Detection of high biliary and fecal viral loads in patients with chronic hepatitis C virus infection

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e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Detección de concentraciones víricas elevadas en la bilis y en las heces de pacientes con infección crónica por el virus de la hepatitis C" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 905 "Ancho" => 3372 "Tamanyo" => 135851 ] ] "descripcion" => array:1 [ "en" => "Correlation between plasmatic viral load and HCV RNA in the bile (A) and stool (B); the correlation between RNA in the bile and stool (C)." ] ] ] "textoCompleto" => "IntroductionChronic hepatitis C affects more than 170 million individuals who are at risk of developing cirrhosis and hepatocellular carcinoma.<a class="elsevierStyleCrossRef" href="#bib0245">1</a> The impact of this disease is evident, and the mortality due to hepatitis C virus (HCV) infection has superseded the mortality from HIV infections in the United States.<a class="elsevierStyleCrossRef" href="#bib0250">2</a> New, oral direct-acting antivirals (DAAs) are showing remarkable results. Nevertheless, DAAs have some shortcomings, such as high cost, risk of developing resistance-associated variants and drug-drug interactions.<a class="elsevierStyleCrossRefs" href="#bib0255">3–5</a> A better understanding of the viral cycle may facilitate the development of alternative treatment strategies or strategies that complement DAAs.HCV circulates in human serum associated with several lipoproteins forming lipo-viral particles (LVPs).<a class="elsevierStyleCrossRefs" href="#bib0270">6–8</a> LVP formation occurs during lipoprotein synthesis in hepatocytes, which is a process that may shield the virus from neutralizing antibodies.<a class="elsevierStyleCrossRef" href="#bib0285">9</a> LVPs are characterized by their low density, presence of apolipoprotein B (apoB) and enrichment of triglycerides.<a class="elsevierStyleCrossRef" href="#bib0290">10</a> HCV is not evenly distributed in the different plasmatic lipid fractions and is especially abundant in the very-low-density fractions, which comprise triglyceride-rich lipoproteins (TRL).<a class="elsevierStyleCrossRef" href="#bib0295">11</a>TRL particles have a density less than 1.006g/mL and have a core made of triglycerides and cholesterol esters surrounded by a phospholipid monolayer of free cholesterol, apoB and other lipoproteins.<a class="elsevierStyleCrossRef" href="#bib0300">12</a> There are two types of TRLs: very-low-density lipoproteins (VLDLs) and chylomicrons. VLDLs are assembled with one apoB100 molecule per particle and are secreted by hepatocytes, whereas chylomicrons contain one molecule of apoB48, which is a truncated form of apoB and is enterocyte specific.<a class="elsevierStyleCrossRef" href="#bib0305">13</a> In humans, apoB100 is synthesized primarily by the liver, whereas apoB48 is synthesized only in the intestines. Intriguingly, apoB100 and apoB48 are equally represented in LVPs purified from HCV-infected patients.<a class="elsevierStyleCrossRef" href="#bib0310">14</a> This observation led to the suggestion that the intestine could be a reservoir of HCV and that enterocytes could contribute to an estimated 18% of the plasmatic viral load.<a class="elsevierStyleCrossRef" href="#bib0310">14</a> An intestinal contribution to the overall HCV load in infected patients could be explained either by viral extrahepatic replication in the enterocyte or by the intestinal absorption of HCV.Based on evidence suggesting that enterocytes can be a reservoir for HCV,<a class="elsevierStyleCrossRefs" href="#bib0310">14,15</a> it is plausible that HCV has an enterohepatic cycle similar to that of cholesterol: secretion into the bile, reabsorption in the enterocyte and secretion bound to chylomicrons. This possibility would imply that some HCV particles could escape reabsorption by enterocyte, shedding to the feces of infected patients. However, detection of HCV particles in bile and stools of infected patients remains controversial. Thus, we designed a study to evaluate the presence of HCV in the bile and feces of Chilean patients chronically infected with the virus. We also assessed whether the viral load correlated with different compartments and plasmatic cholesterol and triglyceride levels.Materials and methodsStudy populationPatients chronically infected with HCV who were followed up at the Viral Hepatitis Unit of the Clinical Hospital, Pontificia Universidad Católica de Chile (PUC) were recruited and invited to participate in this study. The protocols and consent forms used in this study were approved by the Ethical Review Board of the Faculty of Medicine, PUC (protocol number 12-199) and were in accordance with local regulations and the ethical principles originated in the Declaration of Helsinki and with ICH/Good Clinical Practice. Patients were informed about the study and completed a written consent form before donating blood, bile and stool. Patient inclusion criteria were the following: 1) chronic hepatitis C defined as detectable HCV RNA in the plasma for more than 6 months; 2) age greater than 18 years; 3) compensated liver disease (bilirubin<3mg/dL unless having Gilbert's syndrome, albumin>3g/dL, INR<2, no hepatic encephalopathy, no ascites or recent (1 month) history of variceal bleeding); 4) no history of cholecystectomy or known gallstones; 5) no current HCV antiviral treatment; 6) no medications for dyslipidaemia within the preceding 2 months; 7) no abdominal surgery that could alter the biliary or intestinal anatomy; 8) HCV RNA levels>10,000IU/mL; 9) no evidence of sitosterolemia; 10) negative pregnancy test in urine (for females); and 11) signed informed consent document. Subjects who had HIV or hepatitis B virus (HBV) coinfection, who were undergoing anticancer chemotherapy, or who had received previous antiviral treatment with DAAs were excluded from the study.Liver fibrosis was assessed via a liver biopsy or Fibroscan and was categorized according to the METAVIR system.<a class="elsevierStyleCrossRef" href="#bib0320">16</a>Peripheral blood, bile and feces were collected for biochemical and virological assessments. Standard clinical tests, including a lipid profile (total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol), a liver profile (ALT, AST, GGTP, alkaline phosphatase, total and conjugated bilirubin, prothrombin time/INR) and HCV RNA levels were determined from plasma samples.Sample collection and biochemical analysisPeripheral blood was collected into EDTA-Vacutainer™ tubes (Becton Dickinson, Franklin Lakes, NJ, USA), and plasma samples recovered from the donors were stored at 80°C until processed. Bile samples were obtained using the technique of biliary drainage (duodenal aspirate). This technique is routinely performed in our clinical service for both clinical and research purposes.<a class="elsevierStyleCrossRef" href="#bib0325">17</a> Briefly, after 8h fasting, patients underwent an upper digestive endoscopy under conscious sedation with midazolam. An oro-duodenal small diameter tube was positioned with the endoscope. After removing the endoscope, the gallbladder was stimulated with amino acids and bile was aspirated from the duodenum.<a class="elsevierStyleCrossRef" href="#bib0330">18</a> Bile samples were stored at −80°C until processing. Serum lipids and liver function tests were determined by standard clinical chemical assays. Biliary cholesterol and bile acids were measured by enzymatic methods<a class="elsevierStyleCrossRefs" href="#bib0335">19,20</a> and phospholipids were assessed by a colorimetric method.<a class="elsevierStyleCrossRef" href="#bib0345">21</a> Stool samples were preserved in 5mL of RNALater™ Stabilization Solution (Ambion, Thermo Fisher Scientific, Waltham, MA, USA) from the time of collection and were frozen at −80°C for later analysis.<a class="elsevierStyleCrossRef" href="#bib0350">22</a> All measurements in bile and feces were corrected according to the input volume.Viral load determination and HCV genotypingHCV RNA levels in plasma, bile and feces were determined using the COBAS TaqMan HCV Test™ v2.0 (Roche Molecular Systems, Inc, Rotkreuz, Switzerland) with a lower limit of quantification (LLOQ) of 25IU/mL and lower limit of detection (LLOD) of 9.3IU/mL.<a class="elsevierStyleCrossRef" href="#bib0355">23</a> HCV genotyping of the virus present in the plasma was performed using the reverse hybridization line probe assay INNO-LiPA HCV II kit™ (Innogenetics, Ghent, Belgium) according to the manufacturer's instructions.<a class="elsevierStyleCrossRefs" href="#bib0360">24,25</a>RNA extraction and RT-PCR in stool samplesA technique for extracting HCV RNA from stool has been described elsewhere.<a class="elsevierStyleCrossRef" href="#bib0370">26</a> For convenience and more reliable results, we used the PowerMicrobiome™ RNA Isolation Kit (MoBio Laboratories, Carlsbad, CA, USA), which is optimized for removing PCR inhibitors from the stool and gut material. To rule out the possibility that fecal HCV RNA or core protein is a result of contamination from occult blood loss in the gut, an immunochemical assay to detect human hemoglobin (Hemosure™) was performed on the stool samples. This assay is highly specific and sensitive (50ng human hemoglobin/mL), requires no specific diet and is readily available at our institution.<a class="elsevierStyleCrossRef" href="#bib0375">27</a>The HCV RNA extracted by the PowerMicrobiome™ RNA Isolation Kit from the feces was eluted in 60μL of nuclease-free water. Thirty microliters diluted in 470μL of 1× PBS were used to quantify the HCV RNA using the COBAS TaqMan HCV Test™ v2.0. In each case, the results (in IU) were corrected by the input in milligrams of stool and then by the Power PowerMicrobiome™ elution volume. In parallel, the HCV RNA was detected using a one-step reverse transcription (RT) polymerase chain reaction (PCR) using the SuperScriptTM III one-step RT-PCR system with Platinum-Taq DNA Polymerase™ (Invitrogen, Life Technologies, Carlsbad, CA, USA) kit with a lower limit of detection of 1×103 HCV genomic copies per mL following a protocol previously described.<a class="elsevierStyleCrossRef" href="#bib0365">25</a>Determination of core protein levelsThe HCV core protein levels are correlated with HCV RNA levels and may be used as an alternative marker of HCV infection. The level of core protein in the plasma, bile and feces was quantified using the ARCHITECT HCV Ag assay™ (Abbott Laboratories, Abbott Park, IL, USA) following the manufacturer's instructions. The dynamic range of this assay is 3–20,000fmol/L. For this purpose, samples frozen at −80°C (thawed once) were used.Data analysisThe HCV RNA viral load, given its exponential distribution, was logarithmically transformed using base 10, and geometrical means were used. Values below the limit of quantification (25IU/mL) were computed as 12IU/mL, and undetectable values were computed as 4IU/mL for statistical analyses. Similarly, undetectable HCV core protein determinations were considered to be 2fmol/L for the statistical analyses. As previously mentioned, the viral load determinations in the bile were normalized to the bile acid concentration for a meaningful comparison, and the viral loads were expressed as IU/60mg bile salts, which is the normal concentration of bile salts per mL of bile.<a class="elsevierStyleCrossRefs" href="#bib0380">28,29</a> Viral load determinations in feces were expressed as IU/g of stool. To determine if the viral load was correlated with the amounts of core protein and between compartments, a Pearson correlation analysis was performed using Graph Pad V6 and SPSS v20. A p value <0.05 was considered significant.ResultsPatient characteristicsThe clinical features and the serum and bile compositions at the time of sample collection for the twelve patients included in this study are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. The average age of patients was 60 years (range 27–75 years), with roughly equal gender distribution (male 58%). An HCV genotypic analysis confirmed the prevalence of genotype 1b in the majority of patients (n=9), which is consistent with the epidemiology in our country.<a class="elsevierStyleCrossRef" href="#bib0390">30</a> Seven of the twelve patients were cirrhotic at the time of sampling. All patients with cirrhosis were well compensated. Two patients had failed to a previous course of treatment with peginterferon alfa 2b plus ribavirin; the remaining patients were treatment naïve.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>HCV viral load and HCV core protein in bile and stool samplesThe mean HCV viral load in the plasma was 6.08±1.34log10IU/mL. As expected, the HCV core Ag in plasma showed a high correlation with the plasmatic HCV viral load (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). We detected HCV RNA in the bile of 10 patients (83%), and the mean viral load was 2.5log10IU/60mg bile salts (range: undetectable–7.0log10IU/60mg bile salt), which is (on average) 3.6log10 less than the average plasma viral load (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). In feces, HCV RNA was alsodetected in 10 patients (83%). The average viral load was 2.7log10IU/g (range: undetectable–7log10IU/g). The internal control RNA was detected in all samples indicating the lack of RT-PCR inhibitors. Patients with a positive immunochemical fecal occult blood test did not exhibit greater levels of biliary or fecal HCV viral load. The presence of the HCV core protein was confirmed in the bile of only one patient and was not detected in any of the evaluated stool samples.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Correlations between the viral loads in the different compartments and plasmatic lipidsThe plasmatic HCV viral load was not significantly associated with the biliary HCV RNA titers or with the fecal viral load (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A and B). Similarly, biliary and stool viral loads were not correlated (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C). The standardized biliary viral load was weakly correlated with the presence of plasmatic HCV core protein (r=0.603, p=0.038). The fecal viral load was not significantly associated with the lipidic components of plasma or bile (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). The plasma viral load did not show a significant association with the concentration of the plasmatic or biliary lipidic components (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>DiscussionThe existence of extrahepatic reservoirs for HCV replication has long been suspected but remains highly controversial. Previous studies, including several from our laboratory,<a class="elsevierStyleCrossRefs" href="#bib0360">24,25,31,32</a> have observed HCV RNA to be associated with peripheral blood mononuclear cells (PBMCs). Additionally, Deforges et al. reported that the small intestine can be infected by HCV and strongly suggested that this organ may be a reservoir for HCV and a source of LVPs.<a class="elsevierStyleCrossRef" href="#bib0315">15</a> The main evidence of HCV replication in this extrahepatic compartment was the detection of HCV non-structural proteins NS3 and NS5A in intestinal biopsies. HCV protein expression was observed in enterocytes, which are cells that synthesize and secrete chylomicrons. Although this evidence strongly suggests viral replication, herein, we put forward an alternative and yet unexplored possibility. HCV may also have an enterohepatic cycle similar to the cycle described for cholesterol. If true, HCV would constantly be secreted into the bile and would be reabsorbed by the enterocyte and secreted back into the system bound to chylomicrons. Furthermore, the presence of HCV would be expected in the bile (secreted) and stool (not reabsorbed) of chronically infected individuals. In this model, HCV replication in the enterocyte would not be required to explain the apoB48 and high triglyceride content of LVPs. In this study, to indirectly evaluate this alternative model, by establishing whether HCV is present in the bile and stool of chronically infected HCV patients. In these studies we not only detected HCV RNA but we also quantified its levels in each samples. When comparing the HCV viral load in the bile and plasma of the same individual, the viral load was an average of 3.6log10 less in the bile compared to the plasma. No correlation was found between the viral titers in the different compartments and the concentration of the lipidic components of the plasma or bile. Nonetheless, the results of this study suggest that HCV can be shed into the bile and can later be found in the stool.There has been an alarming increase in incidence of acute HCV infection in HIV-infected men who have sex with men (MSM),<a class="elsevierStyleCrossRef" href="#bib0405">33</a> which has been speculated to be related to permucosal transmission.<a class="elsevierStyleCrossRef" href="#bib0410">34</a> The presence of HCV RNA in measurable quantities in stools of infected patients may explain in part these outbreaks.Three earlier studies reported the amplification of HCV RNA from the bile of chronically infected patients.<a class="elsevierStyleCrossRefs" href="#bib0415">35–37</a> These studies detected viral RNA in 19/34 patients (56%), whereas we were able to detect HCV RNA in 10/12 patients (83%). One important difference between our study and the previous report is that we quantified the HCV RNA in the bile using the Roche COBAS TaqMan assay. We also quantified the HCV RNA in the bile components and used this value to normalize the HCV RNA concentration. In our opinion, this normalization provided a better comparison between samples obtained from different patients.HCV core antigen was determined using a commercial kit, but we could detect this protein in the bile of just one patient and none in the stool samples. Heidrich et al.<a class="elsevierStyleCrossRef" href="#bib0430">38</a> in a recent study tested the stools of 98 chronically infected patients and were able to detect HCV RNA in 69% of the samples, but HCV core protein with the same assay (ARCHITECT) in only 24% of samples. Unfortunately the core protein level was not provided nor was the HCV RNA level determined.Aside from the already commented study of Heidrich, the presence of HCV RNA in stool has been tested in other two studies. In the earliest paper,<a class="elsevierStyleCrossRef" href="#bib0435">39</a> attempts to identify HCV RNA in secretions, including feces, were unsuccessful. A second study was able to detect and measure the HCV viral load in relatively high amounts (1–3 logs lower than plasma) in feces in 4 out of 6 chronically infected patients.<a class="elsevierStyleCrossRef" href="#bib0440">40</a> However, in that report, the authors did not rule out blood contamination as the possible source of viral RNA. To overcome this limitation, in our study, a highly sensitive immunochemical method was used to detect blood in the stool, which was negative in 9 of the 12 patients. The three remaining patients did not exhibit a greater viral load in the bile or stool, which suggests a limited role of blood contamination as a source of virus in the tested samples.One of our objectives was to determine whether viral particles were shed into the bile and stool of chronically infected HCV patients. We also sought to detect the presence of an HCV structural protein. Unfortunately, we were unable to detect the HCV core protein in these secretions using the Abbott ARCHITECHT assay. This failure could be explained by either the technical limitations of this assay, which is designed to detect viral protein in plasma samples or by the lower sensitivity of the assay compared to the COBAS TaqMan test considering that the bile and stool samples exhibited lower viral loads when compared to plasma. Despite the lack of core protein detection, the presence of viral RNA suggests that the virus, even though at lower quantities, can be found both in the bile and stool. This observation supports a model in which the virus is shed into the bile where it can later be excreted or reabsorbed by the enterocyte.The proposed model raises a number of additional questions. How can the virus be reabsorbed by the enterocytes or any other intestinal cell if these cells are known to lack the CD81 virus receptor? The discovery of new viral entry factors has revealed that several of these factors are related to lipid metabolism, including the LDL receptor,<a class="elsevierStyleCrossRef" href="#bib0445">41</a> scavenger receptor class B type I (SR-BI),<a class="elsevierStyleCrossRef" href="#bib0450">42</a> and NPC1L1.<a class="elsevierStyleCrossRef" href="#bib0455">43</a> Interestingly, SR-B1 is found on the apical and basal poles of enterocytes and may provide an alternative entry pathway for the virus.<a class="elsevierStyleCrossRefs" href="#bib0460">44,45</a> Additionally, NPC1L1 is also expressed on the apical membrane of enterocytes.<a class="elsevierStyleCrossRefs" href="#bib0455">43,46</a> Previous studies have proposed NPC1L1 as a target for HCV therapeutic interventions.<a class="elsevierStyleCrossRef" href="#bib0455">43</a> In this context, our findings are very clinically relevant and suggest that HCV reabsorption by enterocytes could be targeted for clinical intervention using an NPC1L1 antagonist, such as ezetimibe, which is a drug that disrupts the enterohepatic cycle of endogenous cholesterol.<a class="elsevierStyleCrossRef" href="#bib0475">47</a> Ezetimibe binds to the extracellular loop C at a different domain than cholesterol and the HCV virion and blocks the internalization of the NPC1L1/cholesterol complex.<a class="elsevierStyleCrossRef" href="#bib0480">48</a> Therefore, antagonizing the NPC1L1 cholesterol receptor with ezetimibe may have an inhibitory effect in hepatic and/or intestinal uptake.The presence of HCV RNA in the bile and stool, together with the description that HCV circulates in the plasma equally bound to hepatic-derived apoB100 and intestinally derived apoB48,<a class="elsevierStyleCrossRef" href="#bib0310">14</a> leads to the striking possibility that the blockage of intestinal NPC1L1 can disrupt the possible enterohepatic mode of HCV circulation. While compelling, this hypothesis remains highly speculative and must be specifically evaluated in clinical studies.Conflict of interestsA.S. has received fees as a speaker for MSD, Roche, BMS, he has participated in Advisory Board Meetings for MSD, Abbvie, Gilead, Vertex, Roche, and Janssen and he has stock ownership of Gilead and Achillion. The others authors declare that they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres834743" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objectives" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Materials and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec830669" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres834742" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Materiales y métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec830670" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study population" ] 1 => array:3 [ "identificador" => "sec0020" "titulo" => "Sample collection and biochemical analysis" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Viral load determination and HCV genotyping" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "RNA extraction and RT-PCR in stool samples" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Determination of core protein levels" ] ] ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Data analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0050" "titulo" => "Patient characteristics" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "HCV viral load and HCV core protein in bile and stool samples" ] ] ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Correlations between the viral loads in the different compartments and plasmatic lipids" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflict of interests" ] 9 => array:2 [ "identificador" => "xack280443" "titulo" => "Acknowledgments" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-12-09" "fechaAceptado" => "2017-01-05" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec830669" "palabras" => array:6 [ 0 => "Cholesterol" 1 => "Gut" 2 => "Enterohepatic" 3 => "Bile" 4 => "Feces" 5 => "Hepatitis C virus" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec830670" "palabras" => array:6 [ 0 => "Colesterol" 1 => "Intestino" 2 => "Enterohepática" 3 => "Bilis" 4 => "Heces" 5 => "Virus de la hepatitis C" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundThe life cycle of the hepatitis C virus (HCV) is closely associated with lipid metabolism. Recently, NPC1L1 (a cholesterol transporter) has been reported to function as an HCV receptor. This receptor is expressed in the hepatocyte canalicular membrane and in the intestine; serving as a key transporter for the cholesterol enterohepatic cycle. ObjectivesWe hypothesized that HCV might have a similar cycle, so we aimed to study the presence of HCV in bile and stools of infected patients. Materials and methodsBlood, feces, and duodenal bile samples were collected from patients infected with HCV. The biliary viral load was normalized to the bile salt concentration of each sample and the presence of HCV core protein was also evaluated. A total of 12 patients were recruited. HCV RNA was detected in the bile from ten patients. ResultsThe mean viral load was 2.5log10IU/60mg bile salt. In the stool samples, HCV RNA was detected in ten patients (mean concentration 2.7log10IU/g of feces). ConclusionsHCV RNA is readily detectable and is present at relatively high concentrations in the bile and stool samples of infected patients. This may be relevant as a source of infection in men who have sex with men. Biliary HCV secretion may perhaps play a role in the persistence of viral infection via an enterohepatic cycle of the virus or intrahepatic spread." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objectives" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Materials and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónEl ciclo de vida del virus de la hepatitis C (VHC) está estrechamente ligado al metabolismo lipídico. Recientemente, se ha descrito que el NPC1L1 (un transportador del colesterol) actúa como un receptor del VHC. Este receptor se expresa en la membrana canalicular de los hepatocitos y en el intestino, y actúa como uno de los principales transportadores durante la circulación enterohepática del colesterol. ObjetivosPlanteamos la hipótesis de que el VHC podría tener un ciclo similar, por lo que nuestro objetivo fue estudiar la presencia del VHC en la bilis y en las heces de pacientes infectados. Materiales y métodosSe obtuvieron muestras de sangre, heces y bilis duodenal de pacientes infectados por el VHC. La concentración vírica en la bilis se normalizó respecto a la concentración de sales biliares de cada muestra y también se evaluó la presencia de la proteína central del VHC. Se reclutaron un total de 12 pacientes. Se detectó el ARN del VHC en la bilis de 10 pacientes. ResultadosLa media de la concentración vírica fue 2,5log10UI/60mg de sales biliares. En las muestras de heces, se detectó el ARN del VHC en 10 pacientes (media de la concentración 2,7log10UI/g de heces). ConclusionesEl ARN del VHC es fácilmente detectable y está presente en concentraciones relativamente elevadas en las muestras de bilis y heces de pacientes infectados. Esto puede tener importancia como foco de infección en varones que mantienen relaciones sexuales con otros varones. Es posible que la secreción biliar del VHC pueda desempeñar un papel en la persistencia de la virosis a través de la circulación enterohepática del virus o la propagación intrahepática." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Materiales y métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1184 "Ancho" => 1630 "Tamanyo" => 60163 ] ] "descripcion" => array:1 [ "en" => "Correlation between HCV RNA and HCV core protein in the plasma." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 905 "Ancho" => 3372 "Tamanyo" => 135851 ] ] "descripcion" => array:1 [ "en" => "Correlation between plasmatic viral load and HCV RNA in the bile (A) and stool (B); the correlation between RNA in the bile and stool (C)." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1702 "Ancho" => 3359 "Tamanyo" => 252273 ] ] "descripcion" => array:1 [ "en" => "Correlations between HCV RNA in the plasma and the lipid components of the plasma and bile." ] ] 3 => 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" => "Fibrosis: liver fibrosis by METAVIR scale (F0 to F4). Chol: total cholesterol. TG: triglycerides. HDL: high-density lipoprotein. LDL: low-density lipoprotein. AST: aspartate aminotransferase. ALT: alanine aminotransferase. GGTP: gamma-glutamyl transpeptidase. AP: alkaline phosphatase. TB: total bilirubin. DB: direct bilirubin. SD: standard deviation." 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scope="col" style="border-bottom: 2px solid black">Bile</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col"> \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">Chol \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">TG \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">HDL \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">LDL \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">AST \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">ALT \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">GGTP \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">AP \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">TB \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">DB \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">INR \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col"> \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">Chol (mM) \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">Bile salts (mM) \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">Phospholipids (mM) \t\t\t\t\t\t\n \t\t\t\t</th></tr><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="" 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="" 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="" 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">mg/dL \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">mg/dL \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">mg/dL \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">mg/dL \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">U/mL \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">U/mL \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">U/mL \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">U/mL \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">mg/dL \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">mg/dL \t\t\t\t\t\t\n \t\t\t\t</th><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="" 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="" 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="" 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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">E-02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">112 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">62 \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">57 \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">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">66 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.91 \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><td class="td" title="table-entry " align="char" valign="top">1.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(−) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.4 \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">E-03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">138 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28 \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="char" valign="top">79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">86 \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="char" valign="top">145 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(−) \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><td class="td" title="table-entry " align="char" valign="top">38.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.6 \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">E-04 \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="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">104 \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">60 \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="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">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(−) \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><td class="td" title="table-entry " align="char" valign="top">28.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3 \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">E-05 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">178 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">181 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">260 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">257 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">462 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">164 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(−) \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><td class="td" title="table-entry " align="char" valign="top">25.2 \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">E-06 \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="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">167 \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">54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.19 \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><td class="td" title="table-entry " align="left" valign="top">(−) \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><td class="td" title="table-entry " align="char" valign="top">29.7 \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">E-07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">134 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">74 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">139 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">122 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.29 \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><td class="td" title="table-entry " align="left" valign="top">(−) \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><td class="td" title="table-entry " align="char" valign="top">25.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.3 \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">E-08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">168 \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><td class="td" title="table-entry " align="char" valign="top">83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \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><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="char" valign="top">56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.15 \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><td class="td" title="table-entry " align="left" valign="top">(−) \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><td class="td" title="table-entry " align="char" valign="top">37.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.3 \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">E-09 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F4 \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">56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43 \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="char" valign="top">63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">109 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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">1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \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><td class="td" title="table-entry " align="char" valign="top">75.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.2 \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">E-10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">142 \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><td class="td" title="table-entry " align="char" valign="top">49 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">74 \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="char" valign="top">81 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">72 \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><td class="td" title="table-entry " align="char" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \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><td class="td" title="table-entry " align="char" valign="top">20.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.1 \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">E-11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">167 \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="char" valign="top">56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">62 \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><td class="td" title="table-entry " align="char" valign="top">0.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(−) \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><td class="td" title="table-entry " align="char" valign="top">69.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.8 \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">E-12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">131 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">115 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">66 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">160 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">201 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">74 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">105 \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><td class="td" title="table-entry " align="char" valign="top">0.2 \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><td class="td" title="table-entry " align="left" valign="top">(+) \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><td class="td" title="table-entry " align="char" valign="top">39.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.2 \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">E-13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">116 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">113 \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="char" valign="top">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92 \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">92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">123 \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><td class="td" title="table-entry " align="char" valign="top">0.4 \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><td class="td" title="table-entry " align="left" valign="top">(−) \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><td class="td" title="table-entry " align="char" valign="top">58.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="19" align="char" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mean \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60.0 \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><td class="td" title="table-entry " align="char" valign="top">133.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">90.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">85.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">96.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">94.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">97.3 \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><td class="td" title="table-entry " align="char" valign="top">0.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.1 \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">0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.3 \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">SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.6 \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><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">31.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">41.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">65.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">70.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">118.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">37.2 \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><td class="td" title="table-entry " align="char" valign="top">0.3 \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><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">0.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21.1 \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></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1407625.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Patients’ clinical features and serum and bile compositions." ] ] 4 => 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:2 [ "leyenda" => "ND: not detectable. SD: standard deviation." "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">Subject \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">HCV genotype \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">Plasma HCV RNA (log10IU/mL) \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">Plasma HCV core Ag (fmol/L) \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">Bile HCV RNA (log10IU/60mg bile salt) \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">Stool HCV RNA (log10IU/g) \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">E-02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \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">E-03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2102 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.94 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.58 \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">E-04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">823 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.72 \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">E-05 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1986 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.87 \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">E-06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">807 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.99 \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">E-07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.01 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8464 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.05 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.51 \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">E-08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8438 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.79 \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">E-09 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">91 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.32 \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">E-10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">133 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \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">E-11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.96 \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">E-12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4153 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.98 \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">EZ13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.91 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4172 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.48 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mean \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">6.08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2601 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.69 \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">SD \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">1.34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3105 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.76 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1407624.png" ] ] ] ] "descripcion" => array:1 [ "en" => "HCV genotype, viral load and HCV core protein quantification in plasma, bile and stool samples from patients chronically infected with hepatitis C virus." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:48 [ 0 => array:3 [ "identificador" => "bib0245" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The global burden of hepatitis C" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "D. Lavanchy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1478-3231.2008.01934.x" "Revista" => array:7 [ "tituloSerie" => "Liver Int" "fecha" => "2009" "volumen" => "29" "numero" => "Suppl. 1" "paginaInicial" => "74" "paginaFinal" => "81" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19207969" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0250" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K.N. Ly" 1 => "J. Xing" 2 => "R.M. Klevens" 3 => "R.B. Jiles" 4 => "J.W. Ward" 5 => "S.D. Holmberg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7326/0003-4819-156-4-201202210-00004" "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "2012" "volumen" => "156" "paginaInicial" => "271" "paginaFinal" => "278" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22351712" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0255" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Access to costly new hepatitis C drugs: medicine, money, and advocacy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S.B. Trooskin" 1 => "H. Reynolds" 2 => "J.R. Kostman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/cid/civ677" "Revista" => array:6 [ "tituloSerie" => "Clin Infect Dis" "fecha" => "2015" "volumen" => "61" "paginaInicial" => "1825" "paginaFinal" => "1830" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26270682" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0260" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Resistance of hepatitis C virus to inhibitors: complexity and clinical implications" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "C. Perales" 1 => "J. Quer" 2 => "J. Gregori" 3 => "J.I. Esteban" 4 => "E. Domingo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/v7112902" "Revista" => array:6 [ "tituloSerie" => "Viruses" "fecha" => "2015" "volumen" => "7" "paginaInicial" => "5746" "paginaFinal" => "5766" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26561827" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0265" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug interactions with new hepatitis C oral drugs" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. Soriano" 1 => "P. Labarga" 2 => "P. Barreiro" 3 => "J.V. Fernandez-Montero" 4 => "C. de Mendoza" 5 => "I. Esposito" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1517/17425255.2015.998997" "Revista" => array:6 [ "tituloSerie" => "Expert Opin Drug Metab Toxicol" "fecha" => "2015" "volumen" => "11" "paginaInicial" => "333" "paginaFinal" => "341" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25553890" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0270" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "V. Agnello" 1 => "G. Abel" 2 => "M. Elfahal" 3 => "G.B. Knight" 4 => "Q.X. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci U S A" "fecha" => "1999" "volumen" => "96" "paginaInicial" => "12766" "paginaFinal" => "12771" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10535997" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0275" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of hepatitis C virus in human sera with beta-lipoprotein" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R. Thomssen" 1 => "S. Bonk" 2 => "C. Propfe" 3 => "K.H. Heermann" 4 => "H.G. Kochel" 5 => "A. Uy" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Med Microbiol Immunol" "fecha" => "1992" "volumen" => "181" "paginaInicial" => "293" "paginaFinal" => "300" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1335546" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0280" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association between hepatitis C virus and very-low-density lipoprotein (VLDL)/LDL analyzed in iodixanol density gradients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S.U. Nielsen" 1 => "M.F. Bassendine" 2 => "A.D. Burt" 3 => "C. Martin" 4 => "W. Pumeechockchai" 5 => "G.L. Toms" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/JVI.80.5.2418-2428.2006" "Revista" => array:6 [ "tituloSerie" => "J Virol" "fecha" => "2006" "volumen" => "80" "paginaInicial" => "2418" "paginaFinal" => "2428" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16474148" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0285" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Host neutralizing responses and pathogenesis of hepatitis C virus infection" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.B. Zeisel" 1 => "F.L. Cosset" 2 => "T.F. Baumert" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.22307" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2008" "volumen" => "48" "paginaInicial" => "299" "paginaFinal" => "307" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18508291" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0290" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characterization of low- and very-low-density hepatitis C virus RNA-containing particles" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Andre" 1 => "F. Komurian-Pradel" 2 => "S. Deforges" 3 => "M. Perret" 4 => "J.L. Berland" 5 => "M. Sodoyer" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Virol" "fecha" => "2002" "volumen" => "76" "paginaInicial" => "6919" "paginaFinal" => "6928" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12072493" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0295" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Visualization of hepatitis C virions and putative defective interfering particles isolated from low-density lipoproteins" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A.M. Prince" 1 => "T. Huima-Byron" 2 => "T.S. Parker" 3 => "D.M. Levine" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Viral Hepat" "fecha" => "1996" "volumen" => "3" "paginaInicial" => "11" "paginaFinal" => "17" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8736235" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0300" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E.A. Fisher" 1 => "H.N. Ginsberg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1074/jbc.R100068200" "Revista" => array:6 [ "tituloSerie" => "J Biol Chem" "fecha" => "2002" "volumen" => "277" "paginaInicial" => "17377" "paginaFinal" => "17380" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12006608" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0305" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Developmental regulation of apolipoprotein B mRNA editing is an autonomous function of small intestine involving homeobox gene Cdx1" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.P. Patterson" 1 => "Z. Chen" 2 => "D.C. Rubin" 3 => "V. Moucadel" 4 => "J.L. Iovanna" 5 => "H.B. Brewer Jr." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1074/jbc.M201601200" "Revista" => array:6 [ "tituloSerie" => "J Biol Chem" "fecha" => "2003" "volumen" => "278" "paginaInicial" => "7600" "paginaFinal" => "7606" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12493769" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0310" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Preferential association of Hepatitis C virus with apolipoprotein B48-containing lipoproteins" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "O. Diaz" 1 => "F. Delers" 2 => "M. Maynard" 3 => "S. Demignot" 4 => "F. Zoulim" 5 => "J. Chambaz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1099/vir.0.82033-0" "Revista" => array:6 [ "tituloSerie" => "J Gen Virol" "fecha" => "2006" "volumen" => "87" "paginaInicial" => "2983" "paginaFinal" => "2991" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16963757" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0315" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of hepatitis C virus proteins in epithelial intestinal cells in vivo" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Deforges" 1 => "A. Evlashev" 2 => "M. Perret" 3 => "M. Sodoyer" 4 => "S. Pouzol" 5 => "J.Y. Scoazec" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1099/vir.0.80071-0" "Revista" => array:6 [ "tituloSerie" => "J Gen Virol" "fecha" => "2004" "volumen" => "85" "paginaInicial" => "2515" "paginaFinal" => "2523" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15302945" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0320" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group" ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1994" "volumen" => "20" "paginaInicial" => "15" "paginaFinal" => "20" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8020885" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0325" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "[Occult gallbladder disease or microlithiasis in patients with acute pancreatitis: a frequent clinical event]" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.F. Miquel" 1 => "A. Prado" 2 => "H. Asahi" 3 => "L. Ibanez" 4 => "S. Guzman" 5 => "F. Cruz" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Med Chil" "fecha" => "1997" "volumen" => "125" "paginaInicial" => "869" "paginaFinal" => "878" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9580486" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0330" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical evaluation of ezetimibe on bile lithogenicity in humans: use of transnasal endoscopy for bile sampling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "N. Kishikawa" 1 => "K. Kanno" 2 => "A. Sugiyama" 3 => "K. Yokobayashi" 4 => "M. Mizooka" 5 => "S. Tazuma" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/hepr.12402" "Revista" => array:6 [ "tituloSerie" => "Hepatol Res" "fecha" => "2015" "volumen" => "45" "paginaInicial" => "693" "paginaFinal" => "697" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25132425" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0335" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enzymatic determination of total serum cholesterol" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "C.C. Allain" 1 => "L.S. Poon" 2 => "C.S. Chan" 3 => "W. Richmond" 4 => "P.C. Fu" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Chem" "fecha" => "1974" "volumen" => "20" "paginaInicial" => "470" "paginaFinal" => "475" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4818200" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0340" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enzymic analysis of steroid hormones" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P. Talalay" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Methods Biochem Anal" "fecha" => "1960" "volumen" => "8" "paginaInicial" => "119" "paginaFinal" => "143" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13836707" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0345" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Microdetermination of inorganic phosphate, phospholipids, and total phosphate in biologic materials" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E.S. Baginski" 1 => "P.P. Foa" 2 => "B. Zak" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Chem" "fecha" => "1967" "volumen" => "13" "paginaInicial" => "326" "paginaFinal" => "332" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6036717" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0350" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "DNA/RNA markers for colorectal cancer risk in preserved stool specimens: a pilot study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I. Kato" 1 => "K.Z. Badsha" 2 => "S. Land" 3 => "J.M. Nechvatal" 4 => "L.H. Matherly" 5 => "A.L. Tarca" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Tumori" "fecha" => "2009" "volumen" => "95" "paginaInicial" => "753" "paginaFinal" => "761" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20210241" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0355" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Standardization of hepatitis C virus RNA quantification" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.M. Pawlotsky" 1 => "M. Bouvier-Alias" 2 => "C. Hezode" 3 => "F. Darthuy" 4 => "J. Remire" 5 => "D. Dhumeaux" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2000.16603" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2000" "volumen" => "32" "paginaInicial" => "654" "paginaFinal" => "659" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10960464" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0360" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus quasispecies in plasma and peripheral blood mononuclear cells of treatment naive chronically infected patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Vera-Otarola" 1 => "M.I. Barria" 2 => "U. Leon" 3 => "D. Marsac" 4 => "P. Carvallo" 5 => "A. Soza" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2893.2009.01112.x" "Revista" => array:6 [ "tituloSerie" => "J Viral Hepat" "fecha" => "2009" "volumen" => "16" "paginaInicial" => "633" "paginaFinal" => "643" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19254350" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0365" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic variations in host IL28B links to the detection of peripheral blood mononuclear cells-associated hepatitis C virus RNA in chronically infected patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Angulo" 1 => "K. Pino" 2 => "C. Pavez" 3 => "F. Biel" 4 => "P. Labbe" 5 => "J.F. Miquel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/jvh.12076" "Revista" => array:6 [ "tituloSerie" => "J Viral Hepat" "fecha" => "2013" "volumen" => "20" "paginaInicial" => "263" "paginaFinal" => "272" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23490371" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0370" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "[Detection of HCV-RNA in saliva and stool of patients with HCV infection]" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "I. Tamura" 1 => "T. Koda" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Nihon Rinsho" "fecha" => "1995" "volumen" => "53" "numero" => "Suppl." "paginaInicial" => "483" "paginaFinal" => "486" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7563799" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0375" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New immunochemical fecal occult blood test with two-consecutive stool sample testing is a cost-effective approach for colon cancer screening: results of a prospective multicenter study in Chinese patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Li" 1 => "H. Wang" 2 => "J. Hu" 3 => "N. Li" 4 => "Y. Liu" 5 => "Z. Wu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ijc.21774" "Revista" => array:6 [ "tituloSerie" => "Int J Cancer" "fecha" => "2006" "volumen" => "118" "paginaInicial" => "3078" "paginaFinal" => "3083" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16425283" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0380" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bile composition, bile salt metabolism and gallstones" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.N. Redinger" 1 => "D.M. Small" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "1972" "volumen" => "130" "paginaInicial" => "618" "paginaFinal" => "630" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4629238" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0385" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Critical tables for calculating the cholesterol saturation of native bile" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M.C. Carey" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Lipid Res" "fecha" => "1978" "volumen" => "19" "paginaInicial" => "945" "paginaFinal" => "955" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/731129" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0390" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and epidemiological features of 147 Chilean patients with chronic hepatitis C" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Soza" 1 => "M. Arrese" 2 => "R. Gonzalez" 3 => "M. Alvarez" 4 => "R.M. Perez" 5 => "P. Cortes" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Hepatol" "fecha" => "2004" "volumen" => "3" "paginaInicial" => "146" "paginaFinal" => "151" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15657556" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0395" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Is single-strand conformation polymorphism analysis of the full 5’ untranslated region an adequate approach to study hepatitis C virus quasispecies distribution?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J. Vera-Otarola" 1 => "M.I. Barria" 2 => "U. Leon" 3 => "P. Carvallo" 4 => "A. Soza" 5 => "M. Lopez-Lastra" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/JVI.00971-09" "Revista" => array:6 [ "tituloSerie" => "J Virol" "fecha" => "2009" "volumen" => "83" "paginaInicial" => "9018" "paginaFinal" => "9021" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19553315" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0400" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Influence of extrahepatic viral infection on the natural history of hepatitis C" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.I. Barria" 1 => "J. Vera-Otarola" 2 => "U. Leon" 3 => "V. Vollrath" 4 => "D. Marsac" 5 => "A. Riquelme" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Hepatol" "fecha" => "2008" "volumen" => "7" "paginaInicial" => "136" "paginaFinal" => "143" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18626431" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0405" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Transmission of HCV in HIV-positive populations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Danta" 1 => "A.J. Rodger" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/COH.0b013e32834b4974" "Revista" => array:6 [ "tituloSerie" => "Curr Opin HIV AIDS" "fecha" => "2011" "volumen" => "6" "paginaInicial" => "451" "paginaFinal" => "458" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22001890" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0410" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Danta" 1 => "D. Brown" 2 => "S. Bhagani" 3 => "O.G. Pybus" 4 => "C.A. Sabin" 5 => "M. Nelson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/QAD.0b013e3281053a0c" "Revista" => array:6 [ "tituloSerie" => "AIDS" "fecha" => "2007" "volumen" => "21" "paginaInicial" => "983" "paginaFinal" => "991" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17457092" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0415" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Viral RNA in duodenal bile of cirrhotic patients with chronic hepatitis C" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S.F. Kuan" 1 => "G. Garcia-Tsao" 2 => "R.W. Cartun" 3 => "J.R. Emanuel" 4 => "A.B. West" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Pathol Lab Med" "fecha" => "1997" "volumen" => "121" "paginaInicial" => "847" "paginaFinal" => "852" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9278613" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0420" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Detection of hepatitis C virus RNA in bile" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K. Yanaga" 1 => "T. Yoshizumi" 2 => "H. Uchiyama" 3 => "S. Okano" 4 => "K. Takenaka" 5 => "K. Sugimachi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "1997" "volumen" => "92" "paginaInicial" => "1927" "paginaFinal" => "1928" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9382069" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0425" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Detection of hepatitis C virus in the bile and bile duct epithelial cells of hepatitis C virus-infected patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Y. Haruna" 1 => "T. Kanda" 2 => "M. Honda" 3 => "T. Takao" 4 => "N. 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Sol" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Clin Microbiol" "fecha" => "2000" "volumen" => "38" "paginaInicial" => "3442" "paginaFinal" => "3444" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10970398" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0445" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Apolipoprotein E on hepatitis C virion facilitates infection through interaction with low-density lipoprotein receptor" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "D.M. Owen" 1 => "H. Huang" 2 => "J. Ye" 3 => "M. 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Zhu" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Biochim Biophys Acta" "fecha" => "2002" "volumen" => "1580" "paginaInicial" => "77" "paginaFinal" => "93" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11923102" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0465" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differentiation-dependent expression and localization of the class B type I scavenger receptor in intestine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S.F. Cai" 1 => "R.J. Kirby" 2 => "P.N. Howles" 3 => "D.Y. Hui" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Lipid Res" "fecha" => "2001" "volumen" => "42" "paginaInicial" => "902" "paginaFinal" => "909" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11369797" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0470" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Entry of hepatitis C virus into the cell: a therapeutic target" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.A. Del Campo" 1 => "A. Rojas" 2 => "M. 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Yu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev-physiol-012110-142233" "Revista" => array:6 [ "tituloSerie" => "Annu Rev Physiol" "fecha" => "2011" "volumen" => "73" "paginaInicial" => "239" "paginaFinal" => "259" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20809793" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0480" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Ge" 1 => "J. Wang" 2 => "W. Qi" 3 => "H.H. Miao" 4 => "J. Cao" 5 => "Y.X. Qu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cmet.2008.04.001" "Revista" => array:6 [ "tituloSerie" => "Cell Metab" "fecha" => "2008" "volumen" => "7" "paginaInicial" => "508" "paginaFinal" => "519" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18522832" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack280443" "titulo" => "Acknowledgments" "texto" => "This study was funded by grants FONDECYT #1130357 from the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) to AS and MLL, FONDECYT #1130303 to JFM and P09/016-F of Iniciativa Científica Milenio del Ministerio de Economía, Fomento y Turismo to MLL." 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Detection of high biliary and fecal viral loads in patients with chronic hepatitis C virus infection

Detección de concentraciones víricas elevadas en la bilis y en las heces de pacientes con infección crónica por el virus de la hepatitis C

Hugo Monrroya, Jenniffer Angulob, Karla Pinob, Pilar Labbéa, Juan Francisco Miquela, Marcelo López-Lastrab, Alejandro Sozaa,

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asoza@med.puc.cl

Corresponding author.

a Department of Gastroenterology, Pontificia Universidad Católica de Chile, Chile

b Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile

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    "titulo" => "Detection of high biliary and fecal viral loads in patients with chronic hepatitis C virus infection"
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        "titulo" => "Detecci&#243;n de concentraciones v&#237;ricas elevadas en la bilis y en las heces de pacientes con infecci&#243;n cr&#243;nica por el virus de la hepatitis C"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Correlation between plasmatic viral load and HCV RNA in the bile &#40;A&#41; and stool &#40;B&#41;&#59; the correlation between RNA in the bile and stool &#40;C&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic hepatitis C affects more than 170 million individuals who are at risk of developing cirrhosis and hepatocellular carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">1</span></a> The impact of this disease is evident&#44; and the mortality due to hepatitis C virus &#40;HCV&#41; infection has superseded the mortality from HIV infections in the United States&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">2</span></a> New&#44; oral direct-acting antivirals &#40;DAAs&#41; are showing remarkable results&#46; Nevertheless&#44; DAAs have some shortcomings&#44; such as high cost&#44; risk of developing resistance-associated variants and drug-drug interactions&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">3&#8211;5</span></a> A better understanding of the viral cycle may facilitate the development of alternative treatment strategies or strategies that complement DAAs&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">HCV circulates in human serum associated with several lipoproteins forming lipo-viral particles &#40;LVPs&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">6&#8211;8</span></a> LVP formation occurs during lipoprotein synthesis in hepatocytes&#44; which is a process that may shield the virus from neutralizing antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">9</span></a> LVPs are characterized by their low density&#44; presence of apolipoprotein B &#40;apoB&#41; and enrichment of triglycerides&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">10</span></a> HCV is not evenly distributed in the different plasmatic lipid fractions and is especially abundant in the very-low-density fractions&#44; which comprise triglyceride-rich lipoproteins &#40;TRL&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">TRL particles have a density less than 1&#46;006<span class="elsevierStyleHsp" style=""></span>g&#47;mL and have a core made of triglycerides and cholesterol esters surrounded by a phospholipid monolayer of free cholesterol&#44; apoB and other lipoproteins&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">12</span></a> There are two types of TRLs&#58; very-low-density lipoproteins &#40;VLDLs&#41; and chylomicrons&#46; VLDLs are assembled with one apoB100 molecule per particle and are secreted by hepatocytes&#44; whereas chylomicrons contain one molecule of apoB48&#44; which is a truncated form of apoB and is enterocyte specific&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">13</span></a> In humans&#44; apoB100 is synthesized primarily by the liver&#44; whereas apoB48 is synthesized only in the intestines&#46; Intriguingly&#44; apoB100 and apoB48 are equally represented in LVPs purified from HCV-infected patients&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">14</span></a> This observation led to the suggestion that the intestine could be a reservoir of HCV and that enterocytes could contribute to an estimated 18&#37; of the plasmatic viral load&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">14</span></a> An intestinal contribution to the overall HCV load in infected patients could be explained either by viral extrahepatic replication in the enterocyte or by the intestinal absorption of HCV&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Based on evidence suggesting that enterocytes can be a reservoir for HCV&#44;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">14&#44;15</span></a> it is plausible that HCV has an enterohepatic cycle similar to that of cholesterol&#58; secretion into the bile&#44; reabsorption in the enterocyte and secretion bound to chylomicrons&#46; This possibility would imply that some HCV particles could escape reabsorption by enterocyte&#44; shedding to the feces of infected patients&#46; However&#44; detection of HCV particles in bile and stools of infected patients remains controversial&#46; Thus&#44; we designed a study to evaluate the presence of HCV in the bile and feces of Chilean patients chronically infected with the virus&#46; We also assessed whether the viral load correlated with different compartments and plasmatic cholesterol and triglyceride levels&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study population</span><p id="par0025" class="elsevierStylePara elsevierViewall">Patients chronically infected with HCV who were followed up at the Viral Hepatitis Unit of the Clinical Hospital&#44; Pontificia Universidad Cat&#243;lica de Chile &#40;PUC&#41; were recruited and invited to participate in this study&#46; The protocols and consent forms used in this study were approved by the Ethical Review Board of the Faculty of Medicine&#44; PUC &#40;protocol number 12-199&#41; and were in accordance with local regulations and the ethical principles originated in the Declaration of Helsinki and with ICH&#47;Good Clinical Practice&#46; Patients were informed about the study and completed a written consent form before donating blood&#44; bile and stool&#46; Patient inclusion criteria were the following&#58; 1&#41; chronic hepatitis C defined as detectable HCV RNA in the plasma for more than 6 months&#59; 2&#41; age greater than 18 years&#59; 3&#41; compensated liver disease &#40;bilirubin<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>mg&#47;dL unless having Gilbert&#39;s syndrome&#44; albumin<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#44; INR<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>2&#44; no hepatic encephalopathy&#44; no ascites or recent &#40;1 month&#41; history of variceal bleeding&#41;&#59; 4&#41; no history of cholecystectomy or known gallstones&#59; 5&#41; no current HCV antiviral treatment&#59; 6&#41; no medications for dyslipidaemia within the preceding 2 months&#59; 7&#41; no abdominal surgery that could alter the biliary or intestinal anatomy&#59; 8&#41; HCV RNA levels<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#59; 9&#41; no evidence of sitosterolemia&#59; 10&#41; negative pregnancy test in urine &#40;for females&#41;&#59; and 11&#41; signed informed consent document&#46; Subjects who had HIV or hepatitis B virus &#40;HBV&#41; coinfection&#44; who were undergoing anticancer chemotherapy&#44; or who had received previous antiviral treatment with DAAs were excluded from the study&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Liver fibrosis was assessed via a liver biopsy or Fibroscan and was categorized according to the METAVIR system&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">16</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Peripheral blood&#44; bile and feces were collected for biochemical and virological assessments&#46; Standard clinical tests&#44; including a lipid profile &#40;total cholesterol&#44; triglycerides&#44; HDL cholesterol&#44; LDL cholesterol&#41;&#44; a liver profile &#40;ALT&#44; AST&#44; GGTP&#44; alkaline phosphatase&#44; total and conjugated bilirubin&#44; prothrombin time&#47;INR&#41; and HCV RNA levels were determined from plasma samples&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Sample collection and biochemical analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Peripheral blood was collected into EDTA-Vacutainer&#8482; tubes &#40;Becton Dickinson&#44; Franklin Lakes&#44; NJ&#44; USA&#41;&#44; and plasma samples recovered from the donors were stored at 80<span class="elsevierStyleHsp" style=""></span>&#176;C until processed&#46; Bile samples were obtained using the technique of biliary drainage &#40;duodenal aspirate&#41;&#46; This technique is routinely performed in our clinical service for both clinical and research purposes&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">17</span></a> Briefly&#44; after 8<span class="elsevierStyleHsp" style=""></span>h fasting&#44; patients underwent an upper digestive endoscopy under conscious sedation with midazolam&#46; An oro-duodenal small diameter tube was positioned with the endoscope&#46; After removing the endoscope&#44; the gallbladder was stimulated with amino acids and bile was aspirated from the duodenum&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">18</span></a> Bile samples were stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until processing&#46; Serum lipids and liver function tests were determined by standard clinical chemical assays&#46; Biliary cholesterol and bile acids were measured by enzymatic methods<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">19&#44;20</span></a> and phospholipids were assessed by a colorimetric method&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">21</span></a> Stool samples were preserved in 5<span class="elsevierStyleHsp" style=""></span>mL of RNALater&#8482; Stabilization Solution &#40;Ambion&#44; Thermo Fisher Scientific&#44; Waltham&#44; MA&#44; USA&#41; from the time of collection and were frozen at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C for later analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">22</span></a> All measurements in bile and feces were corrected according to the input volume&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Viral load determination and HCV genotyping</span><p id="par0045" class="elsevierStylePara elsevierViewall">HCV RNA levels in plasma&#44; bile and feces were determined using the COBAS TaqMan HCV Test&#8482; v2&#46;0 &#40;Roche Molecular Systems&#44; Inc&#44; Rotkreuz&#44; Switzerland&#41; with a lower limit of quantification &#40;LLOQ&#41; of 25<span class="elsevierStyleHsp" style=""></span>IU&#47;mL and lower limit of detection &#40;LLOD&#41; of 9&#46;3<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">23</span></a> HCV genotyping of the virus present in the plasma was performed using the reverse hybridization line probe assay INNO-LiPA HCV II kit&#8482; &#40;Innogenetics&#44; Ghent&#44; Belgium&#41; according to the manufacturer&#39;s instructions&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">24&#44;25</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">RNA extraction and RT-PCR in stool samples</span><p id="par0050" class="elsevierStylePara elsevierViewall">A technique for extracting HCV RNA from stool has been described elsewhere&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">26</span></a> For convenience and more reliable results&#44; we used the PowerMicrobiome&#8482; RNA Isolation Kit &#40;MoBio Laboratories&#44; Carlsbad&#44; CA&#44; USA&#41;&#44; which is optimized for removing PCR inhibitors from the stool and gut material&#46; To rule out the possibility that fecal HCV RNA or core protein is a result of contamination from occult blood loss in the gut&#44; an immunochemical assay to detect human hemoglobin &#40;Hemosure&#8482;&#41; was performed on the stool samples&#46; This assay is highly specific and sensitive &#40;50<span class="elsevierStyleHsp" style=""></span>ng human hemoglobin&#47;mL&#41;&#44; requires no specific diet and is readily available at our institution&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">27</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The HCV RNA extracted by the PowerMicrobiome&#8482; RNA Isolation Kit from the feces was eluted in 60<span class="elsevierStyleHsp" style=""></span>&#956;L of nuclease-free water&#46; Thirty microliters diluted in 470<span class="elsevierStyleHsp" style=""></span>&#956;L of 1&#215; PBS were used to quantify the HCV RNA using the COBAS TaqMan HCV Test&#8482; v2&#46;0&#46; In each case&#44; the results &#40;in IU&#41; were corrected by the input in milligrams of stool and then by the Power PowerMicrobiome&#8482; elution volume&#46; In parallel&#44; the HCV RNA was detected using a one-step reverse transcription &#40;RT&#41; polymerase chain reaction &#40;PCR&#41; using the SuperScriptTM III one-step RT-PCR system with Platinum-Taq DNA Polymerase&#8482; &#40;Invitrogen&#44; Life Technologies&#44; Carlsbad&#44; CA&#44; USA&#41; kit with a lower limit of detection of 1<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span> HCV genomic copies per mL following a protocol previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Determination of core protein levels</span><p id="par0060" class="elsevierStylePara elsevierViewall">The HCV core protein levels are correlated with HCV RNA levels and may be used as an alternative marker of HCV infection&#46; The level of core protein in the plasma&#44; bile and feces was quantified using the ARCHITECT HCV Ag assay&#8482; &#40;Abbott Laboratories&#44; Abbott Park&#44; IL&#44; USA&#41; following the manufacturer&#39;s instructions&#46; The dynamic range of this assay is 3&#8211;20&#44;000<span class="elsevierStyleHsp" style=""></span>fmol&#47;L&#46; For this purpose&#44; samples frozen at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C &#40;thawed once&#41; were used&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Data analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">The HCV RNA viral load&#44; given its exponential distribution&#44; was logarithmically transformed using base 10&#44; and geometrical means were used&#46; Values below the limit of quantification &#40;25<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#41; were computed as 12<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#44; and undetectable values were computed as 4<span class="elsevierStyleHsp" style=""></span>IU&#47;mL for statistical analyses&#46; Similarly&#44; undetectable HCV core protein determinations were considered to be 2<span class="elsevierStyleHsp" style=""></span>fmol&#47;L for the statistical analyses&#46; As previously mentioned&#44; the viral load determinations in the bile were normalized to the bile acid concentration for a meaningful comparison&#44; and the viral loads were expressed as IU&#47;60<span class="elsevierStyleHsp" style=""></span>mg bile salts&#44; which is the normal concentration of bile salts per mL of bile&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">28&#44;29</span></a> Viral load determinations in feces were expressed as IU&#47;g of stool&#46; To determine if the viral load was correlated with the amounts of core protein and between compartments&#44; a Pearson correlation analysis was performed using Graph Pad V6 and SPSS v20&#46; A <span class="elsevierStyleItalic">p</span> value &#60;0&#46;05 was considered significant&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Patient characteristics</span><p id="par0070" class="elsevierStylePara elsevierViewall">The clinical features and the serum and bile compositions at the time of sample collection for the twelve patients included in this study are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The average age of patients was 60 years &#40;range 27&#8211;75 years&#41;&#44; with roughly equal gender distribution &#40;male 58&#37;&#41;&#46; An HCV genotypic analysis confirmed the prevalence of genotype 1b in the majority of patients &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&#44; which is consistent with the epidemiology in our country&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">30</span></a> Seven of the twelve patients were cirrhotic at the time of sampling&#46; All patients with cirrhosis were well compensated&#46; Two patients had failed to a previous course of treatment with peginterferon alfa 2b plus ribavirin&#59; the remaining patients were treatment na&#239;ve&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">HCV viral load and HCV core protein in bile and stool samples</span><p id="par0075" class="elsevierStylePara elsevierViewall">The mean HCV viral load in the plasma was 6&#46;08<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;34<span class="elsevierStyleHsp" style=""></span>log10<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#46; As expected&#44; the HCV core Ag in plasma showed a high correlation with the plasmatic HCV viral load &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; We detected HCV RNA in the bile of 10 patients &#40;83&#37;&#41;&#44; and the mean viral load was 2&#46;5<span class="elsevierStyleHsp" style=""></span>log10<span class="elsevierStyleHsp" style=""></span>IU&#47;60<span class="elsevierStyleHsp" style=""></span>mg bile salts &#40;range&#58; undetectable&#8211;7&#46;0<span class="elsevierStyleHsp" style=""></span>log10<span class="elsevierStyleHsp" style=""></span>IU&#47;60<span class="elsevierStyleHsp" style=""></span>mg bile salt&#41;&#44; which is &#40;on average&#41; 3&#46;6<span class="elsevierStyleHsp" style=""></span>log10 less than the average plasma viral load &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; In feces&#44; HCV RNA was alsodetected in 10 patients &#40;83&#37;&#41;&#46; The average viral load was 2&#46;7<span class="elsevierStyleHsp" style=""></span>log10<span class="elsevierStyleHsp" style=""></span>IU&#47;g &#40;range&#58; undetectable&#8211;7<span class="elsevierStyleHsp" style=""></span>log10<span class="elsevierStyleHsp" style=""></span>IU&#47;g&#41;&#46; The internal control RNA was detected in all samples indicating the lack of RT-PCR inhibitors&#46; Patients with a positive immunochemical fecal occult blood test did not exhibit greater levels of biliary or fecal HCV viral load&#46; The presence of the HCV core protein was confirmed in the bile of only one patient and was not detected in any of the evaluated stool samples&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Correlations between the viral loads in the different compartments and plasmatic lipids</span><p id="par0080" class="elsevierStylePara elsevierViewall">The plasmatic HCV viral load was not significantly associated with the biliary HCV RNA titers or with the fecal viral load &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A and B&#41;&#46; Similarly&#44; biliary and stool viral loads were not correlated &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#41;&#46; The standardized biliary viral load was weakly correlated with the presence of plasmatic HCV core protein &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;603&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;038&#41;&#46; The fecal viral load was not significantly associated with the lipidic components of plasma or bile &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; The plasma viral load did not show a significant association with the concentration of the plasmatic or biliary lipidic components &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">The existence of extrahepatic reservoirs for HCV replication has long been suspected but remains highly controversial&#46; Previous studies&#44; including several from our laboratory&#44;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">24&#44;25&#44;31&#44;32</span></a> have observed HCV RNA to be associated with peripheral blood mononuclear cells &#40;PBMCs&#41;&#46; Additionally&#44; Deforges et al&#46; reported that the small intestine can be infected by HCV and strongly suggested that this organ may be a reservoir for HCV and a source of LVPs&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">15</span></a> The main evidence of HCV replication in this extrahepatic compartment was the detection of HCV non-structural proteins NS3 and NS5A in intestinal biopsies&#46; HCV protein expression was observed in enterocytes&#44; which are cells that synthesize and secrete chylomicrons&#46; Although this evidence strongly suggests viral replication&#44; herein&#44; we put forward an alternative and yet unexplored possibility&#46; HCV may also have an enterohepatic cycle similar to the cycle described for cholesterol&#46; If true&#44; HCV would constantly be secreted into the bile and would be reabsorbed by the enterocyte and secreted back into the system bound to chylomicrons&#46; Furthermore&#44; the presence of HCV would be expected in the bile &#40;secreted&#41; and stool &#40;not reabsorbed&#41; of chronically infected individuals&#46; In this model&#44; HCV replication in the enterocyte would not be required to explain the apoB48 and high triglyceride content of LVPs&#46; In this study&#44; to indirectly evaluate this alternative model&#44; by establishing whether HCV is present in the bile and stool of chronically infected HCV patients&#46; In these studies we not only detected HCV RNA but we also quantified its levels in each samples&#46; When comparing the HCV viral load in the bile and plasma of the same individual&#44; the viral load was an average of 3&#46;6<span class="elsevierStyleHsp" style=""></span>log10 less in the bile compared to the plasma&#46; No correlation was found between the viral titers in the different compartments and the concentration of the lipidic components of the plasma or bile&#46; Nonetheless&#44; the results of this study suggest that HCV can be shed into the bile and can later be found in the stool&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">There has been an alarming increase in incidence of acute HCV infection in HIV-infected men who have sex with men &#40;MSM&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">33</span></a> which has been speculated to be related to permucosal transmission&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">34</span></a> The presence of HCV RNA in measurable quantities in stools of infected patients may explain in part these outbreaks&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Three earlier studies reported the amplification of HCV RNA from the bile of chronically infected patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">35&#8211;37</span></a> These studies detected viral RNA in 19&#47;34 patients &#40;56&#37;&#41;&#44; whereas we were able to detect HCV RNA in 10&#47;12 patients &#40;83&#37;&#41;&#46; One important difference between our study and the previous report is that we quantified the HCV RNA in the bile using the Roche COBAS TaqMan assay&#46; We also quantified the HCV RNA in the bile components and used this value to normalize the HCV RNA concentration&#46; In our opinion&#44; this normalization provided a better comparison between samples obtained from different patients&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">HCV core antigen was determined using a commercial kit&#44; but we could detect this protein in the bile of just one patient and none in the stool samples&#46; Heidrich et al&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">38</span></a> in a recent study tested the stools of 98 chronically infected patients and were able to detect HCV RNA in 69&#37; of the samples&#44; but HCV core protein with the same assay &#40;ARCHITECT&#41; in only 24&#37; of samples&#46; Unfortunately the core protein level was not provided nor was the HCV RNA level determined&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Aside from the already commented study of Heidrich&#44; the presence of HCV RNA in stool has been tested in other two studies&#46; In the earliest paper&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">39</span></a> attempts to identify HCV RNA in secretions&#44; including feces&#44; were unsuccessful&#46; A second study was able to detect and measure the HCV viral load in relatively high amounts &#40;1&#8211;3 logs lower than plasma&#41; in feces in 4 out of 6 chronically infected patients&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">40</span></a> However&#44; in that report&#44; the authors did not rule out blood contamination as the possible source of viral RNA&#46; To overcome this limitation&#44; in our study&#44; a highly sensitive immunochemical method was used to detect blood in the stool&#44; which was negative in 9 of the 12 patients&#46; The three remaining patients did not exhibit a greater viral load in the bile or stool&#44; which suggests a limited role of blood contamination as a source of virus in the tested samples&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">One of our objectives was to determine whether viral particles were shed into the bile and stool of chronically infected HCV patients&#46; We also sought to detect the presence of an HCV structural protein&#46; Unfortunately&#44; we were unable to detect the HCV core protein in these secretions using the Abbott ARCHITECHT assay&#46; This failure could be explained by either the technical limitations of this assay&#44; which is designed to detect viral protein in plasma samples or by the lower sensitivity of the assay compared to the COBAS TaqMan test considering that the bile and stool samples exhibited lower viral loads when compared to plasma&#46; Despite the lack of core protein detection&#44; the presence of viral RNA suggests that the virus&#44; even though at lower quantities&#44; can be found both in the bile and stool&#46; This observation supports a model in which the virus is shed into the bile where it can later be excreted or reabsorbed by the enterocyte&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The proposed model raises a number of additional questions&#46; How can the virus be reabsorbed by the enterocytes or any other intestinal cell if these cells are known to lack the CD81 virus receptor&#63; The discovery of new viral entry factors has revealed that several of these factors are related to lipid metabolism&#44; including the LDL receptor&#44;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">41</span></a> scavenger receptor class B type I &#40;SR-BI&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">42</span></a> and NPC1L1&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">43</span></a> Interestingly&#44; SR-B1 is found on the apical and basal poles of enterocytes and may provide an alternative entry pathway for the virus&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">44&#44;45</span></a> Additionally&#44; NPC1L1 is also expressed on the apical membrane of enterocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">43&#44;46</span></a> Previous studies have proposed NPC1L1 as a target for HCV therapeutic interventions&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">43</span></a> In this context&#44; our findings are very clinically relevant and suggest that HCV reabsorption by enterocytes could be targeted for clinical intervention using an NPC1L1 antagonist&#44; such as ezetimibe&#44; which is a drug that disrupts the enterohepatic cycle of endogenous cholesterol&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">47</span></a> Ezetimibe binds to the extracellular loop C at a different domain than cholesterol and the HCV virion and blocks the internalization of the NPC1L1&#47;cholesterol complex&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">48</span></a> Therefore&#44; antagonizing the NPC1L1 cholesterol receptor with ezetimibe may have an inhibitory effect in hepatic and&#47;or intestinal uptake&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The presence of HCV RNA in the bile and stool&#44; together with the description that HCV circulates in the plasma equally bound to hepatic-derived apoB100 and intestinally derived apoB48&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">14</span></a> leads to the striking possibility that the blockage of intestinal NPC1L1 can disrupt the possible enterohepatic mode of HCV circulation&#46; While compelling&#44; this hypothesis remains highly speculative and must be specifically evaluated in clinical studies&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interests</span><p id="par0130" class="elsevierStylePara elsevierViewall">A&#46;S&#46; has received fees as a speaker for MSD&#44; Roche&#44; BMS&#44; he has participated in Advisory Board Meetings for MSD&#44; Abbvie&#44; Gilead&#44; Vertex&#44; Roche&#44; and Janssen and he has stock ownership of Gilead and Achillion&#46; The others authors declare that they have no conflict of interest&#46;</p></span></span>"
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                  "titulo" => "HCV viral load and HCV core protein in bile and stool samples"
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              "titulo" => "Correlations between the viral loads in the different compartments and plasmatic lipids"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The life cycle of the hepatitis C virus &#40;HCV&#41; is closely associated with lipid metabolism&#46; Recently&#44; NPC1L1 &#40;a cholesterol transporter&#41; has been reported to function as an HCV receptor&#46; This receptor is expressed in the hepatocyte canalicular membrane and in the intestine&#59; serving as a key transporter for the cholesterol enterohepatic cycle&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objectives</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We hypothesized that HCV might have a similar cycle&#44; so we aimed to study the presence of HCV in bile and stools of infected patients&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Blood&#44; feces&#44; and duodenal bile samples were collected from patients infected with HCV&#46; The biliary viral load was normalized to the bile salt concentration of each sample and the presence of HCV core protein was also evaluated&#46; A total of 12 patients were recruited&#46; HCV RNA was detected in the bile from ten patients&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The mean viral load was 2&#46;5<span class="elsevierStyleHsp" style=""></span>log10<span class="elsevierStyleHsp" style=""></span>IU&#47;60<span class="elsevierStyleHsp" style=""></span>mg bile salt&#46; In the stool samples&#44; HCV RNA was detected in ten patients &#40;mean concentration 2&#46;7<span class="elsevierStyleHsp" style=""></span>log10<span class="elsevierStyleHsp" style=""></span>IU&#47;g of feces&#41;&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">HCV RNA is readily detectable and is present at relatively high concentrations in the bile and stool samples of infected patients&#46; This may be relevant as a source of infection in men who have sex with men&#46; Biliary HCV secretion may perhaps play a role in the persistence of viral infection via an enterohepatic cycle of the virus or intrahepatic spread&#46;</p></span>"
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          2 => array:2 [
            "identificador" => "abst0015"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El ciclo de vida del virus de la hepatitis C &#40;VHC&#41; est&#225; estrechamente ligado al metabolismo lip&#237;dico&#46; Recientemente&#44; se ha descrito que el NPC1L1 &#40;un transportador del colesterol&#41; act&#250;a como un receptor del VHC&#46; Este receptor se expresa en la membrana canalicular de los hepatocitos y en el intestino&#44; y act&#250;a como uno de los principales transportadores durante la circulaci&#243;n enterohep&#225;tica del colesterol&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Planteamos la hip&#243;tesis de que el VHC podr&#237;a tener un ciclo similar&#44; por lo que nuestro objetivo fue estudiar la presencia del VHC en la bilis y en las heces de pacientes infectados&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materiales y m&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se obtuvieron muestras de sangre&#44; heces y bilis duodenal de pacientes infectados por el VHC&#46; La concentraci&#243;n v&#237;rica en la bilis se normaliz&#243; respecto a la concentraci&#243;n de sales biliares de cada muestra y tambi&#233;n se evalu&#243; la presencia de la prote&#237;na central del VHC&#46; Se reclutaron un total de 12 pacientes&#46; Se detect&#243; el ARN del VHC en la bilis de 10 pacientes&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">La media de la concentraci&#243;n v&#237;rica fue 2&#44;5<span class="elsevierStyleHsp" style=""></span>log10<span class="elsevierStyleHsp" style=""></span>UI&#47;60<span class="elsevierStyleHsp" style=""></span>mg de sales biliares&#46; En las muestras de heces&#44; se detect&#243; el ARN del VHC en 10 pacientes &#40;media de la concentraci&#243;n 2&#44;7<span class="elsevierStyleHsp" style=""></span>log10<span class="elsevierStyleHsp" style=""></span>UI&#47;g de heces&#41;&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">El ARN del VHC es f&#225;cilmente detectable y est&#225; presente en concentraciones relativamente elevadas en las muestras de bilis y heces de pacientes infectados&#46; Esto puede tener importancia como foco de infecci&#243;n en varones que mantienen relaciones sexuales con otros varones&#46; Es posible que la secreci&#243;n biliar del VHC pueda desempe&#241;ar un papel en la persistencia de la virosis a trav&#233;s de la circulaci&#243;n enterohep&#225;tica del virus o la propagaci&#243;n intrahep&#225;tica&#46;</p></span>"
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Gender&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Fibrosis &#40;METAVIR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="11" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Serum</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Hemosure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Bile</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Chol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HDL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LDL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ALT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">GGTP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">DB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Chol &#40;mM&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Bile salts &#40;mM&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Phospholipids &#40;mM&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">U&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">U&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">U&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">U&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E-02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">112&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">79&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;4&nbsp;\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">E-03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">138&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">145&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;6&nbsp;\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">E-04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">104&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;3&nbsp;\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">E-05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">178&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">181&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">260&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">257&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">462&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">164&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;5&nbsp;\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">E-06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">167&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1&nbsp;\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">E-07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">134&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">139&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">122&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;3&nbsp;\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">E-08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">168&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;3&nbsp;\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">E-09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">81&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">109&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">75&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;2&nbsp;\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">E-10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">142&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">81&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;1&nbsp;\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">E-11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">167&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">69&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E-12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">131&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">115&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">160&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">201&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">105&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;2&nbsp;\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">E-13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">113&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">123&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">58&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="19" align="char" 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">Mean&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">133&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">85&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">96&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">94&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">97&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;3&nbsp;\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">SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">41&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">65&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">118&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Subject&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HCV genotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Plasma HCV RNA &#40;log10<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Plasma HCV core Ag &#40;fmol&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Bile HCV RNA &#40;log10<span class="elsevierStyleHsp" style=""></span>IU&#47;60<span class="elsevierStyleHsp" style=""></span>mg bile salt&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Stool HCV RNA &#40;log10<span class="elsevierStyleHsp" style=""></span>IU&#47;g&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E-02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\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">E-03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;58&nbsp;\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">E-04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">823&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;72&nbsp;\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">E-05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1986&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;87&nbsp;\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">E-06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">807&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;99&nbsp;\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">E-07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8464&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;51&nbsp;\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">E-08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8438&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;79&nbsp;\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">E-09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;32&nbsp;\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">E-10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">133&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\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">E-11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;96&nbsp;\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">E-12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4153&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;98&nbsp;\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">EZ13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4172&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" 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">Mean&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2601&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;69&nbsp;\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">SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3105&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">HCV genotype&#44; viral load and HCV core protein quantification in plasma&#44; bile and stool samples from patients chronically infected with hepatitis C virus&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:48 [
            0 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The global burden of hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "D&#46; Lavanchy"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1111/j.1478-3231.2008.01934.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Liver Int"
                        "fecha" => "2009"
                        "volumen" => "29"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "74"
                        "paginaFinal" => "81"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19207969"
                            "web" => "Medline"
                          ]
                        ]
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              "identificador" => "bib0250"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "K&#46;N&#46; Ly"
                            1 => "J&#46; Xing"
                            2 => "R&#46;M&#46; Klevens"
                            3 => "R&#46;B&#46; Jiles"
                            4 => "J&#46;W&#46; Ward"
                            5 => "S&#46;D&#46; Holmberg"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.7326/0003-4819-156-4-201202210-00004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Intern Med"
                        "fecha" => "2012"
                        "volumen" => "156"
                        "paginaInicial" => "271"
                        "paginaFinal" => "278"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22351712"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0255"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Access to costly new hepatitis C drugs&#58; medicine&#44; money&#44; and advocacy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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                            2 => "J&#46;R&#46; Kostman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cid/civ677"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2015"
                        "volumen" => "61"
                        "paginaInicial" => "1825"
                        "paginaFinal" => "1830"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26270682"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Resistance of hepatitis C virus to inhibitors&#58; complexity and clinical implications"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "C&#46; Perales"
                            1 => "J&#46; Quer"
                            2 => "J&#46; Gregori"
                            3 => "J&#46;I&#46; Esteban"
                            4 => "E&#46; Domingo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/v7112902"
                      "Revista" => array:6 [
                        "tituloSerie" => "Viruses"
                        "fecha" => "2015"
                        "volumen" => "7"
                        "paginaInicial" => "5746"
                        "paginaFinal" => "5766"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26561827"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drug interactions with new hepatitis C oral drugs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46; Soriano"
                            1 => "P&#46; Labarga"
                            2 => "P&#46; Barreiro"
                            3 => "J&#46;V&#46; Fernandez-Montero"
                            4 => "C&#46; de Mendoza"
                            5 => "I&#46; Esposito"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1517/17425255.2015.998997"
                      "Revista" => array:6 [
                        "tituloSerie" => "Expert Opin Drug Metab Toxicol"
                        "fecha" => "2015"
                        "volumen" => "11"
                        "paginaInicial" => "333"
                        "paginaFinal" => "341"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25553890"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "V&#46; Agnello"
                            1 => "G&#46; Abel"
                            2 => "M&#46; Elfahal"
                            3 => "G&#46;B&#46; Knight"
                            4 => "Q&#46;X&#46; Zhang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Natl Acad Sci U S A"
                        "fecha" => "1999"
                        "volumen" => "96"
                        "paginaInicial" => "12766"
                        "paginaFinal" => "12771"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10535997"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of hepatitis C virus in human sera with beta-lipoprotein"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "R&#46; Thomssen"
                            1 => "S&#46; Bonk"
                            2 => "C&#46; Propfe"
                            3 => "K&#46;H&#46; Heermann"
                            4 => "H&#46;G&#46; Kochel"
                            5 => "A&#46; Uy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Med Microbiol Immunol"
                        "fecha" => "1992"
                        "volumen" => "181"
                        "paginaInicial" => "293"
                        "paginaFinal" => "300"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1335546"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association between hepatitis C virus and very-low-density lipoprotein &#40;VLDL&#41;&#47;LDL analyzed in iodixanol density gradients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46;U&#46; Nielsen"
                            1 => "M&#46;F&#46; Bassendine"
                            2 => "A&#46;D&#46; Burt"
                            3 => "C&#46; Martin"
                            4 => "W&#46; Pumeechockchai"
                            5 => "G&#46;L&#46; Toms"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/JVI.80.5.2418-2428.2006"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Virol"
                        "fecha" => "2006"
                        "volumen" => "80"
                        "paginaInicial" => "2418"
                        "paginaFinal" => "2428"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16474148"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Host neutralizing responses and pathogenesis of hepatitis C virus infection"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;B&#46; Zeisel"
                            1 => "F&#46;L&#46; Cosset"
                            2 => "T&#46;F&#46; Baumert"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.22307"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2008"
                        "volumen" => "48"
                        "paginaInicial" => "299"
                        "paginaFinal" => "307"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18508291"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterization of low- and very-low-density hepatitis C virus RNA-containing particles"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Andre"
                            1 => "F&#46; Komurian-Pradel"
                            2 => "S&#46; Deforges"
                            3 => "M&#46; Perret"
                            4 => "J&#46;L&#46; Berland"
                            5 => "M&#46; Sodoyer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Virol"
                        "fecha" => "2002"
                        "volumen" => "76"
                        "paginaInicial" => "6919"
                        "paginaFinal" => "6928"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12072493"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Visualization of hepatitis C virions and putative defective interfering particles isolated from low-density lipoproteins"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;M&#46; Prince"
                            1 => "T&#46; Huima-Byron"
                            2 => "T&#46;S&#46; Parker"
                            3 => "D&#46;M&#46; Levine"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Viral Hepat"
                        "fecha" => "1996"
                        "volumen" => "3"
                        "paginaInicial" => "11"
                        "paginaFinal" => "17"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8736235"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0300"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Complexity in the secretory pathway&#58; the assembly and secretion of apolipoprotein B-containing lipoproteins"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46;A&#46; Fisher"
                            1 => "H&#46;N&#46; Ginsberg"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1074/jbc.R100068200"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Biol Chem"
                        "fecha" => "2002"
                        "volumen" => "277"
                        "paginaInicial" => "17377"
                        "paginaFinal" => "17380"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12006608"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0305"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Developmental regulation of apolipoprotein B mRNA editing is an autonomous function of small intestine involving homeobox gene Cdx1"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;P&#46; Patterson"
                            1 => "Z&#46; Chen"
                            2 => "D&#46;C&#46; Rubin"
                            3 => "V&#46; Moucadel"
                            4 => "J&#46;L&#46; Iovanna"
                            5 => "H&#46;B&#46; Brewer Jr&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1074/jbc.M201601200"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Biol Chem"
                        "fecha" => "2003"
                        "volumen" => "278"
                        "paginaInicial" => "7600"
                        "paginaFinal" => "7606"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12493769"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Preferential association of Hepatitis C virus with apolipoprotein B48-containing lipoproteins"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "O&#46; Diaz"
                            1 => "F&#46; Delers"
                            2 => "M&#46; Maynard"
                            3 => "S&#46; Demignot"
                            4 => "F&#46; Zoulim"
                            5 => "J&#46; Chambaz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1099/vir.0.82033-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Gen Virol"
                        "fecha" => "2006"
                        "volumen" => "87"
                        "paginaInicial" => "2983"
                        "paginaFinal" => "2991"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16963757"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expression of hepatitis C virus proteins in epithelial intestinal cells in vivo"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Deforges"
                            1 => "A&#46; Evlashev"
                            2 => "M&#46; Perret"
                            3 => "M&#46; Sodoyer"
                            4 => "S&#46; Pouzol"
                            5 => "J&#46;Y&#46; Scoazec"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1099/vir.0.80071-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Gen Virol"
                        "fecha" => "2004"
                        "volumen" => "85"
                        "paginaInicial" => "2515"
                        "paginaFinal" => "2523"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15302945"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "titulo" => "Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C&#46; The French METAVIR Cooperative Study Group"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1994"
                        "volumen" => "20"
                        "paginaInicial" => "15"
                        "paginaFinal" => "20"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8020885"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0325"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#91;Occult gallbladder disease or microlithiasis in patients with acute pancreatitis&#58; a frequent clinical event&#93;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;F&#46; Miquel"
                            1 => "A&#46; Prado"
                            2 => "H&#46; Asahi"
                            3 => "L&#46; Ibanez"
                            4 => "S&#46; Guzman"
                            5 => "F&#46; Cruz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Med Chil"
                        "fecha" => "1997"
                        "volumen" => "125"
                        "paginaInicial" => "869"
                        "paginaFinal" => "878"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9580486"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical evaluation of ezetimibe on bile lithogenicity in humans&#58; use of transnasal endoscopy for bile sampling"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "N&#46; Kishikawa"
                            1 => "K&#46; Kanno"
                            2 => "A&#46; Sugiyama"
                            3 => "K&#46; Yokobayashi"
                            4 => "M&#46; Mizooka"
                            5 => "S&#46; Tazuma"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/hepr.12402"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatol Res"
                        "fecha" => "2015"
                        "volumen" => "45"
                        "paginaInicial" => "693"
                        "paginaFinal" => "697"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25132425"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enzymatic determination of total serum cholesterol"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "C&#46;C&#46; Allain"
                            1 => "L&#46;S&#46; Poon"
                            2 => "C&#46;S&#46; Chan"
                            3 => "W&#46; Richmond"
                            4 => "P&#46;C&#46; Fu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Chem"
                        "fecha" => "1974"
                        "volumen" => "20"
                        "paginaInicial" => "470"
                        "paginaFinal" => "475"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4818200"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enzymic analysis of steroid hormones"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; Talalay"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Methods Biochem Anal"
                        "fecha" => "1960"
                        "volumen" => "8"
                        "paginaInicial" => "119"
                        "paginaFinal" => "143"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13836707"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Microdetermination of inorganic phosphate&#44; phospholipids&#44; and total phosphate in biologic materials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "E&#46;S&#46; Baginski"
                            1 => "P&#46;P&#46; Foa"
                            2 => "B&#46; Zak"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Chem"
                        "fecha" => "1967"
                        "volumen" => "13"
                        "paginaInicial" => "326"
                        "paginaFinal" => "332"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6036717"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "DNA&#47;RNA markers for colorectal cancer risk in preserved stool specimens&#58; a pilot study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "I&#46; Kato"
                            1 => "K&#46;Z&#46; Badsha"
                            2 => "S&#46; Land"
                            3 => "J&#46;M&#46; Nechvatal"
                            4 => "L&#46;H&#46; Matherly"
                            5 => "A&#46;L&#46; Tarca"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Tumori"
                        "fecha" => "2009"
                        "volumen" => "95"
                        "paginaInicial" => "753"
                        "paginaFinal" => "761"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20210241"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Standardization of hepatitis C virus RNA quantification"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46;M&#46; Pawlotsky"
                            1 => "M&#46; Bouvier-Alias"
                            2 => "C&#46; Hezode"
                            3 => "F&#46; Darthuy"
                            4 => "J&#46; Remire"
                            5 => "D&#46; Dhumeaux"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2000.16603"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2000"
                        "volumen" => "32"
                        "paginaInicial" => "654"
                        "paginaFinal" => "659"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10960464"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus quasispecies in plasma and peripheral blood mononuclear cells of treatment naive chronically infected patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Vera-Otarola"
                            1 => "M&#46;I&#46; Barria"
                            2 => "U&#46; Leon"
                            3 => "D&#46; Marsac"
                            4 => "P&#46; Carvallo"
                            5 => "A&#46; Soza"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2893.2009.01112.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Viral Hepat"
                        "fecha" => "2009"
                        "volumen" => "16"
                        "paginaInicial" => "633"
                        "paginaFinal" => "643"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19254350"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic variations in host IL28B links to the detection of peripheral blood mononuclear cells-associated hepatitis C virus RNA in chronically infected patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Angulo"
                            1 => "K&#46; Pino"
                            2 => "C&#46; Pavez"
                            3 => "F&#46; Biel"
                            4 => "P&#46; Labbe"
                            5 => "J&#46;F&#46; Miquel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jvh.12076"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Viral Hepat"
                        "fecha" => "2013"
                        "volumen" => "20"
                        "paginaInicial" => "263"
                        "paginaFinal" => "272"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23490371"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#91;Detection of HCV-RNA in saliva and stool of patients with HCV infection&#93;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "I&#46; Tamura"
                            1 => "T&#46; Koda"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Nihon Rinsho"
                        "fecha" => "1995"
                        "volumen" => "53"
                        "numero" => "Suppl&#46;"
                        "paginaInicial" => "483"
                        "paginaFinal" => "486"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7563799"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0375"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New immunochemical fecal occult blood test with two-consecutive stool sample testing is a cost-effective approach for colon cancer screening&#58; results of a prospective multicenter study in Chinese patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Li"
                            1 => "H&#46; Wang"
                            2 => "J&#46; Hu"
                            3 => "N&#46; Li"
                            4 => "Y&#46; Liu"
                            5 => "Z&#46; Wu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ijc.21774"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cancer"
                        "fecha" => "2006"
                        "volumen" => "118"
                        "paginaInicial" => "3078"
                        "paginaFinal" => "3083"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16425283"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0380"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bile composition&#44; bile salt metabolism and gallstones"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;N&#46; Redinger"
                            1 => "D&#46;M&#46; Small"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "1972"
                        "volumen" => "130"
                        "paginaInicial" => "618"
                        "paginaFinal" => "630"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4629238"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0385"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Critical tables for calculating the cholesterol saturation of native bile"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46;C&#46; Carey"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Lipid Res"
                        "fecha" => "1978"
                        "volumen" => "19"
                        "paginaInicial" => "945"
                        "paginaFinal" => "955"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/731129"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0390"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical and epidemiological features of 147 Chilean patients with chronic hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Soza"
                            1 => "M&#46; Arrese"
                            2 => "R&#46; Gonzalez"
                            3 => "M&#46; Alvarez"
                            4 => "R&#46;M&#46; Perez"
                            5 => "P&#46; Cortes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Hepatol"
                        "fecha" => "2004"
                        "volumen" => "3"
                        "paginaInicial" => "146"
                        "paginaFinal" => "151"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15657556"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0395"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Is single-strand conformation polymorphism analysis of the full 5&#8217; untranslated region an adequate approach to study hepatitis C virus quasispecies distribution&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46; Vera-Otarola"
                            1 => "M&#46;I&#46; Barria"
                            2 => "U&#46; Leon"
                            3 => "P&#46; Carvallo"
                            4 => "A&#46; Soza"
                            5 => "M&#46; Lopez-Lastra"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/JVI.00971-09"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Virol"
                        "fecha" => "2009"
                        "volumen" => "83"
                        "paginaInicial" => "9018"
                        "paginaFinal" => "9021"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19553315"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Influence of extrahepatic viral infection on the natural history of hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;I&#46; Barria"
                            1 => "J&#46; Vera-Otarola"
                            2 => "U&#46; Leon"
                            3 => "V&#46; Vollrath"
                            4 => "D&#46; Marsac"
                            5 => "A&#46; Riquelme"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Hepatol"
                        "fecha" => "2008"
                        "volumen" => "7"
                        "paginaInicial" => "136"
                        "paginaFinal" => "143"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18626431"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Transmission of HCV in HIV-positive populations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Danta"
                            1 => "A&#46;J&#46; Rodger"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/COH.0b013e32834b4974"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin HIV AIDS"
                        "fecha" => "2011"
                        "volumen" => "6"
                        "paginaInicial" => "451"
                        "paginaFinal" => "458"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22001890"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Danta"
                            1 => "D&#46; Brown"
                            2 => "S&#46; Bhagani"
                            3 => "O&#46;G&#46; Pybus"
                            4 => "C&#46;A&#46; Sabin"
                            5 => "M&#46; Nelson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/QAD.0b013e3281053a0c"
                      "Revista" => array:6 [
                        "tituloSerie" => "AIDS"
                        "fecha" => "2007"
                        "volumen" => "21"
                        "paginaInicial" => "983"
                        "paginaFinal" => "991"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17457092"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Viral RNA in duodenal bile of cirrhotic patients with chronic hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;F&#46; Kuan"
                            1 => "G&#46; Garcia-Tsao"
                            2 => "R&#46;W&#46; Cartun"
                            3 => "J&#46;R&#46; Emanuel"
                            4 => "A&#46;B&#46; West"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Pathol Lab Med"
                        "fecha" => "1997"
                        "volumen" => "121"
                        "paginaInicial" => "847"
                        "paginaFinal" => "852"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9278613"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Detection of hepatitis C virus RNA in bile"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "K&#46; Yanaga"
                            1 => "T&#46; Yoshizumi"
                            2 => "H&#46; Uchiyama"
                            3 => "S&#46; Okano"
                            4 => "K&#46; Takenaka"
                            5 => "K&#46; Sugimachi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Gastroenterol"
                        "fecha" => "1997"
                        "volumen" => "92"
                        "paginaInicial" => "1927"
                        "paginaFinal" => "1928"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9382069"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Detection of hepatitis C virus in the bile and bile duct epithelial cells of hepatitis C virus-infected patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Y&#46; Haruna"
                            1 => "T&#46; Kanda"
                            2 => "M&#46; Honda"
                            3 => "T&#46; Takao"
                            4 => "N&#46; Hayashi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2001.23435"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2001"
                        "volumen" => "33"
                        "paginaInicial" => "977"
                        "paginaFinal" => "980"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11283863"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Frequent detection of HCV RNA and HCVcoreAg in stool of patients with chronic hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Heidrich"
                            1 => "E&#46; Steinmann"
                            2 => "I&#46; Plumeier"
                            3 => "J&#46; Kirschner"
                            4 => "L&#46; Sollik"
                            5 => "S&#46; Ziegert"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jcv.2016.04.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Virol"
                        "fecha" => "2016"
                        "volumen" => "80"
                        "paginaInicial" => "1"
                        "paginaFinal" => "7"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27128354"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0435"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Failure to detect hepatitis C virus genome in human secretions with the polymerase chain reaction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46;H&#46; Hsu"
                            1 => "T&#46;L&#46; Wright"
                            2 => "D&#46; Luba"
                            3 => "M&#46; Martin"
                            4 => "S&#46;M&#46; Feinstone"
                            5 => "G&#46; Garcia"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1991"
                        "volumen" => "14"
                        "paginaInicial" => "763"
                        "paginaFinal" => "767"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1657752"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0440"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Detection and quantitation of hepatitis C virus RNA in feces of chronically infected individuals"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Beld"
                            1 => "R&#46; Sentjens"
                            2 => "S&#46; Rebers"
                            3 => "J&#46; Weel"
                            4 => "P&#46; Wertheim-van Dillen"
                            5 => "C&#46; Sol"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Microbiol"
                        "fecha" => "2000"
                        "volumen" => "38"
                        "paginaInicial" => "3442"
                        "paginaFinal" => "3444"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10970398"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0445"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Apolipoprotein E on hepatitis C virion facilitates infection through interaction with low-density lipoprotein receptor"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "D&#46;M&#46; Owen"
                            1 => "H&#46; Huang"
                            2 => "J&#46; Ye"
                            3 => "M&#46; Gale Jr&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.virol.2009.08.037"
                      "Revista" => array:6 [
                        "tituloSerie" => "Virology"
                        "fecha" => "2009"
                        "volumen" => "394"
                        "paginaInicial" => "99"
                        "paginaFinal" => "108"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19751943"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0450"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Scarselli"
                            1 => "H&#46; Ansuini"
                            2 => "R&#46; Cerino"
                            3 => "R&#46;M&#46; Roccasecca"
                            4 => "S&#46; Acali"
                            5 => "G&#46; Filocamo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "EMBO J"
                        "fecha" => "2002"
                        "volumen" => "21"
                        "paginaInicial" => "5017"
                        "paginaFinal" => "5025"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12356718"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0455"
              "etiqueta" => "43"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Sainz Jr&#46;"
                            1 => "N&#46; Barretto"
                            2 => "D&#46;N&#46; Martin"
                            3 => "N&#46; Hiraga"
                            4 => "M&#46; Imamura"
                            5 => "S&#46; Hussain"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nm.2581"
                      "Revista" => array:7 [
                        "tituloSerie" => "Nat Med"
                        "fecha" => "2012"
                        "volumen" => "18"
                        "paginaInicial" => "281"
                        "paginaFinal" => "285"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22231557"
                            "web" => "Medline"
                          ]
                        ]
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                          "pii" => "S0026049516300166"
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                          "issn" => "00260495"
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0460"
              "etiqueta" => "44"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The identification of intestinal scavenger receptor class B&#44; type I &#40;SR-BI&#41; by expression cloning and its role in cholesterol absorption"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;W&#46; Altmann"
                            1 => "H&#46;R&#46; Davis Jr&#46;"
                            2 => "X&#46; Yao"
                            3 => "M&#46; Laverty"
                            4 => "D&#46;S&#46; Compton"
                            5 => "L&#46;J&#46; Zhu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochim Biophys Acta"
                        "fecha" => "2002"
                        "volumen" => "1580"
                        "paginaInicial" => "77"
                        "paginaFinal" => "93"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11923102"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0465"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differentiation-dependent expression and localization of the class B type I scavenger receptor in intestine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "S&#46;F&#46; Cai"
                            1 => "R&#46;J&#46; Kirby"
                            2 => "P&#46;N&#46; Howles"
                            3 => "D&#46;Y&#46; Hui"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Lipid Res"
                        "fecha" => "2001"
                        "volumen" => "42"
                        "paginaInicial" => "902"
                        "paginaFinal" => "909"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11369797"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0470"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Entry of hepatitis C virus into the cell&#58; a therapeutic target"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;A&#46; Del Campo"
                            1 => "A&#46; Rojas"
                            2 => "M&#46; Romero-Gomez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3748/wjg.v18.i33.4481"
                      "Revista" => array:6 [
                        "tituloSerie" => "World J Gastroenterol"
                        "fecha" => "2012"
                        "volumen" => "18"
                        "paginaInicial" => "4481"
                        "paginaFinal" => "4485"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22969220"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0475"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Niemann-pick C1-like 1 &#40;NPC1L1&#41; protein in intestinal and hepatic cholesterol transport"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46; Jia"
                            1 => "J&#46;L&#46; Betters"
                            2 => "L&#46; Yu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1146/annurev-physiol-012110-142233"
                      "Revista" => array:6 [
                        "tituloSerie" => "Annu Rev Physiol"
                        "fecha" => "2011"
                        "volumen" => "73"
                        "paginaInicial" => "239"
                        "paginaFinal" => "259"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20809793"
                            "web" => "Medline"
                          ]
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                    ]
                  ]
                ]
              ]
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              "etiqueta" => "48"
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                    0 => array:2 [
                      "titulo" => "The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Ge"
                            1 => "J&#46; Wang"
                            2 => "W&#46; Qi"
                            3 => "H&#46;H&#46; Miao"
                            4 => "J&#46; Cao"
                            5 => "Y&#46;X&#46; Qu"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.cmet.2008.04.001"
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                        "tituloSerie" => "Cell Metab"
                        "fecha" => "2008"
                        "volumen" => "7"
                        "paginaInicial" => "508"
                        "paginaFinal" => "519"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18522832"
                            "web" => "Medline"
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Article information

ISSN: 02105705
Original language: English

DOI:10.1016/j.gastrohep.2017.01.004

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 October	6	23	29
2024 September	18	20	38
2024 August	11	26	37
2024 July	7	4	11
2024 June	9	3	12
2024 May	10	6	16
2024 April	17	4	21
2024 March	46	3	49
2024 February	34	2	36
2024 January	12	5	17
2023 December	25	1	26
2023 November	22	6	28
2023 October	20	3	23
2023 September	13	3	16
2023 August	8	0	8
2023 July	16	2	18
2023 June	24	4	28
2023 May	48	0	48
2023 April	33	1	34
2023 March	34	4	38
2023 February	15	23	38
2023 January	23	19	42
2022 December	16	10	26
2022 November	22	17	39
2022 October	24	19	43
2022 September	22	12	34
2022 August	21	13	34
2022 July	27	15	42
2022 June	23	19	42
2022 May	13	15	28
2022 April	24	12	36
2022 March	22	10	32
2022 February	21	6	27
2022 January	34	7	41
2021 December	29	11	40
2021 November	18	10	28
2021 October	28	15	43
2021 September	23	13	36
2021 August	22	5	27
2021 July	19	14	33
2021 June	22	8	30
2021 May	18	14	32
2021 April	62	22	84
2021 March	41	12	53
2021 February	61	13	74
2021 January	23	12	35
2020 December	12	10	22
2020 November	23	6	29
2020 October	17	4	21
2020 September	17	12	29
2020 August	30	19	49
2020 July	29	9	38
2020 June	22	13	35
2020 May	22	10	32
2020 April	20	23	43
2020 March	22	9	31
2020 February	21	9	30
2020 January	29	8	37
2019 December	33	11	44
2019 November	18	9	27
2019 October	27	13	40
2019 September	8	0	8
2019 August	13	0	13
2019 July	29	6	35
2019 June	25	5	30
2019 May	50	32	82
2017 October	2	0	2
2017 August	1	0	1
2017 July	1	0	1
2017 June	4	0	4
2017 May	17	7	24

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