hepatitis was defined as liver transaminases more than three times higher than the upper limit of normal in the presence of symptoms such as nausea&#44; vomiting or abdominal pain&#44; or transaminases more than five times the upper limit of normal without symptoms&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Significant episodes of cutaneous toxicity related to extensive eruption&#44; symptoms like fever and mucous membrane involvement&#44; or to sustained complaints while on medication with anti-histaminic drugs&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Gastrointestinal disturbance was considered major when there was no improvement despite measures such as combining the timing of administration to main meals or proton pump inhibitor medication&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Loss of visual acuity was routinely assessed by a careful ophthalmologic examination and related to anti-TB drugs when all other causes had been excluded&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Statistical analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">Data analysis was executed by IBM SPSS<span class="elsevierStyleSup">&#174;</span> for Windows version 20&#46;0&#46; All demographic and clinical features were reported using frequency and descriptive analyses&#46; 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due to treatment suspension or termination &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Adverse reactions</span><p id="par0155" class="elsevierStylePara elsevierViewall">The most frequent ADR was hepatitis&#46; Five of these patients were alcoholic&#44; two had a previous history of chronic liver disease and one was HIV-positive&#46; Asymptomatic hepatotoxicity occurred in 35 cases and the remaining 18 were symptomatic&#46; The most common symptoms were nausea&#44; vomiting and abdominal pain&#46; One female patient with no history of comorbid conditions had a poor outcome and needed liver transplantation while all others had complete liver transaminases normalization&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Rash occurred in five cases&#44; with itchiness in three of them&#44; and was the second most frequent adverse reaction&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">One patient with chronic inflammatory arthritis and LTBI suffered gastrointestinal toxicity associated to RIF&#46; One other patient with LTBI and no significant comorbid conditions had an episode of angioedema 25 days after initiating INH plus RIF anti-TB regimen which was subsequently interrupted&#46; EMB was responsible for one single case of ocular toxicity in a patient with genitourinary TB whose visual acuity was never restored&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Side effects emerged mainly after 2 months of anti-TB drug regimen and more than half of these patients had their treatment stopped before completing the total number of doses and had&#44; on average&#44; a total time of treatment 0&#46;7 months less than the predicted one&#46; The remaining had an increase in the overall time of treatment due to one or more interruptions&#46; Only seven cases of side effects during this period had LTBI and the majority had pulmonary TB &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">A small proportion of ADR developed during the initial phase of treatment&#44; that is&#44; before completing 2 months of treatment&#46; Eight of those had a decrease and 11 had an increase in the total number of months of treatment&#46; Nine had LTBI&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">It was not possible to identify which specific drug was responsible for the ADR in 82&#37; of the cases since the drug rechallenge occurred with only minor residual effects&#44; allowing treatment to continue&#44; or it was definitively suspended with no further rechallenge&#46; In these situations&#44; all drugs that could have caused that effect were considered responsible&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The combination of INH and RIF was largely responsible for the incidence of side effects&#44; specifically for 41 hepatotoxicity events and 3 cutaneous reactions&#46; Those two drugs plus PZA accounted for six more cases of drug-induced hepatitis&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">PZA&#44; INH&#44; RIF&#44; and EMB were responsible for 5&#44; 3&#44; 2 and 1 major side effect&#44; respectively&#46; SM was not associated to any major ADR&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">No correlation was found between age or sex and the overall incidence of ADR&#46; However&#44; when considering each category of ADR&#44; younger age was meaningfully related to an increased risk of hepatotoxicity &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#44; which was 0&#46;96 times smaller for each year that the age increased&#46; In this group of patients&#44; mean age was 49&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;4 years while those that had no drug-related hepatitis had a mean age of 64&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;4 years&#46; On the other hand&#44; an important association was found between male gender and toxicity to both INH and PZA but this did not achieve statistical significance &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;055&#41;&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Diabetes mellitus and major ADR were significantly associated &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;042&#41; but the same could not be stated for other comorbidities or multidrug resistance risk factors&#46; One diabetic patient had his treatment with oral anti-diabetic drugs changed to insulin therapy after being diagnosed with TB for an optimal glycaemic control&#44; while the remaining were already being treated with insulin&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0205" class="elsevierStylePara elsevierViewall">ADR to first-line antituberculosis medication are frequent and have important implications that may affect the effectiveness of treatment&#44; the course of TB disease and chemoprophylaxis in latent infection&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">In our study&#44; out of 764 patients treated with first-line antituberculosis drugs for active and latent TB&#44; 55 &#40;7&#46;2&#37;&#41; had at least one major side effect for a total of 61 ADR&#44; which was not as high as in other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">11&#44;12</span></a> The overall incidence of severe ADR was highest in combined treatment with INH and RIF&#44; in patients aged 35 years or older and in the male gender&#44; but none of these variables were statistically significant&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">It was only possible to attribute responsibility for the ADR to one particular drug in 18&#46;0&#37; of the cases&#46; The main reason was that when sequential drug rechallenge was implemented&#44; side effects did not recur and the most likely associated drugs were considered probably responsible&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">There was a high incidence of hepatotoxicity &#40;6&#46;9&#37;&#41; compared to previous studies performed in both active and latent TB patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">6&#44;12&#8211;14</span></a> Hepatotoxicity was most likely to be associated to chemotherapy combination of INH and RIF&#44; which has previously been stated to increase the risk of liver injury among patients under antituberculosis treatment compared to regimens containing only one of those drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a> A metabolic idiosyncratic mechanism by which additional toxic INH metabolites are produced seems to be the underlying mechanism promoted by RIF to boost hepatotoxicity of other antituberculosis medications&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">The overall rate of INH-related hepatitis was 0&#46;3&#37; while that associated to LTBI was 0&#46;1&#37;&#44; which is similar to the rates published in recent literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">PZA is recognized as the most hepatotoxic among first-line antituberculosis drugs acting on both dose dependent and idiosyncratic mechanisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">6&#44;11&#44;12&#44;20&#8211;22</span></a> Our findings suggested a slight increase in the incidence of hepatotoxicity &#40;0&#46;8&#37;&#41; when used in combination with INH and RIF with a minor rate of hepatitis attributed to PZA alone &#40;0&#46;5&#37;&#41;&#46; Other studies have also shown an increased risk of hepatotoxicity with PZA especially when added to other antituberculosis drugs such as INH and rifampin&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a> PZA was also responsible for the one single case of severe hepatotoxicity that progressed to liver transplantation&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Hepatotoxicity causes significant morbidity and mortality&#44; which justifies the numerous studies to define its predisposing factors but results are still controversial&#46; Our series found no correlation between reported risk factors such as preexisting liver disease&#44; high alcohol intake or other comorbidities&#44; and hepatotoxicity&#46; However&#44; this may reflect the overall lack of comorbid conditions in the studied population&#44; which usually has a higher prevalence in patients with hospital follow-up&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Cutaneous rash was the second most frequent ADR with an overall incidence of 8&#46;2&#37;&#46; In fact&#44; cutaneous adverse reactions are commonly observed in patients with antituberculosis drugs and are an important cause of treatment discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> Therapeutic regimens with both INH and RIF were mainly responsible for this ADR although most studies suggest that PZA is the most common offending agent&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Other ADR such as angioedema&#44; gastrointestinal upset and ocular toxicity were rare and each occurred in only one patient&#44; accounting for an overall incidence of 1&#46;6&#37;&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Diabetes was significantly correlated to major ADR&#46; Several studies have suggested that diabetes increases the risk of active TB&#44; especially in the elderly&#44; and leads to worst treatment outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">25&#8211;29</span></a> Also&#44; some small series have shown that metabolic disorders such as diabetes may act as independent risk factors for ADR&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">30&#44;31</span></a> Oral anti-diabetic and antituberculosis drugs may interact and lead to a suboptimal glycaemic control on the one hand&#44; and lower the efficacy of TB treatment on the other hand&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">32</span></a> However&#44; in our study&#44; all diabetic patients were being treated with insulin regimens or started insulin treatment after being diagnosed with TB&#46; Given the increasing worldwide incidence of diabetes our findings support the need for additional clinical surveillance of diabetic patients under antituberculosis treatment&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">ADR had a significant repercussion on the overall treatment time&#46; The most frequent change was the extension of the predicted length of treatment that happened with 43&#46;6&#37; of the patients&#46; However&#44; 34&#46;5&#37; of the patients were unable to complete the full treatment due to ADR&#46; Both situations posed a threat for the success of TB treatment and represented a risk of TB treatment failure&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">The most striking result was that hepatotoxicity was considerably more frequent in younger patients with an increased risk of 0&#46;96 per year&#46; This diverges from what has been published by preceding reports that suggest that increasing age is a risk factor for hepatotoxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">11&#44;13&#44;18&#44;19&#44;21&#44;22&#44;33&#44;34</span></a> However&#44; many of these studies failed to prove statistical significance and divergent studies show no relationship between the risk of hepatotoxicity and age&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">35&#8211;37</span></a> Additionally&#44; similar conclusions to ours were reached by a Turkish group in a study that involved a population of 1149 patients with active TB&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a> These results may have been limited by the small amount of patients with hepatotoxicity and aged more than or equal to 60 years &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#41;&#46; One possible explanation for our findings is the possible association between younger age and high alcohol intake&#44; frequently neglected due to often-overlooked consumption habits among this population&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Our study&#44; as all retrospective studies&#44; has intrinsic limitations&#46; The small number of patients with major ADR and the comparison with a minor matched control-group provided limited power to detect significant associations with most of the comorbidities and MDR risk factors that were found in few patients&#46; Furthermore&#44; patients treated on an outpatient basis in itself constitutes a selected population with less comorbid conditions and milder forms of the disease&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">However&#44; our analysis stands out because it includes a wide spectrum of patients submitted to anti-TB treatment&#44; not only with pulmonary or extrapulmonary TB but also LTBI&#44; all treated at single centre&#46; The study design is superimposable to the one related in other series and therefore comparisons can be done&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0275" class="elsevierStylePara elsevierViewall">The development of novel antituberculosis drugs in the middle of the 20th century increased the rate of successfully treated tuberculosis cases&#46; This has&#44; on the other hand&#44; increased the number of drug-related side effects&#44; some of which may significantly interfere with the therapeutic regimen and the whole treatment time&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">This study found a high frequency of ADR which had a strong impact on subsequent therapeutic orientation&#46; Therefore&#44; preliminary clinical assessment and subsequent close monitoring&#44; including laboratory routine analysis&#44; are extremely important for&#44; on the one hand&#44; identification of risk factors and&#44; on the other hand&#44; for early recognition of ADR&#44; assessing the side-effects severity and making prompt treatment decisions&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">Of particular interest is the relationship between ADR and diabetes mellitus and the increased frequency of hepatotoxicity at a younger age&#46; Thus&#44; an extra careful follow-up of these patients is fundamental to avoid subsequent treatment failures&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">New antituberculosis drugs are needed&#44; not only to simplify and improve treatment&#44; but also to reduce the incidence of important side effects&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ethical disclosures</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Protection of human and animal subjects</span><p id="par0295" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Confidentiality of data</span><p id="par0300" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work centre on the publication of patient data&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Right to privacy and informed consent</span><p id="par0305" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicts of interest</span><p id="par0310" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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              "titulo" => "Tuberculosis diagnosis"
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        6 => array:2 [
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              "identificador" => "sec0065"
              "titulo" => "Protection of human and animal subjects"
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    "fechaRecibido" => "2014-05-02"
    "fechaAceptado" => "2014-08-30"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Adverse drug reactions &#40;ADR&#41; to first-line antituberculosis drugs are frequent and have important implications that may affect the effectiveness of treatment and course of tuberculosis &#40;TB&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective data analysis of clinical records and national registration forms from patients with ADR to first line antituberculosis that occurred between 2004 and 2013 at a Portuguese Pulmonology Diagnostic Centre&#44; and from a case&#8211;control population matched by sex&#44; age and year of initiation of treatment&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Of the 764 patients treated with antituberculosis drugs&#44; 55 &#40;52&#46;7&#37; male&#44; 92&#46;7&#37; European&#44; mean age 50&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;5 years&#41; had at least one severe ADR and six had a second ADR&#44; for a total of 61 events&#46; The most frequent ADR were hepatotoxicity &#40;86&#46;9&#37;&#41;&#44; rash &#40;8&#46;2&#37;&#41; and others&#44; such as ocular toxicity&#44; gastrointestinal intolerance and angioedema &#40;4&#46;9&#37;&#41;&#46; Isoniazid&#44; alone or in combination&#44; was the antituberculosis drug most associated to toxicity&#46; Due to ADR&#44; treatment time changed an average of 1&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;6 months &#40;range &#8722;3&#46;4 to 10&#46;6&#41;&#46; There was no correlation between age or gender and the overall incidence of ADR although we found a significant association between younger age and an increased risk of hepatotoxicity &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#46; There was also a statistically significant relationship between ADR and diabetes mellitus &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;042&#41; but not for other comorbidities or multi-resistant TB risk factors&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This study found a high frequency of ADR with strong impact on subsequent therapeutic orientation&#46; What seems to be of particular interest is the relationship between ADR and diabetes mellitus and the increased frequency of hepatotoxicity in younger patients&#46;</p></span>"
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Age&#44; years</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mean &#40;range&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;5 &#40;17&#46;0 to 94&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>17&#8211;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11 &#40;20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>35&#8211;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26 &#40;47&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>60&#8211;94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18 &#40;32&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Sex</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29 &#40;52&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26 &#40;47&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Continent of origin</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Europe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51 &#40;92&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Africa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;7&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Method of detection</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Active &#40;screening of contacts&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11 &#40;20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Active &#40;screening of other groups&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;10&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Passive &#40;symptoms&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38 &#40;69&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Year of diagnosis</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2004&#8211;2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24 &#40;43&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2009&#8211;2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31 &#40;56&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Tuberculosis</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Active disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40 &#40;72&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Pulmonary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30 &#40;54&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Lymphatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Pleural&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Genitourinary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Cutaneous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Latent infection</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;27&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Radiographic pattern</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cavitated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13 &#40;23&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-cavitated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20 &#40;36&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22 &#40;40&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Comorbidities</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>No comorbidities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42 &#40;76&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Neoplasm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;7&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>HIV positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Arterial hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Liver disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Silicosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Obstructive pulmonary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Chronic renal insufficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Psychiatry disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Risk factors</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Community resident&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>IV drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Alcohol abuse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">TB diagnostic test</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Microbiological analysis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28 &#40;50&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Smear positive&#47;culture negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;30&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Smear negative&#47;culture positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;14&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Smear and culture positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Tissue sample biopsy</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;21&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">IGRA test</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;27&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Demographic and clinical characteristics of patients with severe adverse drug reactions to antituberculosis drugs&#58; 2004&#8211;2012&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">INH&#58; isoniazid&#59; RIF&#58; rifampicin&#59; PZA&#58; pyrazinamide&#59; EMB&#58; ethambutol&#59; SM&#58; streptomycin&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ADR&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RIF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">EMB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Hepatitis</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;6&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">41 &#40;67&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;9&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53 &#40;86&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nausea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;13&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nausea and vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Abdominal pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;6&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Asymptomatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30 &#40;49&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35 &#40;57&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="9" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Rash</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Skin eruption&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>With itchiness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="9" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Angioedema</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Ocular toxicity</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Gastrointestinal upset</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Total</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">44 &#40;72&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;9&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">61&#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "identificador" => "tblfn0005"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Hepatitis-related symptoms were occasionally a combination of all the mentioned complaints&#59; however&#44; for statistical purposes&#44; only the chief complaint was considered&#46;</p>"
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              "identificador" => "tblfn0010"
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              "identificador" => "tblfn0015"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Adverse drug reactions to first-line antituberculosis treatment&#44; related symptoms and correspondence to specific antibacilar drugs&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">INH&#58; isoniazid&#59; RIF&#58; rifampicin&#59; PZA&#58; pyrazinamide&#59; EMB&#58; ethambutol&#59; SM&#58; streptomycin&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Initial first-line antituberculosis treatment</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PZA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>EMB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24 &#40;43&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;27&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;27&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PZA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Adverse reaction onset&#44; months after treatment initiation</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8804;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19 &#40;31&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;2 and &#8804;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;24&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;7 &#40;&#8722;3&#46;4 to 10&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr></tbody></table>
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Original article
Incidence and risk factors of major toxicity associated to first-line antituberculosis drugs for latent and active tuberculosis during a period of 10 years
Ana Tavares e Castroa,
Corresponding author
anatavaresecastro@gmail.com

Corresponding author.
, Mariana Mendesb, Sara Freitasa, Paulo Cravo Roxoc
a Hospitais da Universidade de Coimbra – Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
b Centro Hospitalar Cova da Beira, Covilhã,, Portugal
c Pulmonology Diagnostic Centre of Coimbra, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The global burden of tuberculosis &#40;TB&#41; is currently still very high&#46; It represents one of the major causes of infectious disease mortality despite the availability of curative treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a> Moreover&#44; latent tuberculosis infection &#40;LTBI&#41; affects over a third of the worldwide population posing a high risk for later reactivation of the disease&#46; Therefore&#44; TB chemotherapy is essential as an intention-to-cure measure and also as a public health policy to prevent <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> transmission&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Portugal remains the only country in Western Europe with an intermediary-prevalence of tuberculosis&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a> In 2012 alone&#44; a total of 2399 new cases of TB were reported&#44; for an estimated 22&#46;8 cases per 100&#44;000 inhabitants&#44; while 157 patients died of TB while on treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">TB disease is treated with multiple effective drugs combined for a long period of time that extends for a minimum of 6 months&#44; but in special circumstances there is demand for longer treatments&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">3&#44;4</span></a> Treatment completion&#44; defined by the number of doses taken over a period of time&#44; is vital to prevent treatment failure&#44; relapse and development of resistance&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Four drugs form the core of treatment regimens for drug-susceptible organisms&#58; PZA&#44; isoniazid &#40;INH&#41;&#44; rifampicin &#40;RIF&#41; and ethambutol &#40;EMB&#41;&#46; All of these first-line drugs can induce mild to severe adverse drug reactions &#40;ADR&#41;&#44; including&#58; hepatotoxicity associated to INH&#44; RIF and PZA&#59; cutaneous reactions associated to INH&#44; PZA and EMB&#59; gastrointestinal intolerance to RIF&#59; and retrobulbar neuritis related to EMB&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">5&#8211;7</span></a> Since streptomycin &#40;SM&#41; was no longer considered a first-line drug there was a diminished incidence of ototoxicity&#44; its main side effect&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">8</span></a> Regarding latent tuberculosis infection &#40;LTBI&#41;&#44; standard regimens as&#44; for example&#44; short-courses of INH plus RIF are associated with an increased risk for ADR such as hepatotoxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">7&#44;9&#44;10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">When an ADR occurs&#44; especially when severe&#44; one or more drugs may have to be discontinued or treatment interrupted&#44; which has multiple implications&#44; particularly extended treatment time and an increased risk for drug resistance&#44; treatment failure and relapse&#46; In addition&#44; use of alternative regimens are also related to important side effects and pose compliance issues&#46; All patients must be closely monitored to immediately recognize major ADR and activate proper therapeutic measures&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Patient selection and follow-up</span><p id="par0030" class="elsevierStylePara elsevierViewall">Between 2004 and 2013&#44; all patients who experienced major ADR due to first-line antituberculosis drugs provided on ambulatory basis by our Pulmonology Diagnostic Centre &#40;PDC&#41; were identified and all demographic and clinical data were retrospectively collected&#46; Data from a group control consisting of a matched population by sex&#44; age and year of initiation of treatment were also assembled for comorbid conditions analysis&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Inclusion criteria were as follows&#58; age of 17 years or older&#59; established diagnosis of active TB&#44; either pulmonary or extrapulmonary&#44; or proven LTBI&#59; treatment regimen with first-line antituberculosis drugs&#59; confirmed ADR to at least one of the antituberculosis drugs&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">TB was defined as a clinically compatible illness confirmed by microbiological analysis or&#44; when negative&#44; a case with compatible clinical&#44; radiologic&#44; and&#47;or histologic findings&#44; and exhibiting positive response to treatment&#46; LTBI was defined by the absence of clinical features suggestive of TB&#44; normal chest radiographic examination and a positive tuberculin skin test &#40;TST&#41; induration&#46; Since 2008&#44; after the acquisition of laboratory means to perform the interferon gamma release assay &#40;IGRA&#41; using the ELISA method &#40;Quantiferon-TB<span class="elsevierStyleSup">&#174;</span> Gold In-tube&#41;&#44; this highly specific test was implemented as an active screening routine to confirm all positive TST reactions from patients suspected of having TB infection and support treatment decision&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Once having started antituberculosis treatment&#44; all patients were closely monitored for surveillance of possible ADR and other disease-related complications&#46; The first appointment occurred 15 days after beginning treatment&#44; the second appointment at 1-month of treatment and the following ensued at monthly intervals&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Blood tests including complete blood count &#40;CBC&#41;&#44; liver transaminases&#44; bilirubin &#40;total and partial&#41; and creatinine&#44; were routinely checked at 15&#44; 30 and 60 days of treatment and&#44; afterwards&#44; once each 2 months until the treatment was completed&#46; Viral serology for hepatitis and HIV were routinely assessed&#44; mostly before starting antituberculosis treatment&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Whenever necessary&#44; as in the event of a serious side effect or complication&#44; the patient was consulted or serum analyses were done beyond the usual routine&#46; Also&#44; if required&#44; other complementary studies were added to the standard evaluation&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">From patient&#39;s clinical records and national registration forms&#44; information was collected regarding sex&#44; age&#44; nationality&#44; residency&#44; career occupation&#44; symptoms&#44; risk factors such as intravenous drug abuse&#44; alcoholism or residence in a social support community&#44; comorbidities&#44; site of disease&#44; diagnostic tests&#44; initial treatment&#44; adverse effects and outcomes&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Major ADR were defined as those that required discontinuation of one or more drugs&#44; shift to second-line drugs or hospital admission&#46; When all drugs were suspended&#44; they were restarted after clinical and&#47;or laboratory complete resolution&#44; in a sequential way to possibly isolate the drug that caused the toxicity&#46; A second-line treatment was initiated when a slow resolution was anticipated or treatment interruption was not desirable&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Hepatitis was defined as liver transaminases more than three times higher than the upper limit of normal in the presence of symptoms such as nausea&#44; vomiting or abdominal pain&#44; or transaminases more than five times the upper limit of normal without symptoms&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Significant episodes of cutaneous toxicity related to extensive eruption&#44; symptoms like fever and mucous membrane involvement&#44; or to sustained complaints while on medication with anti-histaminic drugs&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Gastrointestinal disturbance was considered major when there was no improvement despite measures such as combining the timing of administration to main meals or proton pump inhibitor medication&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Loss of visual acuity was routinely assessed by a careful ophthalmologic examination and related to anti-TB drugs when all other causes had been excluded&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Statistical analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">Data analysis was executed by IBM SPSS<span class="elsevierStyleSup">&#174;</span> for Windows version 20&#46;0&#46; All demographic and clinical features were reported using frequency and descriptive analyses&#46; Qualitative data were evaluated by chi-square test and quantitative data by Student&#39;s <span class="elsevierStyleItalic">t</span> test&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Results</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Demographics</span><p id="par0095" class="elsevierStylePara elsevierViewall">Demographic and clinical characteristics of the population are described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; From a total of 764 patients treated with antituberculosis regimens&#44; 55 experienced at least one major ADR &#40;7&#46;2&#37;&#41;&#46; Six patients experienced a second ADR&#44; for a total of 61 advents&#46; The majority were male &#40;52&#46;7&#37;&#41; with a mean age of 50&#46;8 years &#40;range 17 to 94 years&#41;&#46; Most of them were European &#40;92&#46;7&#37;&#41; and a small cluster belonged to Portuguese-spoken language African countries &#40;7&#46;3&#37;&#41;&#44; such as Cape Verde&#44; Mozambique and Guinea Bissau&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Fourteen patients &#40;25&#46;5&#37;&#41; had at least one important comorbidity&#46; The most frequent was malignant disease&#44; followed by HIV and hepatitis C co-infection&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Five patients were currently living in community centres&#44; two of which for treatment of drug addiction&#46; One other patient was also a drug addict and five patients were alcoholic&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Tuberculosis diagnosis</span><p id="par0110" class="elsevierStylePara elsevierViewall">Of all 55 patients with severe ADR&#44; 40 &#40;72&#46;7&#37;&#41; had been diagnosed with active TB&#44; either pulmonary or extrapulmonary&#44; while the remaining 15 &#40;27&#46;3&#37;&#41; had confirmed LTBI&#46; Pulmonary TB was the most frequent form of the disease&#44; accounting for more than half of the patients&#46; Extrapulmonary TB was diagnosed in 10 patients&#58; 5 ganglionic&#44; 3 pleural and 1 each of genitourinary and cutaneous TB&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">TB was detected mainly through passive screening of symptomatic patients &#40;69&#46;1&#37;&#41;&#46; Those remaining were diagnosed by active screening &#40;30&#46;9&#37;&#41;&#44; either by the investigation of contacts or assessment of other groups&#44; such as patients submitted to anti-tumour necrosis factor &#40;TNF&#41;-alpha treatment&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">All patients with LTBI or extra-pulmonary TB had normal chest radiographs&#46; Pulmonary cavity TB was recognized in 13 patients while other radiographic patterns occurred in the remaining 17 patients with pulmonary TB and also in all patients with pleural TB&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Pulmonary TB was diagnosed mainly by smear microscopy and&#47;or culture analysis from respiratory sample specimens &#40;93&#46;5&#37;&#41;&#46; Positive microbiological test results were obtained from sputum samples in 17 of these patients and from bronchial lavage samples in the other 10 patients&#46; The remaining three patients with pulmonary TB had negative microbiological tests and were diagnosed through histological analysis from lung biopsies&#46; Genitourinary TB was diagnosed by urine culture examination&#46; All other cases of extrapulmonary TB &#40;pleural&#44; lymphatic and cutaneous&#41; were diagnosed by specimen biopsy from the corresponding tissue sample&#46; All 15 cases of LITB were confirmed by positive IGRA tests&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Treatment regimen</span><p id="par0130" class="elsevierStylePara elsevierViewall">The most common initial treatment&#44; prescribed to 24 patients&#44; was the combination of four first-line anti-TB drugs&#58; INH&#44; RIF&#44; PZA and EMB&#46; One patient was treated with the same regimen except that SM replaced EMB&#46; Nine patients with pulmonary cavity lesions were included in the four-drug standard treatment with EMB because of SM in-hospital absence&#46; Fifteen patients initiated treatment with a three-drug regimen that included INH&#44; RIF and PZA&#46; EMB was not integrated in this group once drug susceptibility was already known and <span class="elsevierStyleItalic">M&#46; tuberculosis</span> was fully susceptible&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The chosen therapeutic regimen for all patients with LTBI included in our study was the combination of INH and RIF administered on a daily basis during a 3-month period&#46; However&#44; the best therapeutic approach was determined on an individual basis and the patient characteristics&#46; Other options included 9 months of INH or 4 months of RIF&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Whenever possible&#44; fixed-doses combination tablets of rifater &#40;INH&#44; RIF and PZA&#41; and rifinah &#40;INH and RIF&#41; were prescribed on a daily continuous basis&#46; However&#44; the emergence of an ADR frequently meant suspension of the combination treatment to remove or assess the ADR-related antituberculosis drug&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Only two patients with pulmonary TB did not undergo directly observed therapy &#40;DOT&#41;&#44; which was strictly related to accessibility difficulties&#46; Neither of the patients with genitourinary and cutaneous TB and none of the patients with LTBI were treated with DOT strategy&#46; Ultimately&#44; a total of 36 patients &#40;65&#46;5&#37;&#41;&#44; 28 with pulmonary TB&#44; all 5 patients with lymphatic TB and all 3 patients with pleural TB&#44; were submitted to DOT&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The majority of patients who suffered severe ADR experienced a deviation from the total predicted time of treatment with a mean variation of 1&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;6 months &#40;range &#8722;3&#46;4 to 10&#46;6&#41; due to treatment suspension or termination &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Adverse reactions</span><p id="par0155" class="elsevierStylePara elsevierViewall">The most frequent ADR was hepatitis&#46; Five of these patients were alcoholic&#44; two had a previous history of chronic liver disease and one was HIV-positive&#46; Asymptomatic hepatotoxicity occurred in 35 cases and the remaining 18 were symptomatic&#46; The most common symptoms were nausea&#44; vomiting and abdominal pain&#46; One female patient with no history of comorbid conditions had a poor outcome and needed liver transplantation while all others had complete liver transaminases normalization&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Rash occurred in five cases&#44; with itchiness in three of them&#44; and was the second most frequent adverse reaction&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">One patient with chronic inflammatory arthritis and LTBI suffered gastrointestinal toxicity associated to RIF&#46; One other patient with LTBI and no significant comorbid conditions had an episode of angioedema 25 days after initiating INH plus RIF anti-TB regimen which was subsequently interrupted&#46; EMB was responsible for one single case of ocular toxicity in a patient with genitourinary TB whose visual acuity was never restored&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Side effects emerged mainly after 2 months of anti-TB drug regimen and more than half of these patients had their treatment stopped before completing the total number of doses and had&#44; on average&#44; a total time of treatment 0&#46;7 months less than the predicted one&#46; The remaining had an increase in the overall time of treatment due to one or more interruptions&#46; Only seven cases of side effects during this period had LTBI and the majority had pulmonary TB &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">A small proportion of ADR developed during the initial phase of treatment&#44; that is&#44; before completing 2 months of treatment&#46; Eight of those had a decrease and 11 had an increase in the total number of months of treatment&#46; Nine had LTBI&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">It was not possible to identify which specific drug was responsible for the ADR in 82&#37; of the cases since the drug rechallenge occurred with only minor residual effects&#44; allowing treatment to continue&#44; or it was definitively suspended with no further rechallenge&#46; In these situations&#44; all drugs that could have caused that effect were considered responsible&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The combination of INH and RIF was largely responsible for the incidence of side effects&#44; specifically for 41 hepatotoxicity events and 3 cutaneous reactions&#46; Those two drugs plus PZA accounted for six more cases of drug-induced hepatitis&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">PZA&#44; INH&#44; RIF&#44; and EMB were responsible for 5&#44; 3&#44; 2 and 1 major side effect&#44; respectively&#46; SM was not associated to any major ADR&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">No correlation was found between age or sex and the overall incidence of ADR&#46; However&#44; when considering each category of ADR&#44; younger age was meaningfully related to an increased risk of hepatotoxicity &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#44; which was 0&#46;96 times smaller for each year that the age increased&#46; In this group of patients&#44; mean age was 49&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;4 years while those that had no drug-related hepatitis had a mean age of 64&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;4 years&#46; On the other hand&#44; an important association was found between male gender and toxicity to both INH and PZA but this did not achieve statistical significance &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;055&#41;&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Diabetes mellitus and major ADR were significantly associated &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;042&#41; but the same could not be stated for other comorbidities or multidrug resistance risk factors&#46; One diabetic patient had his treatment with oral anti-diabetic drugs changed to insulin therapy after being diagnosed with TB for an optimal glycaemic control&#44; while the remaining were already being treated with insulin&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0205" class="elsevierStylePara elsevierViewall">ADR to first-line antituberculosis medication are frequent and have important implications that may affect the effectiveness of treatment&#44; the course of TB disease and chemoprophylaxis in latent infection&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">In our study&#44; out of 764 patients treated with first-line antituberculosis drugs for active and latent TB&#44; 55 &#40;7&#46;2&#37;&#41; had at least one major side effect for a total of 61 ADR&#44; which was not as high as in other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">11&#44;12</span></a> The overall incidence of severe ADR was highest in combined treatment with INH and RIF&#44; in patients aged 35 years or older and in the male gender&#44; but none of these variables were statistically significant&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">It was only possible to attribute responsibility for the ADR to one particular drug in 18&#46;0&#37; of the cases&#46; The main reason was that when sequential drug rechallenge was implemented&#44; side effects did not recur and the most likely associated drugs were considered probably responsible&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">There was a high incidence of hepatotoxicity &#40;6&#46;9&#37;&#41; compared to previous studies performed in both active and latent TB patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">6&#44;12&#8211;14</span></a> Hepatotoxicity was most likely to be associated to chemotherapy combination of INH and RIF&#44; which has previously been stated to increase the risk of liver injury among patients under antituberculosis treatment compared to regimens containing only one of those drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a> A metabolic idiosyncratic mechanism by which additional toxic INH metabolites are produced seems to be the underlying mechanism promoted by RIF to boost hepatotoxicity of other antituberculosis medications&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">The overall rate of INH-related hepatitis was 0&#46;3&#37; while that associated to LTBI was 0&#46;1&#37;&#44; which is similar to the rates published in recent literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">PZA is recognized as the most hepatotoxic among first-line antituberculosis drugs acting on both dose dependent and idiosyncratic mechanisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">6&#44;11&#44;12&#44;20&#8211;22</span></a> Our findings suggested a slight increase in the incidence of hepatotoxicity &#40;0&#46;8&#37;&#41; when used in combination with INH and RIF with a minor rate of hepatitis attributed to PZA alone &#40;0&#46;5&#37;&#41;&#46; Other studies have also shown an increased risk of hepatotoxicity with PZA especially when added to other antituberculosis drugs such as INH and rifampin&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a> PZA was also responsible for the one single case of severe hepatotoxicity that progressed to liver transplantation&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Hepatotoxicity causes significant morbidity and mortality&#44; which justifies the numerous studies to define its predisposing factors but results are still controversial&#46; Our series found no correlation between reported risk factors such as preexisting liver disease&#44; high alcohol intake or other comorbidities&#44; and hepatotoxicity&#46; However&#44; this may reflect the overall lack of comorbid conditions in the studied population&#44; which usually has a higher prevalence in patients with hospital follow-up&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Cutaneous rash was the second most frequent ADR with an overall incidence of 8&#46;2&#37;&#46; In fact&#44; cutaneous adverse reactions are commonly observed in patients with antituberculosis drugs and are an important cause of treatment discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> Therapeutic regimens with both INH and RIF were mainly responsible for this ADR although most studies suggest that PZA is the most common offending agent&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Other ADR such as angioedema&#44; gastrointestinal upset and ocular toxicity were rare and each occurred in only one patient&#44; accounting for an overall incidence of 1&#46;6&#37;&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Diabetes was significantly correlated to major ADR&#46; Several studies have suggested that diabetes increases the risk of active TB&#44; especially in the elderly&#44; and leads to worst treatment outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">25&#8211;29</span></a> Also&#44; some small series have shown that metabolic disorders such as diabetes may act as independent risk factors for ADR&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">30&#44;31</span></a> Oral anti-diabetic and antituberculosis drugs may interact and lead to a suboptimal glycaemic control on the one hand&#44; and lower the efficacy of TB treatment on the other hand&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">32</span></a> However&#44; in our study&#44; all diabetic patients were being treated with insulin regimens or started insulin treatment after being diagnosed with TB&#46; Given the increasing worldwide incidence of diabetes our findings support the need for additional clinical surveillance of diabetic patients under antituberculosis treatment&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">ADR had a significant repercussion on the overall treatment time&#46; The most frequent change was the extension of the predicted length of treatment that happened with 43&#46;6&#37; of the patients&#46; However&#44; 34&#46;5&#37; of the patients were unable to complete the full treatment due to ADR&#46; Both situations posed a threat for the success of TB treatment and represented a risk of TB treatment failure&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">The most striking result was that hepatotoxicity was considerably more frequent in younger patients with an increased risk of 0&#46;96 per year&#46; This diverges from what has been published by preceding reports that suggest that increasing age is a risk factor for hepatotoxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">11&#44;13&#44;18&#44;19&#44;21&#44;22&#44;33&#44;34</span></a> However&#44; many of these studies failed to prove statistical significance and divergent studies show no relationship between the risk of hepatotoxicity and age&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">35&#8211;37</span></a> Additionally&#44; similar conclusions to ours were reached by a Turkish group in a study that involved a population of 1149 patients with active TB&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a> These results may have been limited by the small amount of patients with hepatotoxicity and aged more than or equal to 60 years &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#41;&#46; One possible explanation for our findings is the possible association between younger age and high alcohol intake&#44; frequently neglected due to often-overlooked consumption habits among this population&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Our study&#44; as all retrospective studies&#44; has intrinsic limitations&#46; The small number of patients with major ADR and the comparison with a minor matched control-group provided limited power to detect significant associations with most of the comorbidities and MDR risk factors that were found in few patients&#46; Furthermore&#44; patients treated on an outpatient basis in itself constitutes a selected population with less comorbid conditions and milder forms of the disease&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">However&#44; our analysis stands out because it includes a wide spectrum of patients submitted to anti-TB treatment&#44; not only with pulmonary or extrapulmonary TB but also LTBI&#44; all treated at single centre&#46; The study design is superimposable to the one related in other series and therefore comparisons can be done&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0275" class="elsevierStylePara elsevierViewall">The development of novel antituberculosis drugs in the middle of the 20th century increased the rate of successfully treated tuberculosis cases&#46; This has&#44; on the other hand&#44; increased the number of drug-related side effects&#44; some of which may significantly interfere with the therapeutic regimen and the whole treatment time&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">This study found a high frequency of ADR which had a strong impact on subsequent therapeutic orientation&#46; Therefore&#44; preliminary clinical assessment and subsequent close monitoring&#44; including laboratory routine analysis&#44; are extremely important for&#44; on the one hand&#44; identification of risk factors and&#44; on the other hand&#44; for early recognition of ADR&#44; assessing the side-effects severity and making prompt treatment decisions&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">Of particular interest is the relationship between ADR and diabetes mellitus and the increased frequency of hepatotoxicity at a younger age&#46; Thus&#44; an extra careful follow-up of these patients is fundamental to avoid subsequent treatment failures&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">New antituberculosis drugs are needed&#44; not only to simplify and improve treatment&#44; but also to reduce the incidence of important side effects&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ethical disclosures</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Protection of human and animal subjects</span><p id="par0295" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Confidentiality of data</span><p id="par0300" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work centre on the publication of patient data&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Right to privacy and informed consent</span><p id="par0305" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicts of interest</span><p id="par0310" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Adverse drug reactions &#40;ADR&#41; to first-line antituberculosis drugs are frequent and have important implications that may affect the effectiveness of treatment and course of tuberculosis &#40;TB&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective data analysis of clinical records and national registration forms from patients with ADR to first line antituberculosis that occurred between 2004 and 2013 at a Portuguese Pulmonology Diagnostic Centre&#44; and from a case&#8211;control population matched by sex&#44; age and year of initiation of treatment&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Of the 764 patients treated with antituberculosis drugs&#44; 55 &#40;52&#46;7&#37; male&#44; 92&#46;7&#37; European&#44; mean age 50&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;5 years&#41; had at least one severe ADR and six had a second ADR&#44; for a total of 61 events&#46; The most frequent ADR were hepatotoxicity &#40;86&#46;9&#37;&#41;&#44; rash &#40;8&#46;2&#37;&#41; and others&#44; such as ocular toxicity&#44; gastrointestinal intolerance and angioedema &#40;4&#46;9&#37;&#41;&#46; Isoniazid&#44; alone or in combination&#44; was the antituberculosis drug most associated to toxicity&#46; Due to ADR&#44; treatment time changed an average of 1&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;6 months &#40;range &#8722;3&#46;4 to 10&#46;6&#41;&#46; There was no correlation between age or gender and the overall incidence of ADR although we found a significant association between younger age and an increased risk of hepatotoxicity &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#46; There was also a statistically significant relationship between ADR and diabetes mellitus &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;042&#41; but not for other comorbidities or multi-resistant TB risk factors&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This study found a high frequency of ADR with strong impact on subsequent therapeutic orientation&#46; What seems to be of particular interest is the relationship between ADR and diabetes mellitus and the increased frequency of hepatotoxicity in younger patients&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Material and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
          ]
        ]
      ]
    ]
    "multimedia" => array:3 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Age&#44; years</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mean &#40;range&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;5 &#40;17&#46;0 to 94&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>17&#8211;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11 &#40;20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>35&#8211;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26 &#40;47&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>60&#8211;94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18 &#40;32&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Sex</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29 &#40;52&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26 &#40;47&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Continent of origin</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Europe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51 &#40;92&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Africa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;7&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Method of detection</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Active &#40;screening of contacts&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11 &#40;20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Active &#40;screening of other groups&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;10&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Passive &#40;symptoms&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38 &#40;69&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Year of diagnosis</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2004&#8211;2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24 &#40;43&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2009&#8211;2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31 &#40;56&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Tuberculosis</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Active disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40 &#40;72&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Pulmonary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30 &#40;54&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Lymphatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Pleural&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Genitourinary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Cutaneous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Latent infection</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;27&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Radiographic pattern</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cavitated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13 &#40;23&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-cavitated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20 &#40;36&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22 &#40;40&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Comorbidities</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>No comorbidities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42 &#40;76&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Neoplasm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;7&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>HIV positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Arterial hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Liver disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Silicosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Obstructive pulmonary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Chronic renal insufficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Psychiatry disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Risk factors</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Community resident&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>IV drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Alcohol abuse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">TB diagnostic test</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Microbiological analysis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28 &#40;50&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Smear positive&#47;culture negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;30&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Smear negative&#47;culture positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;14&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Smear and culture positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Tissue sample biopsy</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;21&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">IGRA test</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;27&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab792851.png"
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Demographic and clinical characteristics of patients with severe adverse drug reactions to antituberculosis drugs&#58; 2004&#8211;2012&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">INH&#58; isoniazid&#59; RIF&#58; rifampicin&#59; PZA&#58; pyrazinamide&#59; EMB&#58; ethambutol&#59; SM&#58; streptomycin&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ADR&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RIF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">EMB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Hepatitis</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;6&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">41 &#40;67&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;9&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53 &#40;86&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nausea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;13&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nausea and vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Abdominal pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;6&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Asymptomatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30 &#40;49&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35 &#40;57&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="9" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Rash</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Skin eruption&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>With itchiness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="9" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Angioedema</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Ocular toxicity</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Gastrointestinal upset</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Total</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">44 &#40;72&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;9&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">61&#40;100&#41;&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" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF&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" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RIF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PZA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Adverse reaction onset&#44; months after treatment initiation</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8804;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19 &#40;31&#46;1&#41;&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" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;3 and &#8804;6&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" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Association between antituberculosis drug and adverse reaction</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Confirmed&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;30&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;21&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Data presented as total number &#40;&#37; of total&#41; except if otherwise stated&#46;</p>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Antituberculosis treatment regimens&#44; association between treatment onset and adverse drug reactions&#44; and effect on total treatment time<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
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            0 => array:3 [
              "identificador" => "bib0190"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Global tuberculosis report 2013"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "WHO"
                          ]
                        ]
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                      "titulo" => "Relat&#243;rio do Observat&#243;rio Nacional das Doen&#231;as Respirat&#243;rias"
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              "identificador" => "bib0200"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "American Thoracic Society&#47;Centers for Disease Control and Prevention&#47;Infectious Diseases Society of America&#58; treatment of tuberculosis"
                      "autores" => array:1 [
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                          "etal" => true
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                            0 => "H&#46;M&#46; Blumberg"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
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                      "doi" => "10.1164/rccm.167.4.603"
                      "Revista" => array:6 [
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                        "fecha" => "2003"
                        "volumen" => "167"
                        "paginaInicial" => "603"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12588714"
                            "web" => "Medline"
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                        ]
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                ]
              ]
            ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Abordagem terap&#234;utica da tuberculose e resolu&#231;&#227;o de alguns problemas associados &#224; medica&#231;&#227;o"
                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:1 [
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                      ]
                    ]
                  ]
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                    0 => array:1 [
                      "Revista" => array:6 [
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              ]
            ]
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              "identificador" => "bib0210"
              "etiqueta" => "5"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adverse reactions to first-line antituberculosis drugs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46;J&#46; Forget"
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                      "doi" => "10.1517/14740338.5.2.231"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An official ATS statement&#58; hepatotoxicity of antituberculosis therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:1 [
                            0 => "J&#46;J&#46; Saukkonen"
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                    0 => array:2 [
                      "doi" => "10.1164/rccm.200510-1666ST"
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                        "tituloSerie" => "Am J Respir Crit Care Med"
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                        "paginaInicial" => "935"
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                0 => array:2 [
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                      "titulo" => "Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection&#58; a multicenter clinical trial"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:1 [
                            0 => "R&#46;M&#46; Jasmer"
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                        ]
                      ]
                    ]
                  ]
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                    0 => array:1 [
                      "Revista" => array:6 [
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                        "fecha" => "2002"
                        "volumen" => "137"
                        "paginaInicial" => "640"
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                      "titulo" => "Toxic effect of streptomycin upon balance and hearing"
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                            0 => "T&#46; Cawthorne"
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br Med J"
                        "fecha" => "1957"
                        "volumen" => "1"
                        "paginaInicial" => "1444"
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