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- A multi-variant, viral dynamic model of genotype 1 HCV to assess the in vivo evolution of protease-inhibitor resistant variants (2010)
- Variants resistant to compounds specifically targeting HCV are observed in clinical trials. A multi-variant viral dynamic model was developed to quantify the evolution and in vivo fitness of variants in subjects dosed with monotherapy of an HCV protease inhibitor, telaprevir. Variant fitness was estimated using a model in which variants were selected by competition for shared limited replication space. Fitness was represented in the absence of telaprevir by different variant production rate constants and in the presence of telaprevir by additional antiviral blockage by telaprevir. Model parameters, including rate constants for viral production, clearance, and effective telaprevir concentration, were estimated from 1) plasma HCV RNA levels of subjects before, during, and after dosing, 2) post-dosing prevalence of plasma variants from subjects, and 3) sensitivity of variants to telaprevir in the HCV replicon. The model provided a good fit to plasma HCV RNA levels observed both during and after telaprevir dosing, as well as to variant prevalence observed after telaprevir dosing. After an initial sharp decline in HCV RNA levels during dosing with telaprevir, HCV RNA levels increased in some subjects. The model predicted this increase to be caused by pre-existing variants with sufficient fitness to expand once available replication space increased due to rapid clearance of wild-type (WT) virus. The average replicative fitness estimates in the absence of telaprevir ranged from 1% to 68% of WT fitness. Compared to the relative fitness method, the in vivo estimates from the viral dynamic model corresponded more closely to in vitro replicon data, as well as to qualitative behaviors observed in both on-dosing and long-term post-dosing clinical data. The modeling fitness estimates were robust in sensitivity analyses in which the restoration dynamics of replication space and assumptions of HCV mutation rates were varied.
- Acoustic radiation force impulse imaging for differentiation of thyroid nodules (2012)
- Background: Acoustic Radiation Force Impulse (ARFI)-imaging is an ultrasound-based elastography method enabling quantitative measurement of tissue stiffness. The aim of the present study was to evaluate sensitivity and specificity of ARFI-imaging for differentiation of thyroid nodules and to compare it to the well evaluated qualitative real-time elastography (RTE). Methods: ARFI-imaging involves the mechanical excitation of tissue using acoustic pulses to generate localized displacements resulting in shear-wave propagation which is tracked using correlation-based methods and recorded in m/s. Inclusion criteria were: nodules $5 mm, and cytological/histological assessment. All patients received conventional ultrasound, real-time elastography (RTE) and ARFI-imaging. Results: One-hundred-fifty-eight nodules in 138 patients were available for analysis. One-hundred-thirty-seven nodules were benign on cytology/histology, and twenty-one nodules were malignant. The median velocity of ARFI-imaging in the healthy thyroid tissue, as well as in benign and malignant thyroid nodules was 1.76 m/s, 1.90 m/s, and 2.69 m/s, respectively. While no significant difference in median velocity was found between healthy thyroid tissue and benign thyroid nodules, a significant difference was found between malignant thyroid nodules on the one hand and healthy thyroid tissue (p = 0.0019) or benign thyroid nodules (p = 0.0039) on the other hand. No significant difference of diagnostic accuracy for the diagnosis of malignant thyroid nodules was found between RTE and ARFI-imaging (0.74 vs. 0.69, p = 0.54). The combination of RTE with ARFI did not improve diagnostic accuracy. Conclusions: ARFI can be used as an additional tool in the diagnostic work up of thyroid nodules with high negative predictive value and comparable results to RTE.
- Adaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors (2010)
- Hepatitis C virus (HCV) naturally infects only humans and chimpanzees. The determinants responsible for this narrow species tropism are not well defined. Virus cell entry involves human scavenger receptor class B type I (SR-BI), CD81, claudin-1 and occludin. Among these, at least CD81 and occludin are utilized in a highly species-specific fashion, thus contributing to the narrow host range of HCV. We adapted HCV to mouse CD81 and identified three envelope glycoprotein mutations which together enhance infection of cells with mouse or other rodent receptors approximately 100-fold. These mutations enhanced interaction with human CD81 and increased exposure of the binding site for CD81 on the surface of virus particles. These changes were accompanied by augmented susceptibility of adapted HCV to neutralization by E2-specific antibodies indicative of major conformational changes of virus-resident E1/E2-complexes. Neutralization with CD81, SR-BI- and claudin-1-specific antibodies and knock down of occludin expression by siRNAs indicate that the adapted virus remains dependent on these host factors but apparently utilizes CD81, SR-BI and occludin with increased efficiency. Importantly, adapted E1/E2 complexes mediate HCV cell entry into mouse cells in the absence of human entry factors. These results further our knowledge of HCV receptor interactions and indicate that three glycoprotein mutations are sufficient to overcome the species-specific restriction of HCV cell entry into mouse cells. Moreover, these findings should contribute to the development of an immunocompetent small animal model fully permissive to HCV.
- Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia (2014)
- Background: Ataxia telangiectasia (A-T) is a rare but devastating and progressive disorder characterized by cerebellar dysfunction, lymphoreticular malignancies and recurrent sinopulmonary infections. In A-T, disease of the respiratory system causes significant morbidity and is a frequent cause of death. Methods: We used a self-limited murine model of hydrochloric acid-induced acute lung injury (ALI) to determine the inflammatory answer due to mucosal injury in Atm (A-T mutated)- deficient mice (Atm−/−). Results: ATM deficiency increased peak lung inflammation as demonstrated by bronchoalveolar lavage fluid (BALF) neutrophils and lymphocytes and increased levels of BALF pro-inflammatory cytokines (e.g. IL-6, TNF). Furthermore, bronchial epithelial damage after ALI was increased in Atm−/− mice. ATM deficiency increased airway resistance and tissue compliance before ALI was performed. Conclusions: Together, these findings indicate that ATM plays a key role in inflammatory response after airway mucosal injury.
- Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and ε-aminocaproic acid - a meta-analysis of randomised and observational trials of over 30.000 patients (2013)
- Background: To compare the effect of aprotinin with the effect of lysine analogues (tranexamic acid and ε-aminocaproic acid) on early mortality in three subgroups of patients: low, intermediate and high risk of cardiac surgery. Methods and Findings: We performed a meta-analysis of randomised controlled trials and observational with the following data sources: Medline, Cochrane Library, and reference lists of identified articles. The primary outcome measure was early (in-hospital/30-day) mortality. The secondary outcome measures were any transfusion of packed red blood cells within 24 hours after surgery, any re-operation for bleeding or massive bleeding, and acute renal dysfunction or failure within the selected cited publications, respectively. Out of 328 search results, 31 studies (15 trials and 16 observational studies) included 33,501 patients. Early mortality was significantly increased after aprotinin vs. lysine analogues with a pooled risk ratio (95% CI) of 1.58 (1.13–2.21), p<0.001 in the low (n = 14,297) and in the intermediate risk subgroup (1.42 (1.09–1.84), p<0.001; n = 14,427), respectively. Contrarily, in the subgroup of high risk patients (n = 4,777), the risk for mortality did not differ significantly between aprotinin and lysine analogues (1.03 (0.67–1.58), p = 0.90). Conclusion: Aprotinin may be associated with an increased risk of mortality in low and intermediate risk cardiac surgery, but presumably may has no effect on early mortality in a subgroup of high risk cardiac surgery compared to lysine analogues. Thus, decisions to re-license aprotinin in lower risk patients should critically be debated. In contrast, aprotinin might probably be beneficial in high risk cardiac surgery as it reduces risk of transfusion and bleeding complications.
- Assessment of liver fibrosis and associated risk factors in HIV-infected individuals using transient elastography and serum biomarkers (2012)
- Background: Liver fibrosis in human immunodeficiency virus (HIV)-infected individuals is mostly attributable to co-infection with hepatitis B or C. The impact of other risk factors, including prolonged exposure to combined antiretroviral therapy (cART) is poorly understood. Our aim was to determine the prevalence of liver fibrosis and associated risk factors in HIV-infected individuals based on non-invasive fibrosis assessment using transient elastography (TE) and serum biomarkers (Fibrotest [FT]). Methods: In 202 consecutive HIV-infected individuals (159 men; mean age 47 ± 9 years; 35 with hepatitis-C-virus [HCV] co-infection), TE and FT were performed. Repeat TE examinations were conducted 1 and 2 years after study inclusion. Results: Significant liver fibrosis was present in 16% and 29% of patients, respectively, when assessed by TE (≥ 7.1 kPa) and FT (> 0.48). A combination of TE and FT predicted significant fibrosis in 8% of all patients (31% in HIV/HCV co-infected and 3% in HIV mono-infected individuals). Chronic ALT, AST and γ-GT elevation was present in 29%, 20% and 51% of all cART-exposed patients and in 19%, 8% and 45.5% of HIV mono-infected individuals. Overall, factors independently associated with significant fibrosis as assessed by TE (OR, 95% CI) were co-infection with HCV (7.29, 1.95-27.34), chronic AST (6.58, 1.30-33.25) and γ-GT (5.17, 1.56-17.08) elevation and time on dideoxynucleoside therapy (1.01, 1.00-1.02). In 68 HIV mono-infected individuals who had repeat TE examinations, TE values did not differ significantly during a median follow-up time of 24 months (median intra-patient changes at last TE examination relative to baseline: -0.2 kPa, p = 0.20). Conclusions: Chronic elevation of liver enzymes was observed in up to 45.5% of HIV mono-infected patients on cART. However, only a small subset had significant fibrosis as predicted by TE and FT. There was no evidence for fibrosis progression during follow-up TE examinations.
- Baseline MELD score predicts hepatic decompensation during antiviral therapy in patients with chronic hepatitis C and advanced cirrhosis (2013)
- Background and Aims: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined. Methods: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks). Results: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001). Conclusions: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.
- Comparison of ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis (2010)
- Background: FibroTest (FT) is the most frequently used serum fibrosis marker and consists of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoproteinA1, haptoglobin, GGT, bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of an algorithm of three fibrosis markers (hyaluronic acid, amino-terminal propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1). While a systematic review has shown comparable results for both individual markers, there has been no direct comparison of both markers. Methods: In the present study, the ELF-test was analyzed retrospectively in patients with chronic liver disease, who received a liver biopsy, transient elastography (TE) and the FibroTest using histology as the reference method. Histology was classified according to METAVIR and the Ludwig's classification (F0-F4) for patients with chronic hepatitis C and B virus (HCV, HBV) infection and primary biliary cirrhosis (PBC), respectively. Results: Seventy-four patients were analysed: 36 with HCV, 10 with HBV, and 28 with PBC. The accuracy (AUROC) for the diagnosis of significant fibrosis (F[greater than or equal to]2) for ELF and FibroTest was 0.78 (95%CI:0.67-0.89) and 0.69 (95%-CI:0.57-0.82), respectively (difference not statistically significant, n.s.). The AUROC for the diagnosis of liver cirrhosis was 0.92 (95%CI:0.83-1,00), and 0.91 (95%CI:0.83-0.99), respectively (n.s.). For 66 patients with reliable TE measurements the AUROC for the diagnosis of significant fibrosis (cirrhosis) for TE, ELF and FT were 0.80 (0.94), 0.76 (0.92), and 0.67 (0.91), respectively (n.s.). Conclusion: FibroTest and ELF can be performed with comparable diagnostic accuracy for the non-invasive staging of liver fibrosis. Serum tests are informative in a higher proportion of patients than transient elastography.
- Interleukin-22 predicts severity and death in advanced liver cirrhosis: a prospective cohort study (2012)
- Background: Interleukin-22 (IL-22), recently identified as a crucial parameter of pathology in experimental liver damage, may determine survival in clinical end-stage liver disease. Systematic analysis of serum IL-22 in relation to morbidity and mortality of patients with advanced liver cirrhosis has not been performed so far. Methods: This is a prospective cohort study including 120 liver cirrhosis patients and 40 healthy donors to analyze systemic levels of IL-22 in relation to survival and hepatic complications. Results: A total of 71% of patients displayed liver cirrhosis-related complications at study inclusion. A total of 23% of the patients died during a mean follow-up of 196 +/- 165 days. Systemic IL-22 was detectable in 74% of patients but only in 10% of healthy donors (P <0.001). Elevated levels of IL-22 were associated with ascites (P = 0.006), hepatorenal syndrome (P <0.0001), and spontaneous bacterial peritonitis (P = 0.001). Patients with elevated IL-22 (>18 pg/ml, n = 57) showed significantly reduced survival compared to patients with regular ([less than or equal to]18 pg/ml) levels of IL-22 (321 days versus 526 days, P = 0.003). Other factors associated with overall survival were high CRP ([greater than or equal to]2.9 mg/dl, P = 0.005, hazard ratio (HR) 0.314, confidence interval (CI) (0.141 to 0.702)), elevated serum creatinine (P = 0.05, HR 0.453, CI (0.203 to 1.012)), presence of liver-related complications (P = 0.028, HR 0.258 CI (0.077 to 0.862)), model of end stage liver disease (MELD) score [greater than or equal to]20 (P = 0.017, HR 0.364, CI (0.159 to 0.835)) and age (P = 0.011, HR 1.047, CI (1.011 to 1.085)). Adjusted multivariate Cox proportional-hazards analysis identified elevated systemic IL-22 levels as independent predictors of reduced survival (P = 0.007, HR 0.218, CI (0.072 to 0.662)). Conclusions: In patients with liver cirrhosis, elevated systemic IL-22 levels are predictive for reduced survival independently from age, liver-related complications, CRP, creatinine and the MELD score. Thus, processes that lead to a rise in systemic interleukin-22 may be relevant for prognosis of advanced liver cirrhosis.
- Interobserver agreement of Thyroid Imaging Reporting and Data System (TIRADS) and strain elastography for the assessment of thyroid nodules (2013)
- Background: Thyroid Imaging Reporting and Data System (TIRADS) was developed to improve patient management and cost-effectiveness by avoiding unnecessary fine needle aspiration biopsy (FNAB) in patients with thyroid nodules. However, its clinical use is still very limited. Strain elastography (SE) enables the determination of tissue elasticity and has shown promising results for the differentiation of thyroid nodules. Methods: The aim of the present study was to evaluate the interobserver agreement (IA) of TIRADS developed by Horvath et al. and SE. Three blinded observers independently scored stored images of TIRADS and SE in 114 thyroid nodules (114 patients). Cytology and/or histology was available for all benign (n = 99) and histology for all malignant nodules (n = 15). Results: The IA between the 3 observers was only fair for TIRADS categories 2–5 (Coheńs kappa = 0.27,p = 0.000001) and TIRADS categories 2/3 versus 4/5 (ck = 0.25,p = 0.0020). The IA was substantial for SE scores 1–4 (ck = 0.66,p<0.000001) and very good for SE scores 1/2 versus 3/4 (ck = 0.81,p<0.000001). 92–100% of patients with TIRADS-2 had benign lesions, while 28–42% with TIRADS-5 had malignant cytology/histology. The negative-predictive-value (NPV) was 92–100% for TIRADS using TIRADS-categories 4&5 and 96–98% for SE using score ES-3&4 for the diagnosis of malignancy, respectively. However, only 11–42% of nodules were in TIRADS-categories 2&3, as compared to 58–60% with ES-1&2. Conclusions: IA of TIRADS developed by Horvath et al. is only fair. TIRADS and SE have high NPV for excluding malignancy in the diagnostic work-up of thyroid nodules.