Original Article
Utility of Phenotypic and Genotypic Testing in the Study of Mycobacterium tuberculosis Resistance to First-Line Anti-Tuberculosis Drugs
Utilidad de los métodos fenotípicos y genotípicos en el estudio de resistencias de Mycobacterium tuberculosis a fármacos antituberculosos de primera línea
Luz María Alba Álvareza,
, José María García Garcíab, M. Dolores Pérez Hernándezc, Susana Martínez Gonzáleza, Juan José Palacios Gutiérreza, on behalf of the Red de Laboratorios de Microbiología del SESPA 1
Corresponding author
a Unidad de Referencia Regional de Micobacterias, Servicio de Microbiología, AGC Laboratorio de Medicina del HUCA, Oviedo, Asturias, Spain
b Unidad de Gestión Clínica de Neumología, Hospital San Agustín, Avilés, Asturias, Spain
c Servicio de Vigilancia y Alertas Epidemiológicas, Dirección General de Salud Pública, Consejería de Sanidad, Oviedo, Asturias, Spain
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Although there are major differences between regions, cases of extremely drug-resistant tuberculosis (XDR-TB), defined as MDR-TB that is also resistant to a fluoroquinolone and at least 1 injectable second-line drug, have been reported in most countries in the world, illustrating the magnitude of the problem.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Although incidence of TB in Spain continues to fall, reflecting the epidemiological trend observed in other European countries,<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">4</span></a> control of the disease is threatened by the appearance of MDR-TB and XDR-TB, and therefore all circulating strains must be studied.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The incidence rate of TB in Asturias in 2013 was 14.98 cases per 100,000 inhabitants,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">5</span></a> just above the Spanish mean of 11.88 cases per 100,000 inhabitants.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Insight into resistance among <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> (<span class="elsevierStyleItalic">M. tuberculosis</span>) strains in a specific geographical area can help adjust treatment regimens to the needs of the population, and determine the suitability of existing therapeutic regimens.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Various methodologies have been used to establish the sensitivity pattern of clinical isolates. The most accurate method and the one that provides fewest false results is the multiple proportions method described by Canetti in 1963,<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">8,9</span></a> which is now the most commonly used procedure worldwide.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The delay inherent in standard sensitivity testing has increased interest in molecular techniques, since these provide results in a matter of hours, a critical consideration if the right treatment is to be initiated as soon as possible. The main drawback of molecular testing is that, with the exception of rifampicin, in which 97% of resistances are coded by the <span class="elsevierStyleItalic">rpoB</span> gene, the genetic changes that cause between 20% and 40% of resistances to the remaining first-line drugs are still unknown.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">10</span></a> Another problem is that the high cost of this type of testing may limit its availability in countries with limited economic resources.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Because of the uncertainty surrounding current molecular methods, we must continue to perform phenotypic sensitivity testing, preferably using methodologies meeting internationally accepted quality standards that can be verified using external quality controls to guarantee the reliability of the results. Participation in these quality control programs in Asturias began in 2004.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The main aim of our study was to evaluate the contribution of new molecular techniques to the diagnosis of <span class="elsevierStyleItalic">M. tuberculosis</span> resistance, to compare them with the standard phenotypic method, and to determine the situation of resistance to first-line antituberculosis drugs in Asturias.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and Methods</span><p id="par0050" class="elsevierStylePara elsevierViewall">Prospective study including all <span class="elsevierStyleItalic">M. tuberculosis</span> strains from clinical samples isolated in Asturias during the period between January 2004 and December 2013.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Criteria for the inclusion of isolates were as follows: in patients in whom several samples were obtained from the same site, the first <span class="elsevierStyleItalic">M. tuberculosis</span> isolate obtained from each patient was included. In patients in whom samples were obtained from different sites, one <span class="elsevierStyleItalic">M. tuberculosis</span> strain from each site was included.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Clinical and Laboratory Standards Institute<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">11</span></a> procedures were followed for sensitivity testing, using Canetti's multiple proportions method in Middlebrook 7H10 as the standard method. The following critical concentrations were analyzed: isoniazid 0.2<span class="elsevierStyleHsp" style=""></span>μg/ml, rifampicin 1<span class="elsevierStyleHsp" style=""></span>μg/ml, ethambutol 5<span class="elsevierStyleHsp" style=""></span>μg/ml and streptomycin 2<span class="elsevierStyleHsp" style=""></span>μg/ml. This method was performed on the 1861 <span class="elsevierStyleItalic">M. tuberculosis</span> strains included in the study, and on WHO quality control strains received periodically during the 10-year study period.</p><p id="par0065" class="elsevierStylePara elsevierViewall">All study strains underwent molecular testing for isoniazid and rifampicin resistance, while ethambutol and streptomycin were only studied for the 102 strains that presented phenotypic resistance to any first-line drug. The commercial tests used for the different targets were <span class="elsevierStyleItalic">rpoB</span>, <span class="elsevierStyleItalic">katG</span>, <span class="elsevierStyleItalic">inhA</span>, <span class="elsevierStyleItalic">gyrA</span>, <span class="elsevierStyleItalic">gyrB</span>, <span class="elsevierStyleItalic">rrs</span>, <span class="elsevierStyleItalic">eis</span> (INNOLiPA RIFTB©; GenotypeMDR<span class="elsevierStyleItalic">plus</span>©; GenotypeMDR<span class="elsevierStyleItalic">sl</span>©).</p><p id="par0070" class="elsevierStylePara elsevierViewall">All information was collected in a specially designed Microsoft Excel database. The recommended statistical tests for comparing a diagnostic technique which yielded binary or dichotomous results (molecular testing: presence/absence of mutation) with the gold standard (phenotypic antibiogram) were used. Contingency tables were constructed to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Patients with Microbiological Confirmation of Tuberculosis. Demographic Data</span><p id="par0075" class="elsevierStylePara elsevierViewall">Between January 2004 and December 2013, a total of 1826 cases of microbiological confirmation of TB were recorded in Asturias.</p><p id="par0080" class="elsevierStylePara elsevierViewall">The incidence was higher in men (68.3%) than in women (31.7%), with a ratio of 2.15 men for each woman.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Mean age was 53 years and most cases were detected in the over-75 and 25–44 year age ranges, following the typical bimodal distribution curve. The lowest number of cases of TB was found in the under-15 year age range, with 27 cases (1.4% of the total), as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">The number of cases of TB was clearly higher in men in practically all age ranges, with the exception of the 5–14 range, which contained more females, and in the 15–24 range, in whom the incidence was the same among the sexes, as shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a> shows the number of annual cases of tuberculosis in men and women, and reveals a moderate reduction in cases over all age ranges, but mainly among men, and particularly in the 25–44 range.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085"><span class="elsevierStyleItalic">M. tuberculosis</span> Strains Isolated in Asturias (2004–2013)</span><p id="par0100" class="elsevierStylePara elsevierViewall">A patient may have tuberculosis in more than 1 anatomical site, and for this reason the 1826 cases described above presented 1889 strains of <span class="elsevierStyleItalic">M. tuberculosis</span> complex isolated during the study period in the Regional Mycobacteria Reference Unit of Asturias. <span class="elsevierStyleItalic">Mycobacterium bovis</span> (<span class="elsevierStyleItalic">M. bovis</span>) strains isolated in the urine of patients with transitional cell carcinoma bladder receiving BCG instillations were excluded.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The species identified were distributed as follows: 1861 strains (98.51%) of <span class="elsevierStyleItalic">M. tuberculosis hominis</span>; 20 strains (1.05%) of <span class="elsevierStyleItalic">M. bovis bovis</span>; 5 strains (0.26%) of <span class="elsevierStyleItalic">Mycobacterium africanum</span> type <span class="elsevierStyleSmallCaps">I</span> and 3 strains (0.15%) of <span class="elsevierStyleItalic">M. bovis</span> BCG. None of the other species of the <span class="elsevierStyleItalic">M. tuberculosis</span> complex were identified: <span class="elsevierStyleItalic">Mycobacterium canetti</span>, <span class="elsevierStyleItalic">Mycobacterium caprae</span>, <span class="elsevierStyleItalic">Mycobacterium pinnipedi</span> and <span class="elsevierStyleItalic">Mycobacterium microti</span>.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Origin of <span class="elsevierStyleItalic">M. tuberculosis hominis</span> Isolates</span><p id="par0110" class="elsevierStylePara elsevierViewall">The main site, as expected, was the lung, accounting for 73.9%, as shown in <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>.</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">The lymph node was the most common site among the cases of extrapulmonary tuberculosis, with 65 cases (3.5%). A more detailed analysis of the source of the study samples is given in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Samples from purulent exudates, abscesses and ulcers from unspecified sites were classified as “other extrapulmonary samples”, and accounted for 10.8% of the total.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Resistance Among <span class="elsevierStyleItalic">M. tuberculosis</span> Strains Isolated in Asturias (2004–2013)</span><p id="par0120" class="elsevierStylePara elsevierViewall">Of the 1861 strains of <span class="elsevierStyleItalic">M. tuberculosis hominis</span> included in the study, 102 (5.48%) were resistant (initial and acquired) to a first-line drug, as follows: 81 (4.35%) to a single drug, 14 (0.75%) polyresistant strains (resistance to more than 1 drug, except for simultaneous resistance to isoniazid and rifampicin) and 7 (0.37%) MDR-TB (one of these strains was XDR-TB). The 1759 remaining strains (94.52%) were sensitive to all first-line drugs.</p><p id="par0125" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the distribution of the 102 resistant <span class="elsevierStyleItalic">M. tuberculosis hominis</span> isolates, by resistances to each of the first-line drugs.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">Of the 14 polyresistant strains, 13 were resistant to at least isoniazid, 4 to ethambutol, 13 to streptomycin, 7 to pyrazinamide, and none were resistant to rifampicin. Thus, the total number of drug resistances (137) is higher than the number of resistant strains (102).</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Phenotypic Sensitivity Testing to First-line Drugs</span><p id="par0135" class="elsevierStylePara elsevierViewall">Using the multiple proportions method as reference, the strains were classified as sensitive or resistant to each drug, according to the different cut-off points previously described, as shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">Nine strains with resistance to pyrazinamide were also detected, but this compound was not included in the study as the multiple proportions method is not a reference method for performing sensitivity testing to this antibiotic.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Molecular Detection of Resistance to First-line Drugs</span><p id="par0145" class="elsevierStylePara elsevierViewall">The frequency of resistance mutations to each first-line drug detected in strains determined as resistant or sensitive using the multiple proportions method is detailed in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>. In 20 strains, the presence of mutations did not confer phenotypic resistance, although it should be mentioned that 6 of these had a silent mutation at codon 514 of the <span class="elsevierStyleItalic">rpoB</span> gene, which does not confer resistance to rifampicin.</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Molecular detection of resistance to each of the drugs and their concordance or lack of concordance with the phenotypic methods can be seen in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>. The capacity of genotypic methods to detect mutations in our series ranged from 100% in the case of rifampicin to 10% for streptomycin. Specificity of the genotypic methods was very high, with rates of between 98.90% and 100%.</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0155" class="elsevierStylePara elsevierViewall">The ability of molecular methods to detect resistant strains varies widely, depending on knowledge of the genes involved in resistance to each of the drugs, and the inclusion of these targets in commercial testing systems. In the case of rifampicin, this tool is excellent for detecting and confirming any initial suspicion of multiresistant strains. The analysis of <span class="elsevierStyleItalic">M. tuberculosis</span> strains isolated in Asturias during the 10-year period between 2004 and 2013 revealed that the rate of resistance to first-line drugs is low, and that cases of multiresistance are sporadic.</p><p id="par0160" class="elsevierStylePara elsevierViewall">In our series, as in other publications,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">6</span></a> the population was predominantly male, with a proportion of 2.1 men to each woman. This figure is higher than the Spanish mean of 1.7.</p><p id="par0165" class="elsevierStylePara elsevierViewall">Mean age was 53 years, higher than the Spanish mean of 44 years.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">5</span></a> The lowest number of cases of TB was found in the under-15 year age range (27 cases) representing 1.4% of the overall population.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">12</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">As expected, <span class="elsevierStyleItalic">M. tuberculosis hominis</span> was the most commonly identified species, with 1861 strains accounting for 98.5% of the total. The most common sites were the lung (73.9%) and the pleura (6.7%). These percentages are somewhat higher than overall rates in Spain, where 70% of sites are pulmonary and 4.9% are pleural.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">13</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Good tuberculosis control consists of periodically determining the prevalence of <span class="elsevierStyleItalic">M. tuberculosis</span> resistance to antituberculosis drugs. However, the magnitude of resistance to these drugs in Spain is difficult to calculate since very few studies have been published, and those which are available report widely ranging figures.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">14</span></a> The first prospective study on resistance to first-line antituberculosis drugs in a large patient cohort was published in 2014.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">15</span></a> Our overall data on initial and acquired resistance to 1 or more first-line drugs among <span class="elsevierStyleItalic">M. tuberculosis</span> strains revealed rates 5.5% lower than those of the 2014 study (9.2%).</p><p id="par0180" class="elsevierStylePara elsevierViewall">Resistance rates to each of the first-line drugs were lower than the Spanish mean: isoniazid (3.22% vs 6.7%); rifampicin (0.37% vs 1.9%); ethambutol (0.59% vs 1%); streptomycin (2.68% vs 4.4%), and no case of resistance to rifampicin alone was detected. The percentage of MDR-TB strains was also lower than the Spanish mean (0.37% vs 1.2%). Taking into account the direct relationship between the immigrant population and cases of MDR-TB,<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">16</span></a> the small immigrant population in Asturias (10.4%)<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">17</span></a> compared to other Spanish communities may be a determining factor for these lower rates.</p><p id="par0185" class="elsevierStylePara elsevierViewall">With regard to commercially available molecular testing systems, it must be remembered that not all resistance-related targets are included, nor is the variability among the prevalent mutation types in each geographical area taken into account.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">10</span></a> In our series we found a very high rate of specificity, possibly because the mutation and the corresponding wild-type sequence was analyzed simultaneously.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">18</span></a> In contrast, sensitivity varies widely, depending on the drug analyzed.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Resistance to rifampicin in <span class="elsevierStyleItalic">M. tuberculosis</span> can be explained in 96%–98% of cases by <span class="elsevierStyleItalic">rpoB</span> gene mutations,<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">19</span></a> something that has gone a long way to facilitate the development of molecular techniques for the rapid detection of rifampicin resistance in a strain isolated on culture, or even in a clinical sample.</p><p id="par0195" class="elsevierStylePara elsevierViewall">In the case of rifampicin, all cases with phenotypic resistance were also detected using molecular techniques, all 7 of which were multiresistant strains. These techniques, then, help clinicians predict multiple resistances and select the right pharmacological treatment from the start.</p><p id="par0200" class="elsevierStylePara elsevierViewall">However, even in the case of rifampicin, molecular methods cannot replace phenotypic methods, since 16 study strains had a silent TTC/TTT mutation at codon 514 of the <span class="elsevierStyleItalic">rpoB</span> gene that did not confer phenotypic resistance.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">20</span></a> Similar results have also been reported by other study groups using other molecular methods based on detection of mutations in the <span class="elsevierStyleItalic">rpoB</span> gene.<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">21–23</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Isoniazid resistance in <span class="elsevierStyleItalic">M. tuberculosis</span> is associated with multiple genes (<span class="elsevierStyleItalic">katG</span>, <span class="elsevierStyleItalic">inhA</span>, <span class="elsevierStyleItalic">aphC</span>, <span class="elsevierStyleItalic">ndh</span>, <span class="elsevierStyleItalic">kasA</span>, <span class="elsevierStyleItalic">furA</span>, <span class="elsevierStyleItalic">ethA</span>), of which the first 2 are the most commonly involved (60%–65% of cases),<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">18</span></a> but geographical variations are significant. Of the 1861 strains included in our series, 60 were resistant to isoniazid according to the standard method, and of those, 42 (70%) had mutations in the <span class="elsevierStyleItalic">katG</span> and/or <span class="elsevierStyleItalic">inhA</span> genes. Thirty percent of isoniazid-resistant strains had no alterations in the <span class="elsevierStyleItalic">katG</span> or the <span class="elsevierStyleItalic">inhA</span> genes. The resistance mechanisms in these strains may be caused by other genes involved in isoniazid resistance, not included in commercial tests.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">10</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">As for the other first-line drugs, between 50% and 70% of ethambutol-resistant strains contain a mutation in the ethambutol resistance-determining region of the <span class="elsevierStyleItalic">embB</span> gene.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">24</span></a> Currently, commercial tests for the rapid detection of mutations related with ethambutol resistance are based exclusively on the <span class="elsevierStyleItalic">embB</span>306 target.</p><p id="par0215" class="elsevierStylePara elsevierViewall">In our study, 4 (36.36%) of the 11 ethambutol-resistant strains detected by the standard method had <span class="elsevierStyleItalic">embB</span> gene mutations and 7 (63.64%) did not show any of these mutations.</p><p id="par0220" class="elsevierStylePara elsevierViewall">In the case of streptomycin, mutations were found in the <span class="elsevierStyleItalic">rrs</span> and <span class="elsevierStyleItalic">rpsL</span> genes in 55% of streptomycin-resistant isolates.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">18</span></a> Most specific mutations occur in the <span class="elsevierStyleItalic">rpsL</span> gene, and the most common mutation is the one that occurs at codon 43 and is associated with high-level resistance, while mutations in the <span class="elsevierStyleItalic">rrs</span> gene confer intermediate-low resistance<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">25</span></a> and occur mainly at codons 530 and 912.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">26–29</span></a> However, there are some strains with low phenotypic resistance that present no mutations in those genes, suggesting that alternative targets, such as the <span class="elsevierStyleItalic">gidB</span> gene (that encodes for a specific 16S rRNA methyltransferase)<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">30</span></a> or even efflux pumps, may be involved.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">31</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Commercial tests for detecting streptomycin-resistant mutants have limited results, since mutations of the <span class="elsevierStyleItalic">rpsL</span> gene are not included. In our series, of the 50 strains found to be resistant according to the standard method, 5 (10%) had <span class="elsevierStyleItalic">rrs-eis</span> gene mutations and 45 (90%) did not show any of these mutations.</p><p id="par0230" class="elsevierStylePara elsevierViewall">Molecular techniques provide fast results. However, their sensitivity, while excellent in the case of rifampicin, varies widely depending on the drug under study. These techniques must never replace standard phenotypic sensitivity testing, since a genetic mutation does not always mean phenotypic resistance,<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">20</span></a> nor does the absence of genetic mutations totally rule out the possibility of phenotypic resistance. Looking ahead, efforts to identify new mechanisms of <span class="elsevierStyleItalic">M. tuberculosis</span> resistance must be stepped up and currently available methodologies improved with the incorporation of newly identified targets, as in the case of the <span class="elsevierStyleItalic">rpsL</span> gene and streptomycin, the inclusion of the new drugs for the treatment of tuberculosis (fluoroquinolones, linezolid, bedaquiline, delamanid, etc.), and, ideally, the simultaneous detection of all genetic mutations.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusions</span><p id="par0235" class="elsevierStylePara elsevierViewall">Molecular techniques provide fast results, but their sensitivity varies widely, depending on the drug under study, so results must be confirmed with standard phenotypic sensitivity testing. Resistance rates to first-line drugs in Asturias are low, below that of other regions of Spain, and multiresistant cases are sporadic.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Authorship/Contributors</span><p id="par0240" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0245" class="elsevierStylePara elsevierViewall">Juan José Palacios Gutiérrez: project leader and head of the Unidad de Referencia Regional de Micobacterias del Servicio de Microbiología, HUCA.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0250" class="elsevierStylePara elsevierViewall">Luz María Alba Álvarez: data analysis and manuscript writing.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0255" class="elsevierStylePara elsevierViewall">José María García García: Unidad de Gestión Clínica de Neumología, Hospital San Agustín, Avilés: manuscript correction and project supervision.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0260" class="elsevierStylePara elsevierViewall">María Dolores Pérez Hernández: Servicio de Vigilancia y Alertas Epidemiológicas, Dirección General de Salud Pública, Consejería de Sanidad: contribution and review of demographic data.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0265" class="elsevierStylePara elsevierViewall">Susana Martínez González: review of the references.</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0270" class="elsevierStylePara elsevierViewall">SESPA Microbiology Laboratory Network: isolation of strains submitted by the Unidad de Referencia de Micobacterias, HUCA</p></li></ul></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of Interests</span><p id="par0275" class="elsevierStylePara elsevierViewall">The authors state that they have no conflict of interests.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres825546" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec822018" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres825547" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec822017" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and Methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Patients with Microbiological Confirmation of Tuberculosis. Demographic Data" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "M. tuberculosis Strains Isolated in Asturias (2004–2013)" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Origin of M. tuberculosis hominis Isolates" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Resistance Among M. tuberculosis Strains Isolated in Asturias (2004–2013)" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Phenotypic Sensitivity Testing to First-line Drugs" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Molecular Detection of Resistance to First-line Drugs" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Authorship/Contributors" ] 10 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of Interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-05-07" "fechaAceptado" => "2016-08-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec822018" "palabras" => array:5 [ 0 => "Epidemiology" 1 => "Tuberculosis" 2 => "Resistance" 3 => "Phenotypic methods" 4 => "Molecular methods" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec822017" "palabras" => array:5 [ 0 => "Epidemiología" 1 => "Tuberculosis" 2 => "Resistencias" 3 => "Métodos fenotípicos" 4 => "Métodos moleculares" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determine the utility of molecular techniques in the diagnosis of resistance and the extent of resistance to first-line drugs in our region.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">From 2004 to 2013, 1889 strains of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> complex isolated in Asturias, Spain, were studied using phenotypic (Clinical and Laboratory Standards Institute guidelines) and molecular (INNOLiPA RIF-TB<span class="elsevierStyleSup">©</span>; GenotypeMDR<span class="elsevierStyleItalic">plus</span><span class="elsevierStyleSup">©</span>; GenotypeMDR<span class="elsevierStyleItalic">sl</span><span class="elsevierStyleSup">©</span>) sensitivity tests.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">1759 strains (94.52%) were sensitive to all first-line drugs, and 102 strains (5.48%) showed some resistance: 81 strains (4.35%) were resistant to 1 single drug, 14 (0.75%) were polyresistant, and 7 (0.37%) were multiresistant (resistant to rifampicin and isoniazid). In total, 137 resistances were identified: 60 to isoniazid (3.22%), 7 to rifampicin (0.37%), 9 to pyrazinamide (0.48%), 11 to ethambutol (0.59%), and 50 to streptomycin (2.68%). Of the mutations detected, 75.9% (63/83) correlated with resistance, while 24.09% of mutations detected (20/83) were not associated with resistance; 16 of these involved a silent mutation at codon 514 of the <span class="elsevierStyleItalic">rpoB</span> gene. Between 0% and 90% of strains, depending on the drug under consideration, were resistant even when no gene mutations were detected using marketed systems.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Molecular techniques are very useful, particularly for obtaining rapid results, but these must be confirmed with standard phenotypic sensitivity testing. The rate of resistance in our region is low and multi-drug resistant cases (0.37%) are sporadic.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Conocer la utilidad de las técnicas moleculares para el diagnóstico de resistencias y la situación de las resistencias a fármacos de primera línea en nuestra área geográfica.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y método</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Desde 2004 a 2013, 1.889 cepas de <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> complex aisladas en Asturias, España, fueron estudiadas mediante pruebas de sensibilidad fenotípicas (directrices del <span class="elsevierStyleItalic">Clinical and Laboratory Standards Institute</span>) y moleculares (INNOLiPA RIF-TB<span class="elsevierStyleSup">©</span>; GenotypeMDR<span class="elsevierStyleItalic">plus</span><span class="elsevierStyleSup">©</span>; GenotypeMDR<span class="elsevierStyleItalic">sl</span><span class="elsevierStyleSup">©</span>).</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Mil setecientas cincuenta y nueve cepas (94,52%) eran sensibles a todos los fármacos de primera línea y 102 cepas (5,48%) presentaban alguna resistencia: 81 cepas (4,35%) a un solo fármaco, 14 (0,75%) con polirresistencia y 7 (0,37%) multirresistentes (resistencia a rifampicina e isoniacida). En total hubo 137 resistencias a fármacos: 60 a isoniacida (3,22%), 7 a rifampicina (0,37%), 9 a pirazinamida (0,48%), 11 a etambutol (0,59%) y 50 a estreptomicina (2,68%). El 75,9% de las mutaciones detectadas (63/83) se correlacionaron con resistencia; mientras que un 24,09% de las mutaciones detectadas (20/83) no implicaban resistencia, correspondiendo 16 a una mutación silente en el codón 514 del gen <span class="elsevierStyleItalic">rpoB</span>. Entre un 0 y un 90% de cepas, dependiendo del fármaco que se considere, eran resistentes aunque no presentaban mutaciones en los genes incluidos en los sistemas comerciales.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Las técnicas moleculares resultan muy útiles sobre todo por la rapidez en la obtención de resultados, aunque estos deben confirmarse con las pruebas de sensibilidad fenotípicas de referencia. La tasa de resistencias a fármacos en nuestra región es baja y los casos de multirresistencia (0,37%) son esporádicos.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">SESPA Microbiology Laboratory Network includes the Microbiology Services of: Hospital de Jarrio, Hospital Carmen y Severo Ochoa, Hospital San Agustín, Hospital de Cabueñes, Hospital de Jove, Hospital Grande Covián, Hospital Álvarez-Buylla y Hospital Valle del Nalón.</p>" "identificador" => "fn1" ] 1 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as: Alba Álvarez LM, García García JM, Pérez Hernández MD, Martínez González S, Palacios Gutiérrez JJ, on behalf of the Red de Laboratorios de Microbiología del SESPA. Utilidad de los métodos fenotípicos y genotípicos en el estudio de resistencias de <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> a fármacos antituberculosos de primera línea. Arch Bronconeumol. 2017;53:192–198.</p>" ] ] "multimedia" => array:9 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1014 "Ancho" => 1734 "Tamanyo" => 75669 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Distribution of tuberculosis cases by age ranges.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 786 "Ancho" => 1723 "Tamanyo" => 94477 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Distribution of tuberculosis cases by patient age and sex.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 862 "Ancho" => 1702 "Tamanyo" => 117608 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Number of annual tuberculosis cases by sex.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1387 "Ancho" => 1667 "Tamanyo" => 82305 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Distribution of samples by site.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">CSF: cerebrospinal fluid; FNAB: fine needle aspiration biopsy.</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">Site of Sample \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">No. of Samples \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">% of Total \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Pulmonary</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1375 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Sputum</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1196 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Bronchial aspirate</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">108 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Bronchoalveolar lavage</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Lung biopsy/FNAB</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Gastric lavage</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Pleura</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">124 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pleural fluid</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">101 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pleural biopsy/FNAB</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Extrapulmonary</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">362 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Lymph nodes</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Lymph node biopsy/FNAB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Genitourinary</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Urine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Epidydimal biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Endometrial biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Gastrointestinal</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Ascitic fluid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Omental biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Colonic biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Peritoneal nodule \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Bone-joint</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Synovial fluid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Bone biopsy/punch \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Discal FNAB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Synovial biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Discal biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pericardium</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Pericardial fluid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Pericardial biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Meninges</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>CSF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Other extrapulmonary</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">204 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Total</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1861 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1388515.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Classification of Study Samples by Site.</p>" ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">MDR-TB: multi-drug-resistant tuberculosis; XDR-TB: extremely drug-resistant tuberculosis.</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">Resistances \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">No. \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">Resistant Strains<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \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">% of Total \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Single resistance</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81 (79.40%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.35 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Isoniazid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rifampicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ethambutol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Streptomycin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pyrazinamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Multiple resistance</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 (13.70%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.75 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>MDR-TB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (6.90%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.37 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>XDR-TB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Total</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">102 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">102 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.48 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1388512.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Data are expressed as <span class="elsevierStyleItalic">n</span> (%).</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Distribution of <span class="elsevierStyleItalic">M. tuberculosis</span> Resistance to First-line Drugs in Asturias.</p>" ] ] 6 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "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="left" valign="top" scope="col" style="border-bottom: 2px solid black">Proportions Method \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">Isoniazid \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">Rifampicin \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">Ethambutol \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">Streptomycin \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Cut-off point</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.2<span class="elsevierStyleHsp" style=""></span>μg/ml \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>μg/ml \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>μg/ml \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>μg/ml \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Sensitive</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">n</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1801 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1854 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1850 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1811 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">96.77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99.63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">97.32 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Resistant</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">n</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.68 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1388510.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Classification of Strains as Sensitive or Resistant According to Reference Method.</p>" ] ] 7 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:2 [ 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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Standard Method \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Resistant Strains</th></tr><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genotypic Methods \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">Mutation \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">With Mutation \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">Without Mutation \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 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Isoniazid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">katG-inhA</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifampicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">rpoB</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ethambutol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">embB</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Streptomycin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">rrs-eis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1388513.png" ] ] 1 => 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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Standard Method \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Sensitive Strains</th></tr><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genotypic Methods \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">Mutation \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">With Mutation \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">Without Mutation \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 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Isoniazid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">katG-inhA</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (<span class="elsevierStyleItalic">inh</span>A) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1798 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1801 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rifampicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">rpoB</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 (<span class="elsevierStyleItalic">rpoB</span>514) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1838 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1854 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ethambutol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">embB</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">91 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Streptomycin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">rrs-eis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1388514.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Molecular Detection of Resistances to First-line Drugs in Resistant Strains and Sensitive Strains According to the Standard Phenotypic Method.</p>" ] ] 8 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">NPV: negative predictive value; PPV: positive predictive value.</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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col">Isoniazid</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col">Rifampicin</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col">Ethambutol</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col">Streptomycin</th></tr><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Mutation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">katG-inhA</span></th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">rpoB</span></th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">embB</span></th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">rrs-eis</span></th></tr><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Detection \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">Present \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">Absent \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">Present \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">Absent \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">Present \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">Absent \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">Present \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">Absent \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Resistant strains, <span class="elsevierStyleItalic">n</span> (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a> (70) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 (30) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (36.36) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (63.63) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45 (90) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sensitive strains, <span class="elsevierStyleItalic">n</span> (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a> (0.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1798 (99.83) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">c</span></a> (0.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1838 (99.13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1.09) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">90 (98.90) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 (100) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sensitivity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">70% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36.36% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Specificity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">99.83% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">99.1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">98.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PPV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">93.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">69.56% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">80% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NPV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">99% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92.78% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1388511.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">42 strains (47 mutations: 35 mutations only in <span class="elsevierStyleItalic">katG</span> (58.33%); 2 mutations only in <span class="elsevierStyleItalic">inhA</span> (3.33%); 5 strains with mutation in both genes (8.3%).</p>" ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0015"><span class="elsevierStyleItalic">inhA</span> mutation in the 3 cases.</p>" ] 2 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0020"><span class="elsevierStyleItalic">rpoB</span>514 mutation: silent mutation, strains phenotypically sensitive.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Molecular Detection of Drug Resistances, Concordance or Disconcordance With Phenotypic Sensitivity Methods.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:31 [ 0 => array:3 [ "identificador" => "bib0160" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "World Health Organization. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 5 | 9 |
| 2024 October | 47 | 18 | 65 |
| 2024 September | 57 | 18 | 75 |
| 2024 August | 79 | 33 | 112 |
| 2024 July | 77 | 20 | 97 |
| 2024 June | 99 | 21 | 120 |
| 2024 May | 131 | 25 | 156 |
| 2024 April | 51 | 24 | 75 |
| 2024 March | 57 | 17 | 74 |
| 2024 February | 65 | 17 | 82 |
| 2023 June | 2 | 3 | 5 |
| 2023 March | 8 | 5 | 13 |
| 2023 February | 54 | 30 | 84 |
| 2023 January | 23 | 29 | 52 |
| 2022 December | 74 | 32 | 106 |
| 2022 November | 57 | 33 | 90 |
| 2022 October | 68 | 29 | 97 |
| 2022 September | 33 | 32 | 65 |
| 2022 August | 39 | 48 | 87 |
| 2022 July | 31 | 42 | 73 |
| 2022 June | 34 | 33 | 67 |
| 2022 May | 43 | 47 | 90 |
| 2022 April | 40 | 27 | 67 |
| 2022 March | 55 | 41 | 96 |
| 2022 February | 42 | 33 | 75 |
| 2022 January | 86 | 39 | 125 |
| 2021 December | 52 | 58 | 110 |
| 2021 November | 59 | 45 | 104 |
| 2021 October | 76 | 67 | 143 |
| 2021 September | 89 | 44 | 133 |
| 2021 August | 63 | 49 | 112 |
| 2021 July | 31 | 40 | 71 |
| 2021 June | 72 | 49 | 121 |
| 2021 May | 45 | 55 | 100 |
| 2021 April | 92 | 115 | 207 |
| 2021 March | 88 | 29 | 117 |
| 2021 February | 38 | 29 | 67 |
| 2021 January | 50 | 23 | 73 |
| 2020 December | 49 | 35 | 84 |
| 2020 November | 59 | 21 | 80 |
| 2020 October | 40 | 25 | 65 |
| 2020 September | 69 | 10 | 79 |
| 2020 August | 102 | 15 | 117 |
| 2020 July | 131 | 31 | 162 |
| 2020 June | 32 | 13 | 45 |
| 2020 May | 34 | 9 | 43 |
| 2020 April | 30 | 28 | 58 |
| 2020 March | 25 | 24 | 49 |
| 2020 February | 41 | 15 | 56 |
| 2020 January | 37 | 35 | 72 |
| 2019 December | 39 | 18 | 57 |
| 2019 November | 21 | 26 | 47 |
| 2019 October | 32 | 14 | 46 |
| 2019 September | 25 | 18 | 43 |
| 2019 August | 26 | 15 | 41 |
| 2019 July | 30 | 19 | 49 |
| 2019 June | 33 | 10 | 43 |
| 2019 May | 37 | 17 | 54 |
| 2019 April | 53 | 26 | 79 |
| 2019 March | 34 | 16 | 50 |
| 2019 February | 26 | 23 | 49 |
| 2019 January | 29 | 24 | 53 |
| 2018 December | 33 | 13 | 46 |
| 2018 November | 64 | 26 | 90 |
| 2018 October | 61 | 21 | 82 |
| 2018 September | 29 | 11 | 40 |
| 2018 May | 15 | 1 | 16 |
| 2018 April | 32 | 5 | 37 |
| 2018 March | 24 | 6 | 30 |
| 2018 February | 23 | 12 | 35 |
| 2018 January | 17 | 6 | 23 |
| 2017 December | 22 | 10 | 32 |
| 2017 November | 25 | 3 | 28 |
| 2017 October | 22 | 9 | 31 |
| 2017 September | 33 | 12 | 45 |
| 2017 August | 20 | 15 | 35 |
| 2017 July | 16 | 16 | 32 |
| 2017 April | 0 | 2 | 2 |
| 2017 March | 0 | 1 | 1 |
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