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Background and Aims: Sarcopenia has been associated with poor outcomes in patients with cirrhosis and hepatocellular carcinoma. We investigated the impact of sarcopenia on survival in patients with advanced hepatocellular carcinoma treated with Sorafenib., Methods: A total of 328 patients were retrospectively analyzed. All patients had an abdominal CT scan within 8 weeks prior to the start of treatment. Two cohorts of patients were analyzed: the "Training Group" (215 patients) and the "Validation Group" (113 patients). Sarcopenia was defined by reduced skeletal muscle index, calculated from an L3 section CT image., Results: Sarcopenia was present in 48% of the training group and 50% of the validation group. At multivariate analysis, sarcopenia (HR: 1.47, p = 0.026 in training; HR 1.99, p = 0.033 in validation) and MELD > 9 (HR: 1.37, p = 0.037 in training; HR 1.78, p = 0.035 in validation) emerged as independent prognostic factors in both groups. We assembled a prognostic indicator named "SARCO-MELD" based on the two independent prognostic factors, creating three groups: group 1 (0 prognostic factors), group 2 (1 factor) and group 3 (2 factors), the latter with significantly worse survival and shorter time receiving treatment.

Esophagogastroduodenoscopy (EGD) appropriateness in Open-Access System (OAS) is a relevant issue. The Gastropack Access System (GAS) is a new system to access gastroenterological services, based on the partnership between Gastroenterologists and GPs. This study aims to evaluate if GAS is superior to OAS in terms of EGDS appropriateness. Secondarily, we evaluated the diagnostic yield of EGDS according to ASGE guidelines. The GAS was developed in an area of Bologna where General Practitioners (GPs) could decide to directly prescribe EGDS through OAS or referring to GAS, where EGDS can be scheduled after contact between GPs and specialists sharing a patient's clinical information. Between 2016 and 2019, 2179 cases (M:F = 861:1318, median age 61, IQR 47.72) were referred to GAS and 1467 patients (65%) had a prescription for EGDS; conversely, 874 EGDS were prescribed through OAS (M:F = 383:491; median age 58 yrs, IQR 45.68). Indication was appropriate in 92% in GAS (1312/1424) versus 71% in OAS (618/874), p < 0.001. The rate of clinically significant endoscopic findings (CSEF) was significantly higher in GAS (49% vs. 34.8%, p < 0.001). Adherence to ASGE guidelines was not related to CSEF; however, surveillance for pre-malignant conditions was independently related to CSEF. All neoplasm were observed in appropriate EGD. GAS is an innovative method showing extremely high rates of appropriateness. ASGE guidelines confirmed their validity for cancer detection, but their performance for the detection of other conditions needs to be refined.

To evaluate the potential variability of Manganese (Mn 2+ ) in commercial pineapple juice (PJ) produced in different years and to identify the optimal Mn 2+ concentration in the correct amount of PJ to be administered prior to Magnetic Resonance Cholangiopancreatography (MRCP) in order to suppress the gastroduodenal (GD) liquid signal. The Mn 2+ concentration in PJ produced in different years was defined using Atomic Absorption Spectrometry. The optimal Mn 2+ concentration and the amount of PJ, were estimated in an in-vitro analysis, and were then prospectively tested in a population of patients who underwent MRCP. The results were compared with those achieved with the previous standard amount of PJ used in a similar population. The concentrations of Mn 2+ in commercial PJ produced in different years did not differ. A total amount of 150 ml (one glass) of PJ having a high Mn 2+ content (2.37 mg/dl) was sufficient for the suppression of the GD liquid signal, despite the additional dilution caused by GD liquids since it led to a final concentration of Mn 2+ of 0.5-1.00 mg/dl. The optimized single-dose oral administration of 150 ml (approximately one glass) of PJ having a high Mn 2+ concentration prior to MRCP was adequate to guarantee the correct amount of Mn 2+ to suppress the GD signal., (© 2022. The Author(s).)

Background: Bacterial and fungal infections (BFIs) are frequent in patients with cirrhosis and often trigger acute-on-chronic liver failure (ACLF). This prospective observational study aims to describe the interactions between BFI and ACLF in terms of mortality and related risk factors., Methods: We performed a 2-center prospective observational study enrolling hospitalized patients with cirrhosis admitted for acute decompensation. Data were recorded at admission and during hospitalization. Survival was recorded up to 1 year., Results: Among the 516 patients enrolled, 108 (21%) were infected at admission, while an additional 61 patients (12%) developed an infection during hospital stay. In the absence of ACLF, the 1-year mortality rate of patients with BFI did not differ from that of patients without BFI (33% vs 31%; P  = .553). In contrast, those with ACLF triggered or complicated by BFI had a significantly higher mortality rate than those who remained free from BFI (75% vs 54%; P  = .011). Competing risk analysis showed that the negative impact of ACLF-related BFI on long-term prognosis was independent from Model for End-stage Liver Disease (MELD) incorporating serum sodium concentration score, comorbidity, and basal C-reactive protein level. Finally, multivariable logistic regression showed that higher MELD score ( P  < .001), QuickSOFA score ≥2 points ( P  = .007), and secondary bloodstream ( P  = .022) and multidrug-resistant pathogen isolation ( P  = .030) were independently associated with ACLF in patients with BFI., Conclusions: This large prospective study indicated that the adverse impact of BFI on long-term survival in decompensated cirrhosis is not universal but is limited to those patients who also develop ACLF. Both disease severity and microbiological factors predispose infected decompensated patients to ACLF., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is progressively increasing. The aim of this study was to determine the safety and efficacy of conventional transarterial chemoembolization (TACE) in elderly HCC patients compared with younger adults., Methods: A consecutive cohort of unresectable HCC patients treated with TACE as a first-line treatment was retrospectively analyzed. Patients were categorized into "elderly" (≥ 70 years, 80 patients) and "younger" (< 70 years, 145 patients). Liver-related death and progression-free survival after TACE were compared before and after propensity score matching. A competing risk regression analysis was used for univariate/multivariate survival data analysis., Results: cTACE was well tolerated in both groups. The cumulative risk of both liver-related death and progression-free survival after cTACE was comparable between "elderly" and "younger" (death: 73.8% vs 69.4%, P = 0.505; progression-free survival: 48.2% vs 44.8%, P = 0.0668). Propensity model matched 61 patients in each group for gender and Barcelona Clinic Liver Cancer staging. Even after matching, the cumulative risk of liver-related death and of progression-free survival did not differ between the two groups. At multivariate analysis, Child-Pugh class, tumor gross pathology and alpha-fetoprotein were independently associated with the liver-related mortality risk., Conclusions: This study confirms that TACE is well tolerated and effective in patients aged 70 years or more with unresectable HCC as it is for their younger counterparts (< 70 years). Liver-related mortality was not associated with age ≥ 70 years and primarily predicted by tumor multifocality, Child-Pugh class B and an increased alpha-fetoprotein value (> 31 ng/ml).

Objective:  To evaluate the knowledge related to human papillomavirus (HPV) infection and the rate of HPV vaccination among undergraduate freshmen and senior students of medicine, pharmacy, speech therapy, nursing and physical education in a Brazilian university., Methods:  A questionnaire concerning sociodemographic aspects, sexual background, and knowledge about HPV and its vaccine was filled out by 492 students. Three months later, a second questionnaire, concerning the new rate of vaccination, was applied to 233 students., Results:  Among the 290 women who answered the first questionnaire, 47% of the freshmen and 13% of the seniors stated they were not sexually active, as well as 11% of the 202 freshman and senior male students. Although the knowledge about HPV was higher among women, they reported a lower use of condoms. More than 83% of the women and 66% of the men knew that HPV can cause cervical cancer, but less than 30% of the students knew that HPV can cause vulvar, anal, penile and oropharyngeal cancer. Less than half of the students knew that HPV causes genital, anal and oropharyngeal warts. Comparing the students, the seniors had more knowledge of the fact that HPV is sexually transmitted, and that HPV infection can be asymptomatic. The rate of vaccination was of 26% for women, and of 8% for men, and it increased to 52% and 27% respectively among the 233 students evaluated in the second questionnaire., Conclusion:  As almost half of freshman women declared being sexually inactive, the investment in public health information programs and easier access to the HPV vaccine seem to be a useful strategy for undergraduate students., Competing Interests: The authors have no conflict of interests to declare., (Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil.)

We aimed to evaluate whether pelvic magnetic resonance imaging (MRI) could play a role in better assessing chronic pelvic pain syndrome. We evaluated 44 male patients (median 41 aged) with a clinical history of painful pelvic symptoms, lasting for at least three of the previous 6 months, associated with urinary, anorectal and sexual disorders in the absence of bacterial prostate infection. All these patients underwent ultrasound (US) and MRI evaluation of the pelvis. Prostate imaging findings, such as gland morphology evaluated by US and prostatic signal intensity on MRI, appeared normal in the majority of patients (38/44; 82%). Extraparenchymal alterations were found in 28 patients (63.6%); the most frequent was the dilatation of periprostatic vein plexus (20/28; 71.4%), significantly correlated to chronic pelvic pain syndrome (p = 0.0013), regardless of different clinical presentations. This finding was tested in a control group of 90 patients, demonstrating an excellent specificity (97%), good positive predictive value (87%) and diagnostic accuracy (80%). MRI confirmed its high capability in evaluating prostatic and extraprostatic structures. Periprostatic vein dilatation, which identified approximately two-thirds of the patients with chronic pelvic pain syndrome using pelvic MRI, significantly correlated to chronic pelvic pain syndrome, independently of patient age, symptoms and prostatic volume., (© 2019 Blackwell Verlag GmbH.)

Objectives: This study investigates the diagnostic performance of a new T1 imaging series, generated by the digital subtraction of the opposed phase from in phase T 1 weighted images, in MRI for renal angiomyolipoma (AML) evaluation., Methods: This retrospective study involved 96 patients, 63 (65.6%) with at least one renal AML and 33 (34.4%) healthy patients. Two radiologists having different experience retrospectively reviewed two MR imaging series, starting with in and out-phase T 1 weighted images and then the new subtracted T1 images, in which AML appeared white on black background. The presence, number, location, and dimensions of the AMLs, and reading time were collected separately for the two kidneys. Statistical analysis was carried out using the appropriate tests., Results: The number of lesions identified and the evaluation of lesion dimension did not statistically differ between the different MR imaging series evaluated, without interobserver variability. Both percentage agreement of the total number of observations and the κ coefficient showed very good agreement between the radiologists. The median time for the diagnosis was statistically lower when using the subtracted T1 imaging series for both observers with a median gain from 6.5 to 15 s per identified lesion, resulting in a total time-saving of more than half (52.9%), in both patients with and without AMLs, and in patients with a single or with more than one AML ( p < 0.001)., Conclusions: The new subtracted T1 imaging series proved to be reliable in identifying fat-containing renal lesions, by both expert and non-expert radiologists, resulting in a saving of both time and money. Moreover, this new subtracted T1 imaging series could be an effective tool in non-dedicated kidney examinations in which a faster reading is advisable., Advances in Knowledge: The opportunity of using a single set of MRI images in kidney evaluation for identifying fat-containing lesions, considerably reducing reading time, resulting in cost-effectiveness.

Background & Aims: The electrocardiographic QT interval frequently is prolonged in patients with cirrhosis. Acute gastrointestinal bleeding further prolongs corrected QT (QTc) in patients with cirrhosis, which has been associated with an increased risk of death within 6 weeks. We aimed to confirm these findings and develop a mortality risk index that incorporates QTc., Methods: We collected data from 274 patients with cirrhosis and acute gastrointestinal bleeding from any cause admitted to a hospital in Bologna, Italy, from January 2001 through December 2012 (training set). We used logistic regression analysis to identify patient factors associated with death within 6 weeks (6-week mortality). We validated our findings by using data from 200 patients with cirrhosis and gastrointestinal bleeding treated at 2 separate hospitals in Italy, from 2001 through 2016 and 2007 through 2012. Our primary aim was to confirm the prognostic effects of prolonged QTc in a large population of patients and develop a 6-week mortality risk score for acute gastrointestinal bleeding from any cause that incorporates the QTc interval., Results: In the training set, QTc greater than 456 ms, the model for end-stage liver disease-sodium (MELD-Na) score, previous bleeding, and serum albumin concentration were associated independently with 6-week mortality. We combined these parameters to create a risk scoring system that we named MELD-Na acute gastrointestinal bleeding (MELDNa-AGIB). In the validation set, the MELDNa-AGIB identified patients who died within 6 weeks with an area under the receiver operating characteristic curve (AUROC) of 0.888; this value was higher than that of the MELD score (AUROC, 0.838; P = .031), MELD score with updated calibration (AUROC, 0.837; P = .029), Child-Turcotte-Pugh score (AUROC, 0.789; P = .004), D'Amico score (AUROC, 0.761; P = .003), and Augustin score (AUROC, 0.792; P = .001), with a net reclassification improvement better than the MELD-Na score (0.266; P = .045). In calibration, the MELDNa-AGIB produced a high score in the Hosmer-Lemeshow test (P = .947), which was superior to that of MELD-Na (P = .146). In the training set, only 6.3% of patients with MELDNa-AGIB scores of 4 or less died within 6 weeks. Among patients with a scores of 9, 16, and 25 or higher, 15.5%, 41.5%, and 81% or more patients died within 6 weeks, respectively. The probability of survival progressively and significantly decreased with increasing scores in the training and validation sets., Conclusions: We confirmed QTc as an independent predictor of 6-week mortality in a large population of patients with cirrhosis and acute gastrointestinal bleeding. The combination of QTc, MELD-Na, previous bleeding, and serum albumin (the MELDNa-AGIB score) accurately determines the risk of 6-week mortality, providing timely identification of patients at very high risk of death., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim: To identify, in vitro, the best fruit juice to use as oral contrast agent in magnetic resonance cholangiopancreatography (MRCP) and to test, in vivo, the best natural juice and the new parameters in MRCP sequences identified in vitro., Materials and Methods: The in vitro evaluations consisted of measuring the T2 values of a pure solution of manganese (Mn) and iron (Fe) at different concentrations, measuring the content of Mn and Fe in five commercial juices and their T2 relaxation times, and identifying the optimal juice dilution for suppressing the gastrointestinal fluid signal. The new parameters of MRCP sequences were tested in vivo., Results: Manganese alone strongly influenced the shortening of the T2 values (p=0.004). The T2 value with an echo time (TE) of ≥1,000 ms enabled sufficient intestinal fluid suppression in the case of high juice dilution. A flip angle of 90° maximised the differences between the high signal from static fluids, such as the bile and the fluid in the gastrointestinal tract, using fast imaging employing steady-state acquisition (FIESTA) sequences (p<0.001)., Conclusion: The shortening of the T2 relaxation time depended only on the Mn concentration. All the commercial juices had an Mn concentration sufficient to suppress the gastrointestinal fluid signal using long TE sequences. The oral ingestion of commercial juice before MRCP was enough to suppress the signal from the gastrointestinal fluids, regardless of its dilution after ingestion. When using FIESTA sequences, a flip angle of 90° allowed the best suppression of gastrointestinal fluid signals., (Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: Many improvements have been made in diagnosing hepatocellular carcinoma (HCC), but the radiological hallmarks of HCC have remained the same for many years. We prospectively evaluated the imaging criteria of HCC, early HCC and high-grade dysplastic nodules (HGDNs) in patients under surveillance for chronic liver disease, using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) MRI and diffusion-weighted imaging., Design: Our study population included 420 nodules >1 cm in 228 patients. The MRI findings of each nodule were collected in all sequences/phases. The diagnosis of HCC was made according to the American Association for the Study of Liver Diseases (AASLD) criteria; all atypical nodules were diagnosed using histology., Results: A classification and regression tree was developed using three MRI findings which were independently significant correlated variables for early HCC/HCC, and the best sequence of their application in a new diagnostic algorithm (hepatobiliary hypointensity, arterial hyperintensity and diffusion restriction) was suggested. This algorithm demonstrated, both in the entire study population and for nodules ≤2 cm, higher sensitivity (96% [95% CI 93.5% to 97.6%] and 96.6% [95% CI 93.9% to 98.5%], P<0.001, respectively) and slightly lower specificity (91.8% [95% CI 88.6% to 94.1%], P=0.063, and 92.7% [95% CI 88.9% to 95.4%], P=0.125, respectively) than those of the AASLD criteria. Our new diagnostic algorithm also showed a very high sensitivity (94.7%; 95% CI 92% to 96.6%) and specificity (99.3%; 95% CI 97.7% to 99.8%) in classifying HGDN., Conclusion: Our new diagnostic algorithm demonstrated significantly higher sensitivity and comparable specificity than those of the AASLD imaging criteria for HCC in patients with cirrhosis evaluated using Gd-EOB-DTPA MRI, even for lesions ≤2 cm. Moreover, this diagnostic algorithm allowed evaluating other lesions which could arise in a cirrhotic liver, such as early HCC and HGDN., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Decompensated cirrhosis is associated to extensive post-transcriptional changes of human albumin (HA). This study aims to characterize the occurrence of HA homodimerization in a large cohort of patients with decompensated cirrhosis and to evaluate its association with clinical features and prognosis. HA monomeric and dimeric isoforms were identified in peripheral blood by using a HPLC-ESI-MS technique in 123 cirrhotic patients hospitalized for acute decompensation and 50 age- and sex-comparable healthy controls. Clinical and biochemical parameters were recorded and patients followed up to one year. Among the monomeric isoforms identified, the N- and C-terminal truncated and the native HA underwent homodimerization. All three homodimers were significantly more abundant in patients with cirrhosis, acute-on-chronic liver failure and correlate with the prognostic scores. The homodimeric N-terminal truncated isoform was independently associated to disease complications and was able to stratify 1-year survival. As a result of all these changes, the monomeric native HA was significantly decreased in patients with cirrhosis, being also associated with a poorer prognosis. In conclusion homodimerization is a novel described structural alteration of the HA molecule in decompensated cirrhosis and contributes to the progressive reduction of the monomeric native HA, the only isoform provided of structural and functional integrity.

Aim: We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS)., Methods: We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications., Results: DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively)., Conclusions: The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury., (© 2015 The British Pharmacological Society.)

Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis. As α-fetoprotein (AFP) is considered a poor surveillance test, we tested the performance of its changes over time., Methods: Eighty patients were diagnosed with HCC (cases) during semiannual surveillance with ultrasonography and AFP measurement were recruited and matched for age, gender, etiology and Child-Pugh class with 160 contemporary cancer-free controls undergoing the same surveillance training group (TG). As a validation group (VG) we considered 36 subsequent patients diagnosed with HCC, matched 1 : 3 with contemporary cancer-free controls. α-Fetoprotein values at the time of HCC diagnosis (T0) and its changes over the 12 (Δ12) and 6 months (Δ6) before cancer detection were considered., Results: In both TG and VG, >80% of HCCs were found at an early stage. In TG, AFP significantly increased over time only in cases. T0 AFP and a positive Δ6 were independently associated with HCC diagnosis (odds ratio: 1.031 and 2.402, respectively). The area under the curve of T0 AFP was 0.76 and its best cutoff (BC) was 10 ng ml(-1) (sensitivity 66.3%, specificity 80.6%). The combination of AFP >10 ng ml(-1) or a positive Δ6 composite α-fetoprotein index (CAI) increased the sensitivity to 80% with a negative predictive value (NPV) of 86.2%. Negative predictive value rose to 99%, considering a cancer prevalence of 3%. In the VG, the AFP-BC was again 10 ng ml(-1) (sensitivity 66.7%, specificity 88.9%), and CAI sensitivity was 80.6% with a NPV value of 90.5%., Conclusions: CAI achieves adequate sensitivity and NPV as a surveillance test for the early detection of HCC in cirrhosis.

Background & Aims: The model for end-stage liver disease (MELD) is used for organ allocation in liver transplantation (LT), but its prognostic performance is less accurate in patients with low score. We assess the outcome of patients with MELD < 18 awaiting LT, finding prognostic variables to identify a high dropout risk., Methods: Training set consisted of 277 patients and validation cohort of 292 patients. Competing risk regression analysis, taking into account LT, was used for univariate/multivariate analysis., Results: Ascites, sodium, bilirubin, albumin and glomerular filtration rate were independently associated with a 12-month dropout risk in the training set. Combining these five prognostic parameters, we calculated a new score named liver-renal-risk (LIRER). In the validation set, the 12-month LIRER concordance index showed a discrimination power [0.798, 95% confidence interval (95% CI) 0.793-0.803] better than MELD (0.582, 95% CI 0.575-0.588), Child-Turcotte-Pugh (0.687, 95% CI 0.681-0.693), MELD-sodium (0.721, 95% CI 0.715-0.727) and MELD-ascites-sodium (0.729, 95% CI 0.724-0.735), with a remarkable calibration (Hosmer-Lemeshow test: P = 0.91; R(2) = 0.911). Considering all study patients, the risk of wait list dropout increased with the rise in LIRER. The survival benefit analysis comparing the wait list dropout risk with the mortality of the 216 transplanted patients with same LIRER showed an important benefit for LT in patients with LIRER > 15.9., Conclusions: In patients with low MELD (<18), combination of ascites, sodium, albumin, bilirubin and renal function in a new score (LIRER) discriminates patients at high risk of medium-term adverse outcome from those in whom LT may be safely deferred., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The early detection of bacterial infections and hepatocellular carcinoma (HCC) could ameliorate the prognosis of cirrhosis. C-reactive protein and procalcitonin are under investigation in the setting of cirrhosis as markers of sepsis. In the attempt to discriminate bacterial infection from systemic inflammation, the role of novel biomarkers such as lypopolysaccharide binding-protein, mid-regional fragment of pro-adrenomedullin and delta neutrophil index are currently in development. Concerning HCC, many studies attempted to evaluate biomarkers in the hope of ameliorating the accuracy of the surveillance based on ultrasound. The use of α-fetoprotein (AFP) has been extensively investigated, as well as other biomarkers expressed in the serum of HCC patients like lens culinaris agglutinin-reactive fraction of AFP, des-γ-carboxy prothrombin, glypican-3, α-l-fucosidase and their combined use.

Unlabelled: Beside the regulation of fluid distribution, human serum albumin (HSA) carries other activities, such as binding, transport, and detoxification of many molecules. In patients with cirrhosis, HSA exhibits posttranscriptional alterations that likely affect its functions. This study aimed at identifying the structural HSA alterations occurring in cirrhosis and determining their relationship with specific clinical complications and patient survival. One hundred sixty-eight patients with cirrhosis, 35 with stable conditions and 133 hospitalized for acute clinical complications, and 94 healthy controls were enrolled. Posttranscriptional HSA molecular changes were identified and quantified by using a high-performance liquid chromatography/electrospray ionization mass spectrometry technique. Clinical and biochemical parameters were also recorded and hospitalized patients were followed for up to 1 year. Seven HSA isoforms carrying one or more posttranscriptional changes were identified. Altered HSA isoforms were significantly more represented in patients than in healthy controls. Conversely, the native, unchanged HSA isoform was significantly reduced in cirrhosis. Native HSA and most altered isoforms correlated with both Child-Pugh and Model for End-Stage Liver Disease scores. In hospitalized patients, oxidized and N-terminal truncated isoforms were independently associated with ascites, renal impairment, and bacterial infection. Finally, the native HSA and cysteinylated/N-terminal truncated isoforms were predictors of 1-year survival, with greater prognostic accuracy than total serum albumin concentration., Conclusions: Extensive posttranscriptional changes of HSA, involving several molecular sites and increasing in parallel with disease severity, occur in patients with cirrhosis. Altered isoforms are independently associated with specific clinical complications, whereas the residual, native HSA isoform independently predicts patient survival. These findings support the concept of the "effective albumin concentration," which implies that the global HSA function is related not only to its serum concentration, but also to the preservation of its structural integrity., (© 2014 by the American Association for the Study of Liver Diseases.)

Recurrence of hepatitis C virus (HCV) infection following liver transplantation (LT) is almost universal and can accelerate graft cirrhosis in up to 30% of patients. The development of effective strategies to treat or prevent HCV recurrence after LT remains a major challenge, considering the shortage of donor organs and the accelerated progression of HCV in LT recipients. Standard antiviral therapy with pegylated-interferon plus ribavirin is the current treatment of choice for HCV LT recipients, even though the combination is not as effective as it is in immunocompetent patients. A sustained virological response in the setting of LT improves patient and graft survival, but this is only achieved in 30%-45% of patients and the treatment is poorly tolerated. To improve the efficacy of pre- and post-transplant antiviral therapy, a new class of potent direct-acting antiviral agents (DAAs) has been developed. The aim of this review is to summarize the use of DAAs in LT HCV patients. PubMed, Cochrane Library, MEDLINE, EMBASE, Web of Science and clinical trial databases were searched for this purpose. To date, only three clinical studies on the topic have been published and most of the available data are in abstract form. Although a moderately successful early virological response has been reported, DAA treatment regimens were associated with severe toxicity mitigating their potential usefulness. Moreover, the ongoing nature of data, the lack of randomized studies, the small number of enrolled patients and the heterogeneity of these studies make the results largely anecdotal and questionable. In conclusion, large well-designed clinical studies on DAAs in HCV LT patients are required before these drugs can be recommended after transplantation.

Biopharmaceuticals such as antibodies are produced in cultivated mammalian cells, which must be monitored to comply with good manufacturing practice. We, therefore, developed a fully automated system comprising a specific exhaust gas analyzer, inline analytics and a corresponding algorithm to precisely determine the oxygen uptake rate, carbon dioxide evolution rate, carbon dioxide transfer rate, transfer quotient and respiratory quotient without interrupting the ongoing cultivation, in order to assess its reproducibility. The system was verified using chemical simulation experiments and was able to measure the respiratory activity of hybridoma cells and DG44 cells (derived from Chinese hamster ovary cells) with satisfactory results at a minimum viable cell density of ~2.0 × 10(5) cells ml(-1). The system was suitable for both batch and fed-batch cultivations in bubble-aerated and membrane-aerated reactors, with and without the control of pH and dissolved oxygen.

A microfluidic chip integrating amperometric enzyme sensors for the detection of glucose, glutamate and glutamine in cell-culture fermentation processes has been developed. The enzymes glucose oxidase, glutamate oxidase and glutaminase were immobilized by means of cross-linking with glutaraldehyde on platinum thin-film electrodes integrated within a microfluidic channel. The biosensor chip was coupled to a flow-injection analysis system for electrochemical characterization of the sensors. The sensors have been characterized in terms of sensitivity, linear working range and detection limit. The sensitivity evaluated from the respective peak areas was 1.47, 3.68 and 0.28 μAs/mM for the glucose, glutamate and glutamine sensor, respectively. The calibration curves were linear up to a concentration of 20 mM glucose and glutamine and up to 10 mM for glutamate. The lower detection limit amounted to be 0.05 mM for the glucose and glutamate sensor, respectively, and 0.1 mM for the glutamine sensor. Experiments in cell-culture medium have demonstrated a good correlation between the glutamate, glutamine and glucose concentrations measured with the chip-based biosensors in a differential-mode and the commercially available instrumentation. The obtained results demonstrate the feasibility of the realized microfluidic biosensor chip for monitoring of bioprocesses., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background & Aims: QT interval prolongation is frequent in cirrhosis, and stressful conditions could further prolong QT. We aimed to test this hypothesis and, if it proved correct, to assess its prognostic meaning., Methods: We reviewed the clinical records of 70 consecutive cirrhotic and 40 non-cirrhotic patients with acute gastrointestinal bleeding. All patients had been evaluated before bleeding (T0) and were re-evaluated at the time of bleeding (T1) and 6 weeks afterwards (T2)., Results: QT corrected by heart rate (QTc) lengthened at T1, returning towards baseline values at T2 (mean ± SEM; from 415.9 ± 4.3 to 453.4 ± 4.3 to 422.2 ± 5.7 ms, P < 0.001) in cirrhotics; contrariwise, QTc did not change in non-cirrhotic patients. The 6-week mortality was 29.6% among cirrhotic patients, while no control patient died. At T1, patients who died had longer QTc (P = 0.001) and higher model of end-stage liver disease (MELD) score (P < 0.001) than survivors. MELD and QTc independently predicted survival. Their areas under the ROC curve were 0.88 (CI 95% 0.78-0.95) and 0.75 (CI 95% 0.63-0.85) respectively; the best cut-off values were MELD ≥20 and QTc ≥ 460 ms. Based on these factors, the 6-week mortality was: 0% for patients without risk factors, 32.1% for those with one risk factor and 70.6% for those with both (P < 0.001)., Conclusions: Acute gastrointestinal bleeding further prolongs QTc in cirrhosis. This abnormality independently predicts bleeding-induced mortality. The combined measurement of QTc interval and MELD can clearly identify three patient strata at increasing risk of bleeding-related mortality, thus improving the decision-making for these patients., (© 2012 John Wiley & Sons A/S.)

End-stage alcoholic liver disease is a recognised indication for liver transplantation but some questions on the matter remain open. It is difficult to quantify alcohol consumption, and a single definition of post-transplant relapse is lacking. Moreover, there are no internationally accepted criteria for the selection of candidates for liver transplantation and the eligibility parameters for these patients are controversial. Additional clinical and psychological evaluations are necessary in this setting, especially to establish the risk of alcohol relapse. Nevertheless, patient and graft survival rates after liver transplantation in alcoholic liver disease are comparable to those after transplant for other aetiologies, alcohol consumption relapse being one of the most important problems in the post-transplant phase. In conclusion, alcohol-related liver disease is a good indication for liver transplantation. The main future goals are to formulate a well-defined pre-transplant approach and a single definition of alcohol relapse and to improve prevention strategies., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Adoption of the Model for End-stage Liver Disease (MELD) to select and prioritize patients for liver transplantation represented a turning point in organ allocation. Prioritization of transplant recipients switched from time accrued on the waiting list to the principle of "sickest first". The MELD score incorporates three simple laboratory parameters (serum creatinine and bilirubin, and INR for prothrombin time) and stratifies patients according to their disease severity in an objective and continuous ranking scale. Concordance statistics have demonstrated its high accuracy in stratifying patients according to their risk of dying in the short-term (three months). Further validations of MELD as a predictor of survival at various temporal end-points have been obtained in independent patient cohorts with a broad spectrum of chronic liver disease. The MELD-based liver graft allocation policy has led to a reduction in waitlist new registrations and mortality, shorter waiting times, and an increase in transplants, without altering overall graft and patient survival rates after transplantation. MELD limitations are related either to the inter-laboratory variability of the parameters included in the score, or to the inability of the formula to predict mortality accurately in specific settings. For some conditions, such as hepatocellular carcinoma, widely accepted MELD corrections have been devised. For others, such as persistent ascites and hyponatremia, attempts to improve MELD's predicting power are currently underway, but await definite validation., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Many prognostic systems have been devised to predict the outcome of liver transplantation (LT) candidates. Today, the Model for End-Stage Liver Disease (MELD) is widely used for organ allocation, but it has shown some limitations. The aim of this study was to investigate the performance of MELD compared to 5 different score models. We evaluated the prognostic ability of MELD, modified Child-Turcotte-Pugh, MELD-sodium, United Kingdom MELD, updated MELD, and integrated MELD in 487 candidates with cirrhosis for LT at the Bologna Transplant Centre, Bologna, Italy, between 2003 and 2008. Calibration analysis by Hosmer-Lemeshow test, calibration curves, and concordance c-statistics (area under the receiver operating characteristic curve [AUC]) were calculated at 3, 6, and 12 months. Actual cumulative survival curves, taking into account the event of interest in the presence of competing risk, were obtained using the best cutoffs identified by AUC. For each score, the Hosmer-Lemeshow test revealed a good calibration. Integrated MELD showed calibration curves closer to the line of perfect predicting ability, followed by MELD-sodium at 3 months and modified Child-Turcotte-Pugh at 6 months. MELD-sodium AUCs at 3 and 6 months (0.798 and 0.765, respectively) and integrated MELD AUC at 6 months (0.792) were better than standard MELD (P < 0.05). Actual survival curves showed that these 2 scores were able to identify the patients with the highest drop-out risk. In conclusion, MELD-sodium and integrated MELD were the best prognostic models to predict drop-out rates among patients awaiting LT., ((c) 2010 AASLD.)