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Background & Aims: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal ablation during the waiting phase. The DS involves postponing LT until recurrence. The purpose of this study was to evaluate the DS to make sure that it did not hamper pre- and post-LT outcomes., Methods: Patients listed for HCC in France between 2015 and 2018 were studied. After data extraction from the national LT database, 2,025 patients were identified and classified according to six groups: single tumor entering DS, single tumor not entering DS, multiple tumors, no curative treatment, untreatable HCC or T1 tumors. Kaplan-Meier estimates of the 18-month risk of dropout for death, too sick to be transplanted or tumor progression before LT, 5-year post-LT HCC recurrence and post-LT survival rates were compared., Results: Median waiting-time in the DS group was 910 days. Pre-LT dropout probability was significantly lower in the DS group compared to other groups (13% vs. 19%, p = 0.0043) and significantly higher in the T1 group (25.4%, p = 0.05). Post-LT HCC recurrence rate in the multiple nodules group was significantly higher (19.6%, p = 0.019), while 5-year post-LT survival did not differ among groups and was 74% in the DS group (p = 0.22)., Conclusion: The DELTA-HCC study shows that DS does not negatively impact either pre- nor post-LT patient outcomes, and has the potential to allow for redistribution of organs to patients in more urgent need of LT. It can reasonably be proposed and pursued. The unexpectedly high risk of dropout in T1 patients seems related to the MELD-based offering rules underserving this subgroup., Impacts and Implications: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy was adopted in France in 2015. It involves postponing LT until recurrence in patients listed for any single HCC curatively treated by surgical resection or thermal ablation. The DELTA-HCC study was conducted to evaluate this nationwide strategy. It shows in a European LT program that delayed strategy does not negatively impact pre- nor post-LT patient outcomes and is relevant to up to 20% of LT candidates; thus, it could potentially enable the redistribution of organs to patients in more urgent need of LT. Such a delayed strategy can reasonably be pursued and extended to other LT programs. Of note, an unexpectedly high risk of dropout in T1 patients, seemingly related to MELD-based offering rules which underserve these patients, calls for further scrutinization and revision of allocation rules in this subgroup., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated., Methods: This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200 μmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3 = (D3-D0)/D0., Results: A total of 128 patients were included, with a median age of 52 (39-62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23-21.06; p <0.001), Δ%3-INR ≥0.1% (OR 6.97; 95% CI 1.59-30.46; p <0.01) and Δ%3-bilirubin ≥-8% (OR 5.14; 95% CI 1.09-24.28; p <0.04) were predictive of a non-response. The SURFASA score: -6.80+1.92∗(D0-INR)+1.94∗(Δ%3-INR)+1.64∗(Δ%3-bilirubin), created by combining these variables, was highly predictive of LT or death (AUC = 0.93) (88% specificity; 84% sensitivity) with a cut-off point of <-0.9. Below this cut-off, the chance of responding was 75%. With a score higher than 1.75, the risk of dying or being transplanted was between 85% and 100%., Conclusion: In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort., Lay Summary: The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required., Competing Interests: Conflict of interest EDM: nothing to disclose, AC: nothing to disclose, OC: nothing to disclose, OR: nothing to disclose, JMP: nothing to disclose, PHD: nothing to disclose, FA: nothing to disclose, CS: nothing to disclose, IOH: nothing to disclose, CD: nothing to disclose, AHB: nothing to disclose, SB: nothing to disclose, NG: nothing to disclose, GPP: nothing to disclose, CB: nothing to disclose, MB: nothing to disclose, HF: nothing to disclose, VdL: nothing to disclose, JD: nothing to disclose, FC: nothing to disclose, SR: nothing to disclose, MDG: nothing to disclose, OG: nothing to disclose, FD: nothing to disclose, PP: nothing to disclose, VDM: nothing to disclose, NR: nothing to disclose, PI: nothing to disclose, MS: nothing to disclose, PM: nothing to disclose, HA: nothing to disclose, DS: nothing to disclose, JCDV: nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status., Methods: Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n = 668 enrolled between 08/2012-01/2014)., Results: Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF]., Conclusions: Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs., Lay Summary: Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction., Competing Interests: Conflict of interest Dr. Nahon has received honoraria from and/or consults for Abbvie, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Gilead, Ipsen, MSD, Roche. He received research grants from Abbvie and Bristol-Myers Squibb. Dr. Pol consults for and has received grants from Bristol-Myers Squibb, Gilead, Roche, and MSD. He consults for Gilead, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Abbvie, Roche and MSD. Dr. Guyader has received honoraria and/or grants from Abbvie, Gilead, Janssen and MSD. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis C virus (HCV) infection is associated with reduced patient survival following combined liver-kidney transplantation (LKT). The aim of this study was to assess the efficacy and safety of second-generation direct-acting antivirals (DAAs) in this difficult-to-treat population. The ANRS CO23 "Compassionate use of Protease Inhibitors in Viral C Liver Transplantation" (CUPILT) study is a prospective cohort including transplant recipients with recurrent HCV infection treated with DAAs. The present work focused on recipients with recurrent infection following LKT. The study population included 23 patients. All patients received at least one NS5B inhibitor (sofosbuvir) in their antiviral regimen an average of 90 months after LKT. Ninety-six percent of recipients achieved a sustained virological response (SVR) at week 12 (SVR12). In terms of tolerance, 39% of recipients presented with at least one serious adverse event. None of the patients experienced acute rejection during therapy and there were no deaths during follow-up. The glomerular filtration rate (GFR) decreased significantly from baseline to the end of therapy. However, this study did not show that the decline in GFR persisted over time or that it was directly related to DAAs. The DAA-based regimen is well tolerated with excellent results in terms of efficacy. It will become the gold standard for the treatment of recurrent HCV following LKT., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

This study investigated the trace element bioaccumulation capacity of the Mediterranean seagrass Posidonia oceanica, and its suitability as a bioindicator of contamination in water and sediments. Results showed that P. oceanica leaves accumulate higher concentrations of Ni and Zn. Since P. oceanica regenerates its leaves periodically, the higher concentrations in aerial organs may suggest a "removal" strategy according to which P. oceanica accumulates greater concentrations of trace elements in its temporary organs. In turn, P. oceanica seems to adopt an exclusion strategy for toxic non-essential elements (As, Cr, Pb). Results showed also that P. oceanica organs are correlated with As, Cd, Cu, Ni, and Zn concentrations in sediments. No significant relationship was found between P. oceanica and water. This study showed that P. oceanica may adopt different tolerance strategies compared to mainland-rooted macrophytes, and its possible use as a bioindicator of trace elements in sediments should be considered., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The present study investigated the levels of As, Cd, Cr, Cu, Hg, Mn, Ni, Pb and Zn in the seagrasses Posidonia oceanica and Cymodocea nodosa, and in the wetland macrophytes Phragmites australis, Arundo donax, Typha domingensis, Apium nodiflorum, and Nasturtium officinale. Results showed that the bioaccumulation capacity from sediments, translocation, total levels in plant tissues, and bioindication of metals in sediments, are generally species-specific. In particular, the patterns of metals in the aquatic plants studied were overall independent of ecology (coasts vs wetlands), biomass, anatomy (rhizomatous vs non rhizomatous plants), and life form (hemicrytophytes vs hydrophytes). However, marine phanerogams and wetland macrophytes shared some characteristics such as high levels of heavy metals in their below-ground organs, similar capacity of element translocation in the rhizosphere, compartmentalization of metals in the different plant organs, and potential as bioindicators of Cu, Mn and Zn levels in the substratum. In particular, the present findings indicate that, despite ecological and morphological similarities, different plant species tend to respond differently to exposure to heavy metals. Furthermore, this seems to result from the species individual ability to accumulate and detoxify the various metals rather than being attributed to differences in their ecological and morpho-anatomical characteristics., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background & Aims: HCV recurrence remains a major issue in the liver transplant field, as it has a negative impact on both graft and patient survival. The purpose of this study was to investigate the efficacy and safety of treating HCV recurrence with sofosbuvir (SOF) and daclatasvir (DCV) combination therapy., Methods: From October 2013 to March 2015, 559 liver recipients were enrolled in the prospective multicentre France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) Compassionate use of Protease Inhibitors in viral C Liver Transplantation cohort. We selected 137 patients with an HCV recurrence receiving SOF and DCV, whatever the genotype or fibrosis stage. The use of ribavirin and the duration of therapy were at the investigator's discretion. The primary efficacy end point was a sustained virological response (SVR) 12weeks after the end of treatment., Results: The SVR rate 12weeks after completing treatment was 96% under the intention-to treat analysis and 99% when excluding non-virological failures. Only two patients experienced a virological failure. The serious adverse event (SAE) rate reached 17.5%. Four patients (3%) stopped their treatment prematurely because of SAEs. Anaemia was the most common AE, with significantly more cases in the ribavirin group (56% vs. 18%; p<0.0001). A slight but significant reduction in creatinine clearance was reported. No clinically relevant drug-drug interactions were noted, but 52% of patients required a change to the dosage of immunosuppressive drugs., Conclusions: Treatment with SOF plus DCV was associated with a high SVR12 and low rates of serious adverse events among liver recipients with HCV recurrence., Lay Summary: The recurrence of hepatitis C used to be the first cause of graft failure in infected liver transplanted recipients. Our study demonstrates the great efficacy of one combination of new all-oral direct-acting antiviral, sofosbuvir and daclatasvir, to treat the recurrence of hepatitis C on the graft. Ninety-six per cent of recipients were cured. The safety profile of this combination seemed to be good, especially no relevant drug-drug interaction with immunosuppressive drugs., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Adrenal dysfunction is frequently reported in severe acute hepatitis using serum total cortisol., Aims: Because 90% of serum cortisol is bound to proteins that are altered during stress, we investigated the effect of decreased cortisol-binding proteins on serum total and free cortisol in severe acute hepatitis., Methods: 43 severe and 31 non-severe acute hepatitis and 29 healthy controls were enrolled consecutively and studied prospectively. Baseline (T0) and cosyntropin-stimulated (T60) serum total and free cortisol concentrations were measured., Results: T0 and T60 serum total cortisol did not differ significantly between severe, non-severe hepatitis and healthy controls. Conversely, serum free cortisol (T0p=0.012; T60p<0.001) concentrations increased from healthy controls to severe hepatitis, accompanied by a decrease in corticosteroid-binding globulin and albumin (all p<0.001). In acute hepatitis (n=74), patients with "low" corticosteroid-binding globulin (<28mg/L) had higher T0 serum free cortisol than others (103.1 [61.2-157] vs. 56.6 [43.6-81.9]nmol/L, p=0.0024). Analysis of covariance showed that at equal concentration of total cortisol, the free cortisol concentration was significantly higher in severe than in non-severe hepatitis (p<0.001) or healthy controls (p<0.001)., Conclusions: In severe hepatitis, the decrease in cortisol-binding proteins impairs correct diagnosis of adrenal dysfunction. This could be corrected by measuring or estimating free cortisol., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Mortality related to hepatitis B virus (HBV) is not well known in developed countries. The aim of this study was to investigate in a population-based cohort the excess risk of death in HBV patients compared with mortality in the general population and to identify risk factors related to all-cause mortality and HBV-related mortality., Methods: A specialized population-based registry has recorded data from patients with chronic HBV infection in a population of one million inhabitants in France since 1994. Standardized mortality rates for all-cause death and HBV-related death were calculated. Cumulative mortality rates were calculated using the Kaplan-Meier method. Multivariate analysis was performed using a Cox model., Results: Between 1994 and 2009, 1117 people were diagnosed with chronic HBV infection. Of these 136 (12.2%) died. All-cause mortality was significantly higher in HBV-infected people (standardized mortality ratio (SMR) 1.7 [1.4-2.0]). There was substantial excess mortality due to hepatocellular carcinoma (SMR 15.9 [10-24.1]), non-Hodgkin lymphoma (SMR 8.6 [3.1-18.6]) and liver disease (SMR 10.2 [5.8-16.6]). The cumulative rates for all-cause mortality were 8.6% at 5 years, 12.6% at 10 years and 18.5% at 15 years. The corresponding values for HBV-related mortality were 3.5%, 4.2%, and 5.8%. The multivariate analysis for all-cause mortality and for HBV-related mortality showed that male sex, age over 45 at diagnosis, current alcoholism and nosocomial risk factors were predictors of increased mortality., Conclusion: This study shows increased all-cause mortality in HBsAg-positive patients, with considerable excess mortality due to chronic liver disease, hepatocellular carcinoma and non-Hodgkin lymphoma., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Albumin infusion improves renal function and survival in cirrhotic patients with spontaneous bacterial peritonitis (SBP) but its efficacy in other types of infections remains unknown. We investigated this issue through a multicenter randomized controlled trial., Methods: A total of 193 cirrhotic patients with a Child-Pugh score greater than 8 and sepsis unrelated to SBP were randomly assigned to receive antibiotics plus albumin (1.5 g/kg on day 1 and 1g/kg on day 3; albumin group [ALB]: n=96) or antibiotics alone (control group [CG]: n=97). The primary endpoint was the 3-month renal failure rate (increase in creatinine ⩾50% to reach a final value ⩾133 μmol/L). The secondary endpoint was 3-month survival rate., Results: Forty-seven (24.6%) patients died (ALB: n=27 vs. CG: n=20; 3-month survival: 70.2% vs. 78.3%; p=0.16). Albumin infusion delayed the occurrence of renal failure (mean time to onset, ALB: 29.0 ± 21.8 vs. 11.7 ± 9.1 days, p=0.018) but the 3-month renal failure rate was similar (ALB: 14.3% vs. CG: 13.5%; p=0.88). By multivariate analysis, MELD score (p<0.0001), pneumonia (p=0.0041), hyponatremia (p=0.031) and occurrence of renal failure (p<0.0001) were predictors of death. Of note, pulmonary edema developed in 8/96 (8.3%) patients in the albumin group of whom two died, one on the day and the other on day 33 following albumin infusion., Conclusions: In cirrhotic patients with infections other than SBP, albumin infusion delayed onset of renal failure but did not improve renal function or survival at 3 months. Infusion of large amounts of albumin should be cautiously administered in the sickest cirrhotic patients., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme., Methods: 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16., Results: A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high., Conclusions: The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy., (Copyright © 2013. Published by Elsevier B.V.)

Background & Aims: We aimed at improving prediction of short-term mortality in cirrhotic inpatients by evaluating C-reactive protein (CRP) as a surrogate marker of systemic inflammatory response syndrome (SIRS)., Methods: One-hundred and forty-eight consecutive cirrhotic patients with Child-Pugh score ≥ B8 and without hepatocellular carcinoma were prospectively included and followed for 182 days. The primary end point was 6-month survival., Results: Main baseline characteristics were as follows: alcoholic liver disease in 88.5%; bacterial infection in 37%; hepatorenal syndrome in 7% of cases. CRP range was 1-240 mg/L (median 26 mg/L); 42 patients (28.4%) had SIRS as defined by ACCP/SCCM-criteria. CRP levels were higher in patients with SIRS (50 vs. 21 mg/L; p<0.0001), infection (46 vs. 27 mg/L; p<0.0001), and alcoholic hepatitis (44 vs. 32 mg/L, p=0.049). Forty-two patients died within the first 6 months of follow-up. Short-term mortality was associated with extrahepatic co-morbidities (p=0.002), high MELD score (p<0.001; AUROC=0.67), renal failure (p=0.008), elevated blood lactates (p<0.001), and high baseline CRP levels (p=0.003; AUROC=0.63; best cut-off value at 29 mg/L). Among patients with baseline CRP ≥ 29 mg/L, 32 still had CRP ≥ 29 mg/L at day 15 (group A). Group A was associated with 6-month mortality in the overall population (p<0.001) and also through sensitivity analyses restricted to patients without infection or alcoholic hepatitis. Multivariate analysis (Cox) adjusted for age identified three predictors of mortality: high MELD score (HR=1.08; 95% CI: 1.03-1.12; p<0.001), extrahepatic co-morbidities (HR=2.51; 95% CI: 1.31-4.84; p=0.006), and CRP level (group A) (HR=2.73; 95% CI: 1.41-5.26; p=0.003). The performance of the three variables taken together for predicting death was 0.80 (AUROC)., Conclusions: In Child-Pugh score ≥ B8 cirrhotic patients, persistent CRP levels ≥ 29 mg/L predicted short-term mortality independently of age, MELD, and co-morbidities, and better than infection or clinically-assessed SIRS., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Ribavirin remains today a pivotal drug in the treatment of hepatitis C; in standard double therapy, as well as in triple combination with direct antiviral agents, ribavirin reduces relapse and can double the sustained virological response obtained with peginterferon alone or in association with direct antiviral agents. In the complex network of interacting factors determining sustained virological response independently of known predictive factors related to host and virus, two modern tools are emerging: polymorphisms in the IL28B gene and very early exposure to ribavirin. The use of a pharmacokinetic-pharmacodynamic model of early ribavirin exposure to adjust the dose individually would help promote a safer ribavirin use and improve sustained virological response. The variability of the influence of ribavirin exposure on anaemia is probably genetically determined; however, the low prevalence of the implicated protective alleles of the inosine triphosphate pyrophosphatase gene could explain their lack of influence on sustained virological response., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The present study aimed to identify a sub-group of inoperable alveolar echinococcosis (AE) patients undergoing long-term treatment with benzimidazole (BZM) who presented with an evolution suggestive of a parasitocidal effect. An evolution compatible with parasite death was observed in five patients.

Background/aims: In France, geographic access to medical care may affect the diagnosis of hepatitis C. The aims of this study were to compare the detection rates of hepatitis C in urban and rural areas after adjusting for distance to medical care, and evaluating the impact of the place of residence on patients' clinical characteristics., Methods: Between 1994 and 2001, 1938 newly detected cases were recorded in a French population of 1,005,817 inhabitants. Age and sex-adjusted detection rates for 10(5) inhabitants were estimated for urban and rural areas and for classes of distance to the nearest practitioner., Results: Detection rates were lower in rural than in urban areas [14.1, (95CI: 12.5-15.7) versus 24.7, (95CI: 23.5-26.0)] and decreased as the distance to the general practitioner increased [27.0, (95CI: 25.5-28.4) versus 13.7, (95CI: 12.1-15.3) for a cutoff value of 1.5 km]. In multivariate analyses, detection rates were only influenced by the distance to general practitioner. Hepatocellular carcinoma at diagnosis was more frequent among rural than among urban patients (adjusted OR = 2.28, 95CI: 0.97-5.39, P = 0.059)., Conclusions: A poorer geographic access to care explained the lower detection of hepatitis C in rural areas. Hepatocellular carcinoma was more frequent in rural patients. It may result from later detection and/or involvement of environmental factors on hepatocarcinogenesis.

Mucous macro-aggregates of both pelagic and benthic origin are recurrently observed in the meadows formed by the seagrass Posidonia oceanica around the island of Ischia (Gulf of Naples, Italy). In the past two decades, major events occurred in 1991, 1993 and 2000, when a thick layer of mucilage covered vast areas of the meadows. To investigate the environmental triggers for mucilage formation and the effects of macro-aggregates on the functional and structural status of P. oceanica, a number of abiotic and biotic parameters were monitored over three years within the frame of a research project on Adriatic and Tyrrhenian mucilages (MAT). Basic environmental parameters (salinity, temperature, irradiance, dissolved oxygen concentration) in the water column and inorganic nutrient concentrations above and within P. oceanica meadows were measured. As descriptors of the status of the seagrass, shoot density and the nitrogen content of the leaves were monitored. Moreover, a reconstructive technique (lepidochronology) was employed to track back annual plant production. During the three-year study, mucous aggregates produced by benthic algae were observed in spring-summer and a major event of macro-aggregates of pelagic origin affecting P. oceanica canopy was observed in autumn 2000. Each of these episodes was observed for a few weeks to one month. We hypothesize nutrient limitation to explain the short duration of the benthic algal blooms that were responsible of macroaggregate formation; a highly dynamic circulation resulted in the dispersion of the pelagic aggregates deposited on the meadows. None of the descriptors of the structure of the meadow and of plant performance showed any obvious alterations in relation to the occurrence of mucilage coverage. Presumably, the short duration of the mucilage episodes recorded were not enough to induce such alterations, at least at the temporal and spatial scales considered.

Background Aims: Liver biopsy is the gold standard for assessing hepatitis B virus (HBV)-related histology. The aim was to determine the diagnostic utility of noninvasive serum markers in patients with chronic hepatitis B., Methods: The aminotransferases and indices including alpha(2)-macroglobulin, apolipoprotein A1, haptoglobin, gamma-glutamyl-transpeptidase (GGT), and total bilirubin (Fibrotest), and ALT (Actitest) were compared with liver histology. The primary outcomes were A2-A3 activity and F2-F4 fibrosis (METAVIR)., Results: Two hundred and nine patients were included. Forty-one patients (20%) had A2-A3 activity and 61 (29%) had F2-F4 fibrosis. AST and GGT (P<0.001) were independently associated with A2-A3 activity. AST, ALT, and Actitest accurately predicted activity ((areas under receiver operating characteristic (ROC) curves (AUROC), 0.81-0.82+/-0.04)); an AST or ALT< or =30IU/l excluded significant activity with 96% certainty. Fibrotest accurately predicted F2-F4 fibrosis (AUROC, 0.78+/-0.04). Fibrotest scores (range, 0-1.0) < or =0.20 and >0.80 had negative and positive predictive values of 92%, respectively. Restricting biopsy to patients with intermediate scores (>0.20 and < or =0.80) may prevent liver biopsies in 46% of patients while maintaining 92% accuracy., Conclusions: The aminotransferases and an index including five biochemical markers are accurate noninvasive markers of HBV-related activity and fibrosis, respectively.

Background/aims: The prevalence and risks factors of bacteriuria in cirrhotics have not been assessed by case-control study, and there are conflicting data concerning the role of liver failure and of ascites. The aims of this study were: i) to evaluate the prevalence of bacteriuria in cirrhotics, ii) to search for associated factors, iii) to evaluate the role of bladder post-void residual volume, and iv) to test the sensitivity of isolated bacteria to norfloxacin., Methods: The prevalence and risk factors of bacteriuria on admission were determined by a multicenter prospective case-control study., Results: Two hundred and forty-four cirrhotic patients and 240 controls were studied. Bacteriuria was present in 38 patients (15.6%; IC 5%: 11%-20%) and 18 controls (7.5%; IC 5%: 4.2%-11%; p<0.001). By univariate analysis, female sex and ongoing diuretic treatment were associated with bacteriuria (p<0.0001 and p<0.04, respectively). Pugh's grade, ascites and bladder residual volume were not associated with bacteriuria. By multivariate analysis, female sex (p<0.0001) and Child-Pugh score (p<0.03) were predictors of bacteriuria. Sensitivity of bacteria to norfloxacin was observed in 94.7%; sterile urine cultures were noted in 95.2% of patients treated with this antibiotic., Conclusion: Bacteriuria is twice as frequent in cirrhotic patients as in matched controls, and there is a trend to association with female sex and liver insufficiency.

Chemostat cultures of the unicellular alga Cyanidium caldarium have shown that under conditions of phosphate limitation nitrate reductase is completely derepressed even in cells growing in a large excess of ammonium, but that it occurs mainly in a catalytically inactive form. It is hypothesized that phosphate limitation contributes to maintaining intracellular level of glutamine suitable to stimulate inactivation but not repression of nitrate reductase. It is not excluded that in addition to variations in the intracellular level of glutamine, there are other metabolic events of the cell by which repression and inactivation of nitrate reductase could be differently influenced.