Original Article
Diabetes is Associated With Severe Adverse Events in Multidrug-Resistant Tuberculosis
La diabetes se asocia con reacciones adversas graves en la tuberculosis multirresistente
Marcela Muñoz-Torricoa, José Caminero-Lunab, Giovanni Battista Miglioric,
, Lia D’Ambrosioc,d, José Luis Carrillo-Alduendae, Héctor Villareal-Velardea, Alfredo Torres-Cruza, Héctor Flores-Vergaraa, Dina Martínez-Mendozaa, Cecilia García-Sanchof, Rosella Centisc, Miguel Ángel Salazar-Lezamaa, Rogelio Pérez-Padillae
Corresponding author
a Clínica de Tuberculosis, Instituto Nacional de Enfermedades Respiratorias de México (INER), Ciudad de México, Mexico
b Departamento de Neumología, Hospital Universitario de Gran Canaria «Dr. Negrín», Las Palmas, Canarias, Spain
c WHO Collaborating Centre for TB and Lung Diseases, Maugeri Institute, IRCCS, Tradate, Italy
d Public Health Consulting Group, Lugano, Switzerland
e Clínica del Sueño, Instituto Nacional de Enfermedades Respiratorias de México (INER), Ciudad de México, Mexico
f Departamento de Epidemiología, Instituto Nacional de Enfermedades Respiratorias de México (INER), Ciudad de México, Mexico
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=> array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 12 => array:3 [ "nombre" => "Rogelio" "apellidos" => "Pérez-Padilla" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:6 [ 0 => array:3 [ "entidad" => "Clínica de Tuberculosis, Instituto Nacional de Enfermedades Respiratorias de México (INER), Ciudad de México, Mexico" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Neumología, Hospital Universitario de Gran Canaria «Dr. Negrín», Las Palmas, Canarias, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "WHO Collaborating Centre for TB and Lung Diseases, Maugeri Institute, IRCCS, Tradate, Italy" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Public Health Consulting Group, Lugano, Switzerland" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Clínica del Sueño, Instituto Nacional de Enfermedades Respiratorias de México (INER), Ciudad de México, Mexico" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Departamento de Epidemiología, Instituto Nacional de Enfermedades Respiratorias de México (INER), Ciudad de México, Mexico" "etiqueta" => "f" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La diabetes se asocia con reacciones adversas graves en la tuberculosis multirresistente" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The Region of the Americas accounts for <10% of the global total of tuberculosis (TB) cases, the lowest burden of TB in the world<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a>; however, it is among the regions with the highest prevalence of diabetes mellitus (DM): 11.4% according to the International Diabetes Federation.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">2</span></a> DM is a known risk factor for the development of TB (it increases the risk between 2 and 4 fold) depending on the population.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">During the last decade, a decreasing trend in TB cases has been reported in Mexico; however, there is also a persistent increase in cases of multidrug-resistant tuberculosis (MDR-TB; <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> strain resistant to, at least, isoniazid and rifampicin)<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">4</span></a> and extensively drug-resistant TB(XDR-TB) (an MDR strain with additional resistance to a fluoroquinolone and to, at least, one second-line injectable drug).<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Mexico, in particular, is facing an overall increasing rate of DM, from 5.8% in 2000 to 9.2% in 2012.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">6</span></a> To date, it is not clear by which extent DM predisposes to worse outcomes in MDR-TB patients and/or to adverse events (AE) of anti-TB drugs.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The main objective of this study, therefore, was to describe the outcomes of TB treatment, the impact of DM and the prevalence of AE in a cohort of patients with MDR/XDR pulmonary TB treated at the national TB referral centre in Mexico City.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">The study was performed under a cooperative project, which involved the Mexican National Tuberculosis Programme, the <span class="elsevierStyleItalic">Instituto Nacional de Enfermedades Respiratorias</span> (INER) in Mexico City, the International Union Against Tuberculosis and Lung Disease, the <span class="elsevierStyleItalic">Asociación Latinoamericana de Tórax</span>, and the European Respiratory Society (ERS/ALAT SinTB project). The INER, as the national reference centre for TB, receives mostly uninsured patients from several Mexican states, the majority from Mexico City and neighbouring states.</p><p id="par0030" class="elsevierStylePara elsevierViewall">This is a retrospective study based on a review of the clinical charts of drug resistant pulmonary TB patients monitored at the INER's tuberculosis clinic; therefore no special approval by the institutional ethics committee was required. The study was not interventional, and confidentiality was ensured.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In Mexico, culture and drug susceptibility tests (DST) are only performed in patients suspected of having drug-resistant TB, e.g. patients with a history of previous treatment. Mycobacterial culture and DST are carried out at national reference laboratories, including the INER Clinical Microbiology Laboratory (which belongs to the network of World Health Organization (WHO) reference Laboratories).</p><p id="par0040" class="elsevierStylePara elsevierViewall">All pulmonary samples were decontaminated by the modified Petroff method and were grown on Löwenstein-Jensen medium and in BACTEC-960 Mycobacterial Growth Indicator Tubes (MGIT). Identification was made using molecular methods and DST was performed using the following doses: isoniazid (0.1<span class="elsevierStyleHsp" style=""></span>μg/ml and 0.4<span class="elsevierStyleHsp" style=""></span>μg/ml); rifampicin (1.0<span class="elsevierStyleHsp" style=""></span>μg/ml); ethambutol (5.0<span class="elsevierStyleHsp" style=""></span>μg/ml); streptomycin (1.0<span class="elsevierStyleHsp" style=""></span>μg/ml), and pyrazinamide (100.0<span class="elsevierStyleHsp" style=""></span>μg/ml). After 2013, all samples resistant to, at least, rifampicin (RR-TB) were also tested for the following second-line drugs: amikacin (1.0<span class="elsevierStyleHsp" style=""></span>μg/ml); kanamycin (2.5<span class="elsevierStyleHsp" style=""></span>μg/ml); ofloxacin (2.0<span class="elsevierStyleHsp" style=""></span>μg/ml), and ethionamide (5.0<span class="elsevierStyleHsp" style=""></span>μg/ml), which was previously performed only if requested and if the resource was available.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Once the diagnosis of RR-TB or MDR-TB was established, a pulmonary physician evaluated all patients, focussing particularly on anti-TB drug history and the presence of other co-morbidities such as DM, Human Immunodeficiency Virus (HIV) infection, and chronic kidney failure. All patients underwent blood tests as part of the routine pre-treatment assessment or during the first week of therapy. DM was defined as fasting blood glucose >126<span class="elsevierStyleHsp" style=""></span>mg/dL in patients with no known history of DM; in patients with a previous history of DM, evolution and treatment type were also assessed. In addition, blood biometry, blood chemistry, glycated haemoglobin (HbAC1), thyroid-stimulating hormone (TSH) at baseline and final visits were performed.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The placement of an indwelling central venous line for intravenous (IV) drug administration was offered to all patients on admission to hospital (standard double lumen central venous line, 7 Fr, Arrow International or a peripherally inserted central double lumen catheter,5 Fr Groshong, BARD Access Systems, Inc.). After discharge (2 weeks on average), treatment was administered in a primary care centre (PCC) under strict directly observed therapy (DOT).<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">7,8</span></a> Follow-up was performed monthly during the intensive phase of treatment, and thereafter every 2 months until treatment completion (20–24 months). At each visit, blood tests were requested to assess AE and a sputum sample for culture was obtained to monitor treatment. DST was repeated only if the patients did not convert culture after 6 months of treatment.</p><p id="par0055" class="elsevierStylePara elsevierViewall">All treatment regimens were individualized and based on WHO and Mexican guidelines,<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">9–12</span></a> the patient's anti-TB drug history, and the <span class="elsevierStyleItalic">M. tuberculosis</span> culture and DST results. Each regimen included at least 4 active drugs. Drug was considered to be active on the basis of DST results coupled with evidence that the patient had not taken the drug for 30 days or more. The regimens always included at least 1 fluoroquinolone (ofloxacin, levofloxacin, or moxifloxacin), 1 second-line injectable drug (amikacin, kanamycin, capreomycin), and 1 of the former WHO group 4<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">13–15</span></a> (prothionamide, cycloserine, para-aminosalicylic acid [PAS]) or group 5<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">16</span></a> (linezolid, amoxicillin/clavulanate, and high-dose isoniazid) drugs, if necessary. The prescription of each drug was based on the patient's body weight and the presence of co-morbidities such as DM, chronic kidney failure, and a history of central nervous system or psychiatric disorders. All drugs were provided by the National Tuberculosis Programme (NTP) and were administered from Monday to Saturday at the PCC. All patients were prescribed pyridoxine (at least 200<span class="elsevierStyleHsp" style=""></span>mg), and other ancillary drugs were administered only if needed.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Statistical Analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">We conducted a bivariate analysis of variables considered either categorical or numerical, according to their distribution. Variables with a significant association with adverse events or outcomes were considered for a multivariate logistic regression analysis that included age, gender, HIV status, arterial hypertension, malnutrition and alcoholism. All analyses were performed using the STATA statistical software package, version 9.0 (StataCorp LP, College Station, TX, USA).</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Results</span><p id="par0065" class="elsevierStylePara elsevierViewall">From 2010 to 2015, we identified 90 patients with drug-resistant pulmonary TB: 73 (81.1%) patients were identified as RR-TB (1 case) or MDR-TB (72 cases), 11 (12.2%) as pre-XDR-TB (10 samples with MDR-TB and additional resistance to a fluoroquinolone and 1 with additional resistance to a second-line injectable drug), while 6 (6.7%) patients were diagnosed as XDR-TB. Eighty-nine patients were diagnosed by culture and DST; in only one case, the diagnosis was established by Xpert<span class="elsevierStyleSup">®</span> MTB/RIF, showing RR <span class="elsevierStyleItalic">M. tuberculosis</span> (a culture sample could not be obtained for this patient). We could only assess DST to all second-line drugs in 71/90 (79%) patients because of the limited availability of these tests in Mexico. Of the total study sample, 8 (9%) patients were treatment-naïve (5 being close contacts of an MDR-TB patient), while the remaining 82 had previously been treated. The characteristics of patients with and without DM are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. The pattern of resistance was similar in DM and non-DM patients.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">At the time of this report, the study cohort comprised 77/90 patients. We excluded 13 patients (6 MDR, 4 pre-XDR, and 3 XDR) from the analysis because they refused to be treated, requested to be transferred to another programme, died, or were lost to follow-up before completing at least 1 month of treatment; 21/77 patients (27.3%)are still undergoing treatment (11 with and 10 without DM).</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Treatment Outcomes</span><p id="par0075" class="elsevierStylePara elsevierViewall">Among the 56 patients who concluded their treatment, 33/56 (59%) were cured according to the WHO definition,<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">12</span></a> 4/56 (7.1%) completed treatment, and 2/56 (3.6%) failed treatment. Seven patients discontinued treatment despite strong advice to continue (7/56, 12.5%). Ten out of 56 died during treatment (18%); while TB was the direct cause of death in 5 cases, the remaining 5 died from other causes (1 from acute complications of DM, community-acquired pneumonia, heroin overdose, and 2 from stroke). Overall, treatment was successful in 37/56 (66.1%) patients (cure plus treatment completion); there were no statistically significant differences between outcomes in DM versus non-DM patients (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), although the percentage of cure was slightly higher in the non-DM group compared with DM patients (<span class="elsevierStyleItalic">P</span>=0.054, Fisher's exact test).</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Effects of Diabetes</span><p id="par0080" class="elsevierStylePara elsevierViewall">As expected in our population, the most frequent co-morbidity was DM. In <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, 49/90 (54.4%) patients with DM are compared with 41/90 (45.5%) patients without DM. In bivariate analysis, arterial hypertension was positively associated with DM (<span class="elsevierStyleItalic">P</span>=0.0001), as well as chronic kidney failure (<span class="elsevierStyleItalic">P</span>=0.006). However, after adjusting for age and gender, no association was found. Age, weight, and body mass index (BMI) were higher in patients with DM compared to patients without DM (<span class="elsevierStyleItalic">p</span><0.001). In terms of laboratory findings, urea, creatinine and, of course, glucose levels differed significantly between patients with and without DM (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><p id="par0085" class="elsevierStylePara elsevierViewall">Among patients with a previous history of DM, mean evolution was 11.7 years (±6.7 years), 3 patients were diagnosed when drug-resistant TB was identified, and the mean level of glycated haemoglobin was 9.5% (±2.1). Insulin was prescribed to42/49 (86%); however, glucose control was poor in the post-treatment phase (fasting blood glucose >126<span class="elsevierStyleHsp" style=""></span>mg/dL). The final serum glucose level in patients concluding treatment and in those who at least completed the intensive phase of treatment at the time of this report was 175.3<span class="elsevierStyleHsp" style=""></span>mg/dl (±84.3), with 8.8% (±2.3) glycated haemoglobin (although we could not assess this latter test in all patients); after treatment, glucose and glycated haemoglobin levels did not differ significantly (<span class="elsevierStyleItalic">P</span>=0.17 and <span class="elsevierStyleItalic">P</span>=0.72), respectively. The body weight increase in patients with DM was slightly higher than in patients without DM, although this was not statistically significant (6.0 (±8.5)<span class="elsevierStyleHsp" style=""></span>kg vs 4.6 (±5.3)<span class="elsevierStyleHsp" style=""></span>kg, respectively, <span class="elsevierStyleItalic">P</span>=0.51).</p><p id="par0090" class="elsevierStylePara elsevierViewall">Although treatment regimens were not exactly similar in all patients, they were based on the same WHO<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">10–12</span></a> and local guidelines.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">4</span></a> Regimens included an average of 6 drugs, irrespective of the presence or absence of DM. The regimens used included the following drugs: ofloxacin (12); levofloxacin (51); moxifloxacin (14); amikacin (36); kanamycin (4); capreomycin (37); prothionamide (67); cycloserine (62), and PAS (15). Duration of the intensive phase and full treatment were similar between patients with and without DM (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><p id="par0095" class="elsevierStylePara elsevierViewall">The time-to-sputum-culture conversion was longer in patients without DM (78.3±34.4 days) than in diabetic patients (51.1±25.7 days), although this difference was not statistically significant (<span class="elsevierStyleItalic">P</span>=0.06).</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Adverse Events</span><p id="par0100" class="elsevierStylePara elsevierViewall">The most frequent adverse reaction was gastrointestinal intolerance; all patients reported some degree of epigastric disturbance after treatment intake, including nausea and/or vomiting, but these were easily managed and did not differ between patients with and without DM. When comparing patients with and without DM, nephrotoxicity (increase in serum creatinine of ≥0.5<span class="elsevierStyleHsp" style=""></span>mg/dL (≥0.3<span class="elsevierStyleHsp" style=""></span>mg/dL after 2013) hypothyroidism (TSH-thyroid-stimulating hormone ≥10<span class="elsevierStyleHsp" style=""></span>μg/dl or TSH 4.5–10<span class="elsevierStyleHsp" style=""></span>μg/dl if any symptoms and/or goitre) were significantly higher in the DM group (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). In addition, ototoxicity was higher in patients with DM (56% vs 32% in patients without DM; OR, 2.8; [95% Confidence Interval (CI), 0.8–10.6]), but the difference was not statistically significant. Psychiatric disorders evaluated by a psychiatrist (anxiety, panic attack, suicide attempt, depression, psychosis) were documented in 13 (17%) patients; in 3 of these, cycloserine had to be stopped (no difference was found in DM vs non DM cases). We observed 6 allergic drug reactions, including 1 case of DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) associated with levofloxacin. Severity of AEs forced 7 patients to stop treatment (6 DM and 1 non-DM patient; <span class="elsevierStyleItalic">P</span>=0.08), in spite of efforts to improve treatment tolerance.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Sixty patients accepted placement of a central venous line to receive the injectable drug. The most frequently observed AEs were the following: local infection at the insertion site, accidental removal, rupture of the line, and thrombosis. There were no significant differences in secondary AEs associated with a central line between patients with and without DM (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><p id="par0110" class="elsevierStylePara elsevierViewall">We performed a multivariate analysis for some of the adverse events and for a combination of those events requiring treatment interruption or additional treatment (nephrotoxicity, hypothyroidism, ototoxicity, or psychiatric disorders). Male gender seemed to be a risk factor for more adverse events (OR=4.9; 95% CI 1.7–14), and DM continued to be a risk factor (OR=3.7; 95% CI 1.2–11.7) after adjusting for gender, age, hypertension, malnutrition, HIV status and alcoholism (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). We also performed a multivariate analysis grouping outcomes into negative (lost to follow-up, death, and failure) and positive (cure and treatment completion); DM, after adjusting for the same variables, did not have an impact on outcomes (OR 2.0; 95% CI 0.5–8.2).</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0115" class="elsevierStylePara elsevierViewall">The aim of this study was to describe the outcomes of TB treatment, the impact of DM and the prevalence of AE in a cohort of patients with MDR/XDR pulmonary TB treated in the Mexican national reference centre. The main results of this study suggest the following: (a) The prevalence of DM in our cohort of TB-resistant patients is high (54.4%); (b) treatment outcomes were similarly high in both patients with and without DM, with an overall success rate of 66.1% (37/56), and (c) patients with DM had higher frequency and severity of AEs to anti-TB treatment.</p><p id="par0120" class="elsevierStylePara elsevierViewall">The prevalence of drug-resistant TB in Mexico has gradually increased over the last 10 years<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">5</span></a>; according to the most recent survey, 2.8% (95% CI, 1.9–4) of all cases are resistant to isoniazid and rifampicin.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">17</span></a> Unfortunately, as in other Latin American programmes,<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">18</span></a> notifications underestimate the true number of MDR-TB cases, as DST is not routinely performed in all TB cases.</p><p id="par0125" class="elsevierStylePara elsevierViewall">DM is a well-known determinant of negative outcomes among TB patients, and has been associated with an increased risk of failure of primary treatment in new and/or first-line drugs in pan-susceptible pulmonary TB cases.<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">6,19</span></a> Likewise, 54.4% of patients in our MDR-TB population had DM, and we found no difference in the prevalence of MDR-TB among new cases (8.2 vs 9.5%; <span class="elsevierStyleItalic">P</span>=0.07; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><p id="par0130" class="elsevierStylePara elsevierViewall">In Mexico, the high prevalence of DM in the general population is mirrored in TB cases, where the prevalence of DM among TB patients is higher in comparison with other cohorts. Our results are not even comparable with those of TB patients without MDR: in Malaysia (where DM is also common) the prevalence of DM among TB patients was 26.7% (338/1267 patients).<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">20</span></a> In a U.S. study, 42 (14%) of 297 patients with TB had DM, and Odds Ratio (OR) for death was 6.5 (95% CI, 1.1–38.0; <span class="elsevierStyleItalic">P</span>=0.039) in patients with DM.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">21</span></a> However, for reasons that are unclear, a recent study in Brazil reported a reduced mortality in diabetic patients with TB compared with non-diabetic individuals (OR 0.69; 95% CI 0.49–0.96; <span class="elsevierStyleItalic">P</span>=0.03).<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">22</span></a> Although there is strong evidence of the effect of DM on the development of tuberculosis, its influence varies depending on the population studied, and therefore further investigation is needed.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Type 2 Diabetes Mellitus has been associated with the risk of MDR-TB; in a cohort of patients with TB and DM, after controlling for homelessness, HIV status, and DOT status, the relative risk of MDR-TB was calculated as 8.6 (95% CI, 3.1–23.6) in the group with DM compared with the control group (TB),<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">23</span></a> although estimates vary in different studies. In Mexico, Jiménez-Corona et al. reported an increased risk of TB recurrence in patients with DM (Hazard Ratio [HR], 1.8; 95% CI, 1.1–2.8; <span class="elsevierStyleItalic">p</span><0.05)<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">24</span></a>; the authors demonstrated by genotyping that most second episodes among patients with DM were caused by the same bacteria, although it is not clear whether there was acquired resistance.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">24</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">The use of a fixed drug combination at the programmatic level in new TB cases has helped improve treatment adherence. This, however, may not be entirely appropriate in DM patients because of the different pharmacokinetics of anti-TB drugs in this population. Different studies have described reduced serum concentrations of rifampicin and isoniazid,<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">25,26</span></a> suggesting that these drugs should be prescribed according to body weight, as DM patients usually have higher BMI; this might explain both the negative outcomes and the higher prevalence of drug-resistant TB in this group.</p><p id="par0145" class="elsevierStylePara elsevierViewall">In our cohort of MDR-TB and DM, all patients received second-line drugs separately, with doses adjusted according to body weight,<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">4,10,11</span></a> although no serum levels were measured to confirm proper dosage adjustment.</p><p id="par0150" class="elsevierStylePara elsevierViewall">This, to the best of our knowledge, is the first study comparing adverse events in a cohort of MDR-TB patients with and without DM. MDR-TB regimens require the use of multiple drugs, and therefore carry a high risk of AEs, some of which, such as neuropathy and ototoxicity, are irreversible. In our cohort, the severity of AEs varied from mild gastritis to the life-threatening DRESS syndrome, and included permanent disturbance such as aminoglycoside-related hypoacusia. AEs were common, as previously reported,<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">27</span></a> and according to our data were more frequent in patients with DM (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). This was particularly true of nephrotoxicity and hypothyroidism, and possibly ototoxicity (<span class="elsevierStyleItalic">P</span>=0.08), most likely due to the small number of patients included. Although we tried to improve glycaemic control during second-line TB treatment, glycated haemoglobin levels at the beginning and end of treatment were higher than expected. This clearly predisposes to the development of systemic chronic complications, and therefore, to AEs of anti-TB drugs.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">28</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Prior to 2010, treatment of MDR-TB in Mexico was limited, due to the lack of second-line drugs. These drugs were only available at the US–Mexican border (where high incidence of DM in Mexican and Mexican-American patients was reported<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">29</span></a>) under the oversight of the U.S. authorities.<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">30,31</span></a> In spite of the economic and programmatic limitations encountered by the Mexican NTP, the treatment success in our cohort (37/56, 66.1%), is slightly higher than that described in the different meta-analyses.<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">32–35</span></a> Although treatment was administered in a primary care centre, it was continuously overseen by the reference centre, which could explain the slightly higher cure rate. We found no differences in treatment outcomes among DM and non-DM patients, though the cure rate seems to be slightly higher in non-DM patients (<span class="elsevierStyleItalic">P</span>=0.054).</p><p id="par0160" class="elsevierStylePara elsevierViewall">The Official Mexican Guidelines<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">36</span></a> for the treatment of TB recommend culture and DST only in patients suspected of harbouring drug-resistant isolates; the Guidelines consider DM as a risk factor for drug-resistant TB, but only in areas where DM incidence is high. However, it is not clear if the increasing prevalence of DM MDR-TB is due to late MDR diagnosis or to DM-induced changes to the pharmacokinetics of first-line drugs. Therefore, the Mexican TB Programme is considering the possibility of performing culture and DST in all cases of TB. Although the cost of this diagnostic approach is high, second-line treatment costs are even higher, being associated with increased patient disability and lower success rates.<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">37,38</span></a> Finally, we would stress the importance of ensuring tighter glucose control in DM patients and strengthening early detection of both TB and DM (as recommended in the 2013 update of the Mexican Guidelines).<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">36</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Our study has limitations, including its retrospective nature, the relatively small sample size, the impossibility of assessing second-line DST in all samples, and the difficulty of ensuring patient adherence to the audiological and laboratory monitoring prescribed. However, the results are encouraging, given the limited resources available, and could be applied to other middle-income countries.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusions</span><p id="par0170" class="elsevierStylePara elsevierViewall">DM is a recognized risk factor for TB (and MDR-TB) infection. Although DM MDR-TB cases appear to be at an increased risk of serious treatment toxicity (such as nephrotoxicity and hypothyroidism), outcomes are similar to non-DM cases if properly managed.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflict of Interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres834116" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Results" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec830155" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres834117" "titulo" => "Resumen" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Resultados" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec830156" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Statistical Analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0020" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Treatment Outcomes" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Effects of Diabetes" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Adverse Events" ] ] ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-08-03" "fechaAceptado" => "2016-10-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec830155" "palabras" => array:5 [ 0 => "Tuberculosis" 1 => "Multidrug-resistant tuberculosis" 2 => "Diabetes mellitus" 3 => "Adverse events" 4 => "Mexico" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec830156" "palabras" => array:5 [ 0 => "Tuberculosis" 1 => "Tuberculosis multirresistente" 2 => "Diabetes mellitus" 3 => "Reacciones adversas" 4 => "México" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Diabetes mellitus (DM), a very common disease in Mexico, is a well-known risk factor for tuberculosis (TB). However, it is not known by which extent DM predisposes to adverse events (AE) to anti-TB drugs and/or to worse outcomes in patients with multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB). The main objective of this study was to describe the outcomes of TB treatment, the impact of DM and the prevalence of AE in a cohort of patients with MDR-/XDR pulmonary TB treated at the national TB referral centre in Mexico City.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Results</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Ninety patients were enrolled between 2010 and 2015: 73 with MDR-TB (81.1%), 11 with pre-XDR-TB (12.2%) and 6 (6.7%) with XDR-TB, including 49 (54.4%) with DM, and 3 with Human Immunodeficiency Virus (HIV) co-infection (3.3%). In 98% of patients, diagnosis was made by culture and drug susceptibility testing, while in a single case the diagnosis was made by a molecular test. The presence of DM was associated with an increased risk of serious drug-related AEs, such as nephrotoxicity (Odds Ratio [OR]=6.5; 95% Confidence Interval [95% CI]: 1.9–21.8) and hypothyroidism (OR=8.8; 95% CI: 1.8–54.2), but not for a worse outcome.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusions</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Our data suggest that DM does not impact second-line TB treatment outcomes, but patients with DM have a higher risk of developing serious AEs to drug-resistant TB treatment, such as nephrotoxicity and hypothyroidism.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Results" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introducción</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">La diabetes mellitus (DM), una enfermedad muy frecuente en México, es un factor de riesgo bien conocido para el desarrollo de tuberculosis (TB). Sin embargo, se desconoce en qué medida la DM predispone al desarrollo de reacciones adversas (RA) a los fármacos anti-tuberculosis y/o si predispone a un peor resultado en pacientes con pacientes con TB multirresistente (TB-MR) y TB extremadamente resistente (TB-XR). El objetivo principal de este estudio fue describir los resultados del tratamiento anti-tuberculosis, el impacto de la DM y la prevalencia de RA en una cohorte de pacientes con TB pulmonar MR/XR tratados en el centro de referencia nacional para TB, en la Ciudad de México.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Resultados</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Entre 2010 y 2015 se incluyeron 90 pacientes —73 con TB-MR (81,1%), 11 con TB pre-XR (12,2%) y 6 (6,7%) con TB-XR—, 49 (54,4%) de los cuales tenían DM y 3 con co-infección por el virus de la inmunodeficiencia humana (VIH) (3,3%). El diagnóstico se realizó mediante cultivo y pruebas de fármaco-sensibilidad (PFS) en el 98% de los pacientes y mediante prueba molecular en un caso. La presencia de DM se asoció con un mayor riesgo de RA graves, tales como nefrotoxicidad (odds ratio [OR]<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6,5; intervalo de confianza del 95% [IC 95%]: 1,9–21,8) e hipotiroidismo (OR<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8,8; IC 95%: 1,8–54,2), aunque no con peor resultado del tratamiento.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusiones</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Nuestros datos sugieren que la DM no tiene un impacto sobre los resultados del tratamiento anti-tuberculosis de segunda línea, pero los pacientes con DM tienen mayor riesgo de presentar RA graves secundarias al tratamiento, tales como nefrotoxicidad e hipotiroidismo.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Resultados" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0055">Please cite this article as: Muñoz-Torrico M, Caminero-Luna J, Migliori GB, D’Ambrosio L, Carrillo-Alduenda JL, Villareal-Velarde H, et al. La diabetes se asocia con reacciones adversas graves en la tuberculosis multirresistente. Arch Bronconeumol. 2017;53:245–250.</p>" ] ] "multimedia" => array:3 [ 0 => 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:3 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Values are expressed as mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>standard Deviation (SD). BMI: Body Mass Index; DM: Diabetes Mellitus; HIV: Human Immunodeficiency Virus; MDR: Multidrug-resistant; ND=Not Done; Pre-XDR: pre-extensively drug-resistant; XTSH: Thyroid Stimulating Hormone; DR: extensively drug-resistant.</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">Characteristic \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">DM (<span class="elsevierStyleItalic">n</span>=49) \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 DM (<span class="elsevierStyleItalic">n</span>=41) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span> Value \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">Male (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31 (63%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25 (61%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8 \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">Age, yr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">49.5 (±11.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36.4 (±14.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.0001 \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">Weight (kg) baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60.1 (±14.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">51.7(±12.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.003 \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">BMI (kg/m<span class="elsevierStyleSup">2</span>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23.3 (±4.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19.3 (±3.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.0001 \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">Weight (kg) final<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">67.5 (±15.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">56.3 (±12.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.008 \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">Arterial hypertension<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 (27.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (5.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.005 \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">Chronic renal failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 (23.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" 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">0.001 \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">Number of previous treatments<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>[<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">1.7 (±0.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.7 (±1.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.9 \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>0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (8.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (9.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8 \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>1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 (36.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 (36.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1 \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>2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 (30.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 (34.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.7 \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>≥3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 (24.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 (19.1%) \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">HIV infection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (2.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (4.8) \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">Albumin (gr/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.1 (±0.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.4 (±0.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.05 \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">Haemoglobin (gr/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.3 (±2.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.6 (2.2) \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">Urea (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28.8 (±17.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19.6 (±7.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.004 \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">Creatinine (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.8 (±0.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.7 (±0.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.04 \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">TSH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.6 (±1.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.3 (±1.7) \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" title="table-entry " colspan="4" align="left" valign="top">Type of resistance</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 (%)<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39 (79.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">34 (83%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.7 \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>Pre-XDR (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (12.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (12.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1 \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 (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (8.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (4.9%) \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">Number of drugs with resistance<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.6 (±1.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.1 (±1.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1 \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">Intensive phase (months)<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.5 (±1.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.6 (±1.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.006 \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">Treatment duration (months)<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23.5 (±2.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24.1 (±1.9) \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" title="table-entry " colspan="4" align="left" valign="top">Outcomes (<span class="elsevierStyleItalic">n</span>=56)<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">f</span></a></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>Cure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15/32 (46.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18/24 (75%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.054 \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>Treatment completion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3/32 (9.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1/24 (4.2%) \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>Lost to follow-up \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5/32 (15.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/24 (8.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.7 \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>Failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/32 (6.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" 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">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>Death \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7/32 (21.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3/24 (12.5%) \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></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1406634.png" ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Includes only patients who completed at least the intensive phase of treatment (<span class="elsevierStyleItalic">n</span>=48).</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Arterial hypertension was defined as history of previous diagnosis or serial blood pressure levels of ≥140<span class="elsevierStyleHsp" style=""></span>mm Hg (systolic blood pressure) or ≥90<span class="elsevierStyleHsp" style=""></span>mmHg(diastolic blood pressure), or both.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Three patients had a history of failure to a previous second-line treatment.</p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Includes 1 patient diagnosed only as rifampicin resistant on the basis of Xpert MTB/RIF.</p>" ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Includes only patients with MDR and pre-XDR (27 DM and 25 non-DM patients).</p> <p class="elsevierStyleNotepara" id="npar0030">P values were estimated using independent group <span class="elsevierStyleItalic">t</span> test for continuous variables, <span class="elsevierStyleItalic">X</span><span class="elsevierStyleSup">2</span> for categorical variables.</p>" ] 5 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "f" "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Fisher's exact test in the case of small sample size.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">General Characteristics of Patients With Tuberculosis (TB) With or Without Diabetes Mellitus (DM).</p>" ] ] 1 => 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="spar0055" class="elsevierStyleSimplePara elsevierViewall">Same patients could have >1 adverse event. 95% CI: 95% Confidence Interval; DM: Diabetes Mellitus; OR: Odds Ratio.</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">Adverse event \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">DM<br>(<span class="elsevierStyleItalic">N</span>, [%]) \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 DM<br>(<span class="elsevierStyleItalic">N</span>, [%]) \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">OR (95% CI) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span> value \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">Psychiatric disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7/38 (18) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6/31 (19) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.9 (0.3–3.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.9 \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">Hypo-thyroidism<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15/27 (55.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3/24(12.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8.8 (1.8–54.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.001 \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">Nephrotoxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28/38 (73.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9/30 (30.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.5 (1.9–21.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0003 \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">Subsequent ototoxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13/23 (56.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8/25 (32.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.8 (0.8–10.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.08 \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">Allergic reactions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4/38 (10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/31 (6.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.6 (0.2–18.0) \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">Central venous line complications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11/27 (40.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5/18 (27.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.8 (0.4–8.2) \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></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1406633.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Three patients had sub-clinical hypothyroidism prior to treatment.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Frequency of Adverse Events in Multidrug-Resistant Tuberculosis Cases With or Without Diabetes Mellitus.</p>" ] ] 2 => 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:3 [ "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">CI: confidence interval; OR: Odds Ratio.</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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Adjusted OR \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">[95% CI] \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span> value \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">DM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.2–11.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.022<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a> \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">Sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.7–13.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.003<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">b</span></a> \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">Age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.9–1.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.7 \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">Arterial Hypertension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3–5.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8 \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">Malnutrition \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8–8.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1 \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">Alcohol abuse \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1–5.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1406632.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0045">Adverse events that required treatment interruption or required additional treatment</p>" ] 1 => array:3 [ "identificador" => "tblfn0040" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0050"><span class="elsevierStyleItalic">P</span><0.005</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Association of severe adverse events<span class="elsevierStyleSup">*</span> (nephrotoxicity, hypothyroidism, ototoxicity, and psychiatric disorders) with diabetes mellitus and other patient characteristics, by multivariate analysis.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:38 [ 0 => array:3 [ "identificador" => "bib0195" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global Tuberculosis Report 2015. WHO/HTM/TB/2015.22" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "World Health Organization" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2015" "editorial" => "World Health Organization" "editorialLocalizacion" => "Geneva" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0200" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: <span class="elsevierStyleInterRef" id="intr0010" href="http://www.diabetesatlas.org/">www.diabetesatlas.org</span> [accessed 02.08.16]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IDF Diabetes Atlas" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "International Diabetes Federation" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:2 [ "edicion" => "7th ed." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 2 | 8 |
| 2024 October | 69 | 18 | 87 |
| 2024 September | 74 | 12 | 86 |
| 2024 August | 92 | 31 | 123 |
| 2024 July | 72 | 20 | 92 |
| 2024 June | 85 | 24 | 109 |
| 2024 May | 135 | 38 | 173 |
| 2024 April | 63 | 35 | 98 |
| 2024 March | 47 | 19 | 66 |
| 2024 February | 49 | 17 | 66 |
| 2023 March | 19 | 3 | 22 |
| 2023 February | 65 | 19 | 84 |
| 2023 January | 31 | 28 | 59 |
| 2022 December | 77 | 27 | 104 |
| 2022 November | 85 | 34 | 119 |
| 2022 October | 83 | 39 | 122 |
| 2022 September | 50 | 36 | 86 |
| 2022 August | 34 | 53 | 87 |
| 2022 July | 39 | 44 | 83 |
| 2022 June | 40 | 34 | 74 |
| 2022 May | 47 | 31 | 78 |
| 2022 April | 50 | 45 | 95 |
| 2022 March | 51 | 42 | 93 |
| 2022 February | 66 | 35 | 101 |
| 2022 January | 86 | 38 | 124 |
| 2021 December | 80 | 45 | 125 |
| 2021 November | 147 | 54 | 201 |
| 2021 October | 94 | 65 | 159 |
| 2021 September | 69 | 58 | 127 |
| 2021 August | 74 | 32 | 106 |
| 2021 July | 70 | 38 | 108 |
| 2021 June | 46 | 29 | 75 |
| 2021 May | 73 | 50 | 123 |
| 2021 April | 135 | 113 | 248 |
| 2021 March | 98 | 34 | 132 |
| 2021 February | 65 | 29 | 94 |
| 2021 January | 61 | 17 | 78 |
| 2020 December | 72 | 31 | 103 |
| 2020 November | 76 | 24 | 100 |
| 2020 October | 64 | 17 | 81 |
| 2020 September | 72 | 22 | 94 |
| 2020 August | 68 | 15 | 83 |
| 2020 July | 46 | 18 | 64 |
| 2020 June | 51 | 14 | 65 |
| 2020 May | 55 | 12 | 67 |
| 2020 April | 49 | 20 | 69 |
| 2020 March | 63 | 12 | 75 |
| 2020 February | 58 | 26 | 84 |
| 2020 January | 56 | 17 | 73 |
| 2019 December | 61 | 32 | 93 |
| 2019 November | 49 | 25 | 74 |
| 2019 October | 74 | 18 | 92 |
| 2019 September | 70 | 22 | 92 |
| 2019 August | 43 | 19 | 62 |
| 2019 July | 45 | 22 | 67 |
| 2019 June | 56 | 17 | 73 |
| 2019 May | 49 | 19 | 68 |
| 2019 April | 61 | 62 | 123 |
| 2019 March | 62 | 39 | 101 |
| 2019 February | 50 | 22 | 72 |
| 2019 January | 68 | 31 | 99 |
| 2018 December | 46 | 29 | 75 |
| 2018 November | 117 | 38 | 155 |
| 2018 October | 164 | 29 | 193 |
| 2018 September | 70 | 7 | 77 |
| 2018 May | 11 | 1 | 12 |
| 2018 April | 61 | 12 | 73 |
| 2018 March | 61 | 8 | 69 |
| 2018 February | 23 | 11 | 34 |
| 2018 January | 8 | 12 | 20 |
| 2017 December | 31 | 9 | 40 |
| 2017 November | 26 | 10 | 36 |
| 2017 October | 33 | 19 | 52 |
| 2017 September | 39 | 15 | 54 |
| 2017 August | 31 | 24 | 55 |
| 2017 July | 1 | 2 | 3 |
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