Search

Non‐invasive methods have largely replaced biopsy to identify advanced fibrosis in hepatitis C virus (HCV). Guidelines vary regarding testing strategy to balance accuracy, costs and loss to follow‐up. Although individual test characteristics are well‐described, data comparing the accuracy of using two tests together are limited. We calculated combined test characteristics to determine the utility of combined strategies. This study synthesizes empirical data from fibrosis staging trials and the literature to estimate test characteristics for Fibrosis‐4 (FIB4), APRI or a commercial serum panel (FibroSure®), followed by transient elastography (TE) or FibroSure®. We simulated two testing strategies: (1) second test only for those with intermediate first test results (staged approach), and (2) second test for all. We summarized empiric data with multinomial distributions and used this to estimate test characteristics of each strategy on a simulated population of 10,000 individuals with 4.2% cirrhosis prevalence. Negative predictive value (NPV) for cirrhosis from a single test ranged from 98.2% (95% CB 97.6–98.8%) for FIB‐4 to 99.4% (95% CB 99.0–99.8%) for TE. Using a staged approach with TE second, sensitivity for cirrhosis rose to 93.3–96.9%, NPV to 99.7–99.8%, while PPV dropped to <32%. Using TE as a second test for all minimally changed estimated test characteristics compared with the staged approach. Combining two non‐invasive fibrosis tests barely improves NPV and decreases or does not change PPV compared with a single test, challenging the utility of serial testing modalities. These calculated combined test characteristics can inform best methods to identify advanced fibrosis in various populations. [ABSTRACT FROM AUTHOR]

Summary: Background: No prospective diagnostic studies have directly compared widespread non‐invasive liver tests in patients with type 2 diabetes (T2D) using the intention‐to‐diagnose method for each of the three main histological features of metabolic dysfunction associated steatotic liver disease ‐ namely fibrosis, metabolic dysfunction‐associated steatohepatitis (MASH), and steatosis. Aims: To compare the performance of nine tests using the intention‐to‐diagnose rather than the standard method, which would exclude non‐evaluable participants Methods: Biopsy was used as the reference with predetermined cut‐offs, advanced fibrosis being the main endpoint. The Nash‐FibroTest panel including FibroTest‐T2D, SteatoTest‐T2D and MashTest‐T2D was optimised for type 2 diabetes. FibroTest‐T2D was compared to vibration‐controlled transient elastography stiffness (VCTE), two‐dimensional shear‐wave elastography stiffness (TD‐SWE), and Fibrosis‐4 blood test. NashTest‐T2D was compared to aspartate aminotransferase. SteatoTest‐T2D was compared to the controlled attenuation parameter and the hepatorenal gradient. Results: Among 402 cases, non‐evaluable tests were 6.7% for VCTE, 4.0% for hepatorenal gradient, 3.2% for controlled attenuation parameter, 1.5% for TD‐SWE, 1.2% for NashTest‐T2D, and 0.02% for Fibrosis‐4, aspartate aminotransferase and SteatoTest‐T2D. The VCTE AUROC for advanced fibrosis was over‐estimated by 6% (0.83 [95% CI: 0.78–0.87]) by standard analysis compared to intention‐to‐diagnose (0.77 [0.72–0.81] p = 0.008). The AUROCs for advanced fibrosis did not differ significantly in intention‐to‐diagnose between FibroTest‐T2D (0.77; 95% CI: 0.73–0.82), VCTE (0.77; 95% CI: 0.72–0.81) and TD‐SWE(0.78; 0.74–0.83) but were all higher than the Fibrosis‐4 score (0.70; 95% CI all differences ≥7%; p ≤ 0.03). For MASH, MashTest‐T2D had a higher AUROC (0.76; 95% CI: 0.70–0.80) than aspartate aminotransferase (0.72; 95% CI: 0.66–0.77; p = 0.035). For steatosis, AUROCs did not differ significantly between SteatoTest‐T2D, controlled attenuation parameter and hepatorenal gradient. Conclusions: In intention‐to‐diagnose analysis, FibroTest‐T2D, TD‐SWE and VCTE performed similarly for staging fibrosis, and out‐performed Fibrosis‐4 in outpatients with type 2 diabetes. The standard analysis over‐estimated VCTE performance. ClinicalTrial.gov: NCT03634098. [ABSTRACT FROM AUTHOR]

In 2016, the Hepatitis B and C Public Policy Association (HepBCPPA), gathered all the main stakeholders in the field of hepatitis C virus (HCV) to launch the now landmark HCV Elimination Manifesto, calling for the elimination of HCV in the EU by 2030. Since then, many European countries have made progress towards HCV elimination. Multiple programmes—from the municipality level to the EU level—were launched, resulting in an overall decrease in viremic HCV infections and liver‐related mortality. However, as of 2021, most countries are not on track to reach the 2030 HCV elimination targets set by the WHO. Moreover, the COVID‐19 pandemic has resulted in a decrease in HCV diagnoses and fewer direct‐acting antiviral treatment initiations in 2020. Diagnostic and therapeutic tools to easily diagnose and treat chronic HCV infection are now well established. Treating all patients with chronic HCV infection is more cost‐saving than treating and caring for patients with liver‐related complications, decompensated cirrhosis or hepatocellular carcinoma. It is more important than ever to reinforce and scale‐up action towards HCV elimination. Yet, efforts urgently need the dedicated commitment of policymakers at all governmental and policy levels. Therefore, the third EU Policy Summit, held in March 2021, featured EU parliamentarians and other key decision makers to promote dialogue and take strides towards securing wider EU commitment to advance and achieve HCV elimination by 2030. We have summarized the key action points and reported the 'Call‐to‐Action' statement supported by all the major relevant European associations in the field. [ABSTRACT FROM AUTHOR]

We report a neonate with severe Marfan syndrome (MS), prenatally identified to have persistent atrial tachycardia, biventricular dysfunction, and an unusual structure within the atria. Detailed postnatal echocardiographic evaluation and cross‐sectional imaging confirmed congenital pseudoaneurysm of the mitral‐aortic intervalvular fibrosa. Emergent testing by next‐generation sequencing identified a FBN1 pathological variant, key to establishing goals of care. To our knowledge, this is the first reported case of a congenital pseudoaneurysm of the mitral‐aortic intervalvular fibrosa in MS. [ABSTRACT FROM AUTHOR]

Background and aims: Non‐alcoholic steatohepatitis (NASH) is a chronic disease that can progress to end‐stage liver disease (ESLD). A large proportion of early‐stage NASH patients remain undiagnosed compared to those with advanced fibrosis, who are more likely to receive disease management interventions. This study estimated the disease burden and economic impact of diagnosed NASH in the adult population of France, Germany, Italy, Spain and the United Kingdom in 2018. Methods: The socioeconomic burden of diagnosed NASH was estimated using cost‐of‐illness methodology applying a prevalence approach to estimate the number of adults with NASH and the attributable economic and wellbeing costs. Given undiagnosed patients do not incur costs in the study, the probability of diagnosis is central to cost estimation. The analysis was based on a literature review, databases and consultation with clinical experts, economists and patient groups. Results: The proportion of adult NASH patients with a diagnosis ranged from 11.9% to 12.7% across countries, which increased to 38.8%‐39.1% for advanced fibrosis (F3‐F4 compensated cirrhosis). Total economic costs were €8548‐19 546M. Of these, health system costs were €619‐1292M. Total wellbeing costs were €41 536‐90 379M. The majority of the undiagnosed population (87.3%‐88.2% of total prevalence) was found to have early‐stage NASH, which, left untreated, may progress to more resource consuming ESLD over time. Conclusions: This study found that the majority of economic and wellbeing costs of NASH are experienced in late disease stages. Earlier diagnosis and care of NASH patients could reduce future healthcare costs. [ABSTRACT FROM AUTHOR]

Background & Aims: Liver stiffness measured with 2‐dimensional shear wave elastography by Supersonic Imagine (2DSWE‐SSI) is well‐established for fibrosis diagnostics, but non‐conclusive for portal hypertension. Methods: We performed an individual patient data meta‐analysis of 2DSWE‐SSI to identify clinically significant portal hypertension (CSPH), severe portal hypertension and large varices in cirrhosis patients, using hepatic venous pressure gradient and upper endoscopy as reference. We used meta‐analytical integration of diagnostic accuracies with optimized rule‐out (sensitivity‐90%) and rule‐in (specificity‐90%) cut‐offs. Results: Five studies from seven centres shared data on 519 patients. After exclusion, we included 328 patients. Eighty‐nine (27%) were compensated and 286 (87%) had CSPH. 2DSWE‐SSI < 14 kPa ruled out CSPH with a summary AUROC (sROC), sensitivity and specificity of 0.88, 91% and 37%, and correctly classified 85% of patients, with minimal between‐study heterogeneity. The false negative rate was 60%, of which decompensated patients accounted for 78%. 2DSWE‐SSI ≥ 32 kPa ruled in CSPH with sROC, sensitivity, specificity and correct classifications of 0.83, 47%, 89% and 55%. In a subgroup analysis, the 14 kPa cut‐off showed consistent sensitivity and higher specificity for patients with compensated cirrhosis, without ascites, viral aetiology or BMI < 25 kg/m2. 2DSWE‐SSI ruled out severe portal hypertension and large varices with fewer correctly classified and lower sROC, and with minimal benefit for ruling in. Conclusion: Liver stiffness using 2‐dimensional shear wave elastography below 14 kPa may be used to rule out clinically significant portal hypertension in cirrhosis patients, but this would need validation in populations of compensated liver disease. 2DSWE‐SSI cannot predict varices needing treatment. [ABSTRACT FROM AUTHOR]

Despite affecting around one‐fourth of the general population worldwide, non‐alcoholic fatty liver disease (NAFLD) remains a largely under‐recognized disease in primary healthcare, with not more than 10% of patients diagnosed with NAFLD referred to specialists. The main challenge in clinical practice is the identification of those with advanced liver fibrosis or cirrhosis, as they are at the greatest risk of developing complications. Liver biopsy appears to be an unrealistic and unsuitable option because of the large number of high‐risk patients and the well‐known limitations of this technique. This has favoured the development of non‐invasive tests, which have been an area of intensive research in the past decade. Transient elastography, FIB‐4 and the NAFLD fibrosis score are the most extensively used and best validated tests, with summary AUROC values for detecting advanced fibrosis in NAFLD patients of 0.88, 0.84 and 0.84 respectively. Although much work remains to be done to establish cost‐effective strategies for the screening for advanced fibrosis, the sequential use of non‐invasive tests (serum biomarkers, then measurement of liver stiffness using transient elastography) appears to be the most promising strategy. The next step is to establish effective pathways in primary healthcare and/or diabetes clinics where most NAFLD patients are seen, to identify those who need to be referred to liver clinics for further assessment. [ABSTRACT FROM AUTHOR]

Summary: Background: Two algorithms based on sequential measurements of liver and spleen stiffness using two‐dimensional shearwave elastography (2D‐SWE) have been recently proposed to estimate clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] ≥10 mm Hg) in patients with cirrhosis, with excellent diagnostic accuracy. Aim: To validate externally these algorithms in a large cohort of patients with cirrhosis. Methods: One hundred and ninety‐one patients with stable cirrhosis (Child‐Pugh class A 39%, B 29% and C 31%) who underwent liver and spleen stiffness measurements using 2D‐SWE at the time of HVPG measurement were included. Diagnostic accuracy of the 2 algorithms was assessed by calculating sensitivity, specificity, positive and negative predictive values. Results: The first algorithm, using liver stiffness <16.0 kilopascals (kPa) and then spleen stiffness <26.6 kPa, was used to rule‐out HVPG ≥10 mm Hg. In our population, its sensitivity and negative predictive value were 95% and 63% respectively. The second algorithm, using liver stiffness >38.0 kPa, or liver stiffness ≤38.0 kPa but spleen stiffness >27.9 kPa, was used to rule‐in HVPG ≥10 mm Hg. In our population, its specificity and positive predictive value were 52% and 83% respectively. Restricting the analyses to the 74 patients without any history of decompensation of cirrhosis or to the 65 patients with highly reliable liver stiffness measurement did not improve the results. Conclusion: In our population, diagnostic accuracies of non‐invasive algorithms based on sequential measurements of liver and spleen stiffness using 2D‐SWE were acceptable, but not good enough to replace HVPG measurement or to base clinical decisions. [ABSTRACT FROM AUTHOR]

Abstract: Non‐alcoholic fatty liver disease is a major cause of liver disease worldwide and the most common liver disorder in Western countries, affecting around 25% of the general population. Fibrosis is the major long‐term histological prognostic criteria of this disease. Liver biopsy cannot be realistically performed in such a huge population and, moreover, has well‐known limitations (invasiveness, rare but potentially life‐threatening complications and sampling variability). Over the past decade, there has been a growing interest in alternative novel strategies for the non‐invasive evaluation of fibrosis. These tests rely on two different but complementary approaches: either measuring the levels of serum biomarkers, or liver stiffness, using ultrasound‐based elastography techniques. In non‐alcoholic fatty liver disease patients, transient elastography, FIB‐4 and the non‐alcoholic fatty liver disease fibrosis score are the best validated tests, with summary area under the ROC curve values for diagnosing severe fibrosis‐cirrhosis of 0.88, 0.84 and 0.84 respectively. They can also identify the subgroup of non‐alcoholic fatty liver disease patients at high risk of developing liver‐related complications and death. As a result, non‐invasive tests are now widely used in routine clinical practice and included in national and international guidelines. The next step is the use of non‐invasive tests as first‐line tools for screening non‐alcoholic fatty liver disease in the general population to identify patients who should be referred to specialized centres. [ABSTRACT FROM AUTHOR]

Aims To evaluate the diagnostic performance of CT, MRI and CEUS alone and in combination, for the diagnosis of HCC between 10 and 30 mm, in a large population of cirrhotic patients. Patients and methods In a multicentre prospective trial, 442 patients have been enrolled. Within a month, CEUS, CT and MRI were performed for all patients. A composite algorithm was defined to obtain the more accurate gold standard. Results A total of 544 nodules in 381 patients have been retained for the performance analysis. Eighty-two percent of the patients were male, mean age was 62 years. For the 10-20 mm nodules (n=342), the sensitivity (Se) and specificity (Sp) for the diagnosis of HCC were, respectively, 70.6% and 83.2% for MRI, 67.9% and 76.8% for CT and 39.6% and 92.9% for CEUS. For the 20-30 mm nodules (n=202), the Se and Sp were, respectively, 72.3% and 89.4% for MRI, 71.6% and 93.6% for CT and 52.9% and 91.5% for CEUS. The best combination for the 10-20 mm nodules was MRI + CT (Se: 55.1%, Sp: 100.0%). After a first inconclusive technique, CEUS as second image technique allowed the highest specificity with only a slight drop of sensitivity for 10-20 mm nodules and the highest sensitivity and specificity for 20-30 mm nodules. Conclusion This large multicentre study validates the EASL/ AASLD recommendations in daily practice. Specificity using CT or MRI in 10-20 mm HCC was low, but we do not recommend combined imaging at first as sensitivity would be very low. The best sequential approach combined MRI and CEUS. [ABSTRACT FROM AUTHOR]

ABSTRACT The last glacial millennial Heinrich and Dansgaard-Oeschger events have been the subject of many studies in recent decades. However, significant uncertainties remain, notably regarding associated oceanic mechanisms. Here we investigate the evolution of hydrographical conditions in the 3-41 ka cal BP interval of core MD99-2285 located in the southern Norwegian Sea. Our results reveal an unusual scheme with: (i) warm Greenland interstadials marked by a relatively cold and homogeneous upper water column seasonally ice-covered and active deep water formation, (ii) cold Greenland and Heinrich stadials marked by a warm, low-salinity and nearly sea ice-free surface layer with iceberg calving, separated by a strong halocline from a colder and saltier subsurface layer, as well as strongly reduced deep convection, and (iii) close to modern Holocene oceanic conditions, but showing significant differences from interstadial conditions. Hence, our work strongly suggests different deep-water convection modes in the Nordic Seas, with, notably, interstadial deep water formation mainly forced by brine release. According to our results, the transition from the glacial mode of deep water formation to the modern open ocean convection mode might have occurred at the end of deglaciation/beginning of the Holocene, when both modes probably occurred. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most common malignant brain tumor in adults. Baseline health-related quality of life (HRQoL) is a major subject of concern for these patients. We aimed to assess the independent prognostic value of HRQoL in unresectable glioblastoma (UGB) patients for death risk stratification. One hundred and thirty-four patients with UGB were enrolled from the TEMAVIR trial. HRQoL was evaluated at baseline using the EORTC QLQ-C30 and BN20 brain cancer module. Clinical and HRQoL parameters were evaluated in univariable and multivariable Cox analysis as prognostic factors for overall survival (OS). Performance assessment and internal validation of the final model were evaluated with Harrel's C-index, calibration plot, and bootstrap sample procedure. Two OS independent predictors were identified: future uncertainty and sensitivity deficit. The final model exhibited good calibration and acceptable discrimination (C statistic = 0.63). The internal validity of the model was verified with robust uncertainties around the hazard ratio. The prognostic score identified three groups of patients with distinctly different risk profiles with median OS estimated at 16.2, 9.2, and 4.5 months. We demonstrated the additional prognostic value of HRQoL in UGB for death risk stratification and provided a score that may help to guide clinical management and stratification in future clinical trials. [ABSTRACT FROM AUTHOR]

Objective: Sex chromosome aneuploidies are frequently detected fortuitously in a prenatal diagnosis. Most cases of 47, XXX and 47, XYY syndromes are diagnosed in this context, and parents are thus faced with an unexpected situation. The objective of the present study was to characterize a French cohort of prenatally diagnosed cases of 47, XXX and 47, XYY and to evaluate the termination of pregnancy (TOP) rate before and after France's implementation of multidisciplinary centres for prenatal diagnosis in 1997.Methods: This retrospective study identified respectively 291 and 175 cases of prenatally diagnosed 47, XXX and 47, XYY between 1976 and 2012. For each case, the indication, maternal age, karyotype and outcome were recorded.Results: Most diagnoses of the two conditions were fortuitous. The occurrence of 47, XXX was associated with advanced maternal age. The overall TOP rate was higher for 47, XXX (22.9%) than for 47, XYY (14.6%), although this difference was not statistically significant. However, the TOP rates fell significantly after 1997 (from 41.1% to 11.8% for 47, XXX and from 25.8% to 6.7% for 47, XYY).Conclusion: The TOP rates after prenatal diagnoses of 47, XXX and 47, XYY fell significantly after 1997, following France's implementation of multidisciplinary centres for prenatal diagnosis. © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background & Aims Although potentially very useful in optimizing patient selection and follow-up, the individual response to transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) is generally unpredictable. The aim of this study was to identify tissue predictors of tumour resistance to TACE for use in clinical practice on pretreatment biopsies. Methods We investigated the association of residual tumour in post-TACE-resected HCC with pathological and immunophenotypical features, mainly related to hypoxia and angiogenesis. Comparison of tumour phenotype between post-TACE HCC and both paired pre-TACE biopsies and control TACE-untreated HCC was performed. Cases showing >50% residual tumour (RT) were defined as TACE-resistant. Results A consecutive series of 108 HCC from 41 patients was studied. Overall, 45/108 (44%) HCC were classified as TACE-resistant. Among these, 32 (71%) and 40 (89%) showed diffuse CD34 vascular staining and negative VEGF staining respectively (p<0.05). The association of these two parameters in a weighted score (TRIP) was able to predict TACE resistance with 81% accuracy, 89% sensitivity and 59% specificity. The effectiveness of TRIP was validated in an independent series of 28 HCC biopsies from patients subsequently treated with TACE and for whom radiological follow-up was available. Conclusions This study demonstrates the potential value of pretreatment tumour biopsy as predictors of TACE resistance in HCC. [ABSTRACT FROM AUTHOR]

Key Clinical Message We report on a phenotypically normal 41-year-old azoospermic man with a 45 chromosomes karyotype including one normal chromosome 21, one normal chromosome 22, and a der(22)ins(22;21). Array CGH showed a 1.8 Mb terminal deletion of bands 21pter to 21q21.1 and a 341 kb terminal deletion on band 21q22.3. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives The objectives of this study were to report pregnancy outcomes after prenatal diagnosis of Turner syndrome (TS) and to compare and assess termination of pregnancy rates during two periods. The intervals selected were before and after 1997 when multidisciplinary centers for prenatal diagnosis (MCPDs) were established in France. Methods A database of 975 cases of TS diagnosed between 1980 and 2012 was created from 21 French cytogenetics laboratories. For each case, the karyotype indication, maternal age, year of prenatal testing, sampling procedure, karyotype, associated ultrasound findings, and outcomes were recorded. Results Karyotypes were mainly performed because of abnormal sonographic findings (84%). Before 1997, there were no changes in the rate of termination (90%) of affected fetuses. After 1997, the rate fell to 80%. This decrease was mainly observed in cases of mosaicism, incidental diagnosis, and in later gestations. US abnormalities were more likely to be associated with a full 45,X karyotype. Conclusion There was an evolution in the way genetic counseling was performed following prenatal diagnosis of Turner syndrome that coincided with the opening of MCPDs in France. This resulted in a decrease in the rate of termination of affected fetuses. © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Liver biopsy, which was traditionally considered to be the gold standard for the staging of fibrosis, has been challenged in the past decade by non-invasive techniques. These techniques rely on two distinct but complementary approaches: a 'biological' approach, based on the quantification of biomarkers of fibrosis in serum, and a 'physical' approach, based on the measurement of liver stiffness using elastography-based technologies. Advantages of serum biomarkers include their high applicability (>95%) and good reproducibility. However, as none are liver specific their results can be influenced by comorbid conditions (risk of false positive results with FibroTest® in patients with Gilbert's syndrome or with APRI in case of acute hepatitis). Transient elastograpy has the advantages of being a user's friendly procedure that can be performed at the bedside or in an outpatient clinic with high performance for detecting cirrhosis. However, its applicability is lower (80%) than that of serum biomarker (particularly in case of ascites, obesity and limited operator experience) with the risk of false positive results in case of ALT flares. Although these non-invasive methods were initially developed and validated in patients with chronic hepatitis C, they are now increasingly used in patients with hepatitis B, reducing the need for liver biopsy. [ABSTRACT FROM AUTHOR]

Objectives Combining noninvasive tests increases diagnostic accuracy for staging liver fibrosis in hepatitis C virus ( HCV)-infected patients, but this strategy remains to be validated in HIV/ HCV coinfection. We compared the performances of transient elastography ( TE), Fibrotest ( FT), the aspartate aminotransferase-to-platelet ratio index ( APRI) and two algorithms combining TE and FT ( Castera) or APRI and FT ( SAFE) in HIV/ HCV coinfection. Methods One hundred and sixteen HIV/ HCV-coinfected patients (64% male; median age 44 years) enrolled in two French multicentre studies (the HEPAVIH cohort and FIBROSTIC) for whom TE, FT and APRI data were available were included in the study. Diagnostic accuracies for significant fibrosis ( METAVIR F ≥ 2) and cirrhosis ( F4) were evaluated by measuring the area under the receiver-operating characteristic curve ( AUROC) and calculating percentages of correctly classified ( CC) patients, taking liver biopsy as a reference. Results For F ≥ 2, both TE and FT ( AUROC = 0.87 and 0.85, respectively) had a better diagnostic performance than APRI ( AUROC = 0.71; P < 0.005). Although the percentage of CC patients was significantly higher with Castera's algorithm than with SAFE (61.2% vs. 31.9%, respectively; P < 0.0001), this percentage was lower than that for TE (80.2%; P < 0.0001) or FT (73.3%; P < 0.0001) taken separately. For F4, TE ( AUROC = 0.92) had a better performance than FT ( AUROC = 0.78; P = 0.005) or APRI ( AUROC = 0.73; P = 0.025). Although the percentage of CC patients was significantly higher with the SAFE algorithm than with Castera's (76.7% vs. 68.1%, respectively; P < 0.050), it was still lower than that for TE (85.3%; P < 0.033). Conclusions In HIV/ HCV-coinfected patients, TE and FT have a similar diagnostic accuracy for significant fibrosis, whereas for cirrhosis TE has the best accuracy. The use of the SAFE and Castera algorithms does not seem to improve diagnostic performance. [ABSTRACT FROM AUTHOR]

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus ( HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention ( CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2012; 35: 92-104 Summary Background Preliminary data suggest that performance of non-invasive markers for liver fibrosis in hepatitis C may improve when combined. Three algorithms based on the combination of Fibrotest, Forns' index and AST-to-platelet ratio (APRI) have been proposed: Sequential Algorithm for Fibrosis Evaluation (SAFE biopsy); Fibropaca algorithm; Leroy algorithm. Aim To compare three algorithms to diagnose significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4). Methods A total of 1013 HCV monoinfected cases undergoing liver biopsy were consecutively enrolled in seven centres. Fibrotest, APRI and Forns' index were measured at the time of liver biopsy, considered the reference standard. Results Overall, performance of combination algorithms was significantly higher than the single non-invasive methods ( P < 0.0001). SAFE biopsy and Fibropaca algorithm saved a significantly higher number of liver biopsies than the single methods ( P < 0.0001). For ≥F2, Fibropaca algorithm saved more biopsies than SAFE biopsy (51.7% vs. 43.8%, P = 0.0003), but with lower accuracy (87.6% vs. 90.3%, P = 0.05). Regarding F4, the number of saved liver biopsies did not differ between SAFE biopsy and Fibropaca algorithm (79.1% vs. 76.2%, P = 0.12). However, SAFE biopsy showed a lower accuracy when compared with Fibropaca algorithm (91.2% vs. 94%, P = 0.02). As to Leroy algorithm, although it showed a good performance for ≥F2 (93.5% accuracy), it saved less liver biopsies than SAFE biopsy and Fibropaca algorithm (29.2% vs. 43.8% and 51.7% respectively, P < 0.0001). Conclusions SAFE biopsy and the Fibropaca algorithm have excellent performance for liver fibrosis in hepatitis C, allowing a significant reduction in the need for liver biopsies. They can be useful in clinical practice and for large-scale screening. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2011; 34: 1202-1216 Summary Background Performance of non-invasive fibrosis biomarkers may be influenced by aetiology of chronic liver disease (CLD) and the stages of hepatic fibrosis, but large-scale studies are pending. Aim To investigate the effect of aetiogy and stages of hepatic fibrosis on the performance of fibrosis biomarkers. Methods A total of 2411 patients with compensated CLD (HCV = 75.1%, HBV = 10.5%, NASH = 7.9%, HIV/HCV = 6.5%) were consecutively enrolled in 9 centres. APRI, Forns'index, Lok index, AST-to-ALT ratio, Fib-4, platelets and Fibrotest-Fibrosure were tested against liver biopsy, considered the gold standard. The effect of the stages of hepatic fibrosis to diagnose significant fibrosis and cirrhosis (≥F2 and F4 respectively) was investigated through difference between advanced and non-advanced fibrosis stages (DANA). Performance was expressed as observed area under the ROC curve (ObAUROC) and AUROC adjusted for DANA (AdjAUROC). Results Performance of APRI and Fibrotest-Fibrosure was higher than other biomarkers. In all aetiologies, AdjAUROC was higher than ObAUROC. APRI showed its best performance in HCV monoinfected cases, with an AdjAUROC of 0.77 and 0.83 for ≥F2 and F4 respectively. In HBV and non-alcoholic steatohepatitis (NASH) patients, its performance was poor (AdjAUROC <0.70). Performance of Fibrotest-Fibrosure was good in all aetiologies for both ≥F2 and F4 (AdjAUROC >0.73), except for ≥F2 in NASH (AdjAUROC = 0.64). Performance of all biomarkers was reduced in HCV cases with normal ALT. Conclusions Aetiology is a major factor influencing the performance of liver fibrosis biomarkers. Even after correction for DANA, APRI and Fibrotest-Fibrosure exhibit the best performance. However, liver biopsy is not replaceable, especially to diagnose ≥F2 and in HCV carriers with normal ALT. [ABSTRACT FROM AUTHOR]

The assessment of liver fibrosis is a major issue in the management of patients with chronic hepatitis C. Liver biopsy has traditionally been considered the gold standard for the evaluation of tissue damage, including fibrosis. In addition, it detects associated lesions such as steatosis, steatohepatitis or iron overload, which provide useful information for patient management and prognosis. Liver biopsy is, however, an invasive procedure, with a risk of rare but potentially life-threatening complications and it is prone to sampling errors. These limitations have led to the development of non-invasive methods. Currently available tests rely on two different but complementary approaches: (i) a 'biological' approach based on the dosage of serum biomarkers of fibrosis; (ii) a 'physical' approach based on the measurement of liver stiffness, using transient elastography. Although significant progress has been made in the non-invasive diagnosis of fibrosis, it is increasingly clear that these methods will not completely replace liver biopsy. Instead, non-invasive methods and liver biopsy should be used in an integrated approach for more efficient and convenient management of patients with chronic hepatitis C. The aim of this review is to discuss the advantages and limitations of liver biopsy and non-invasive methods and the perspectives for their use in clinical practice. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the association of 46, XX ovotesticular disorders of sex development (DSD) with a SOX3 gene duplication in a boy with SRY-negative gene.

Olive leaves are a very abundant vegetable material containing various phenolic compounds, such as secoiridoids and flavonoids, that are expected to exert strong antioxidant capacity. However, little is known about the variation of olive-leaf phenolic composition during maturation and its influence on antioxidant capacity. To answer this question, young and mature Olea Europaea L. leaves were submitted to successive extraction with dichloromethane, ethyl acetate, and methanol, then characterized by ESI-MS. It appeared that mature olive-leaf extracts contained higher levels of verbascoside isomers and glucosylated forms of luteolin, while young ones presented higher contents of oleuropein, ligstroside, and flavonoid aglycones. Moreover, antioxidant capacity evaluation using our newly developed conjugated autoxidizable triene assay showed that, in a lipid-based emulsified system, this phenolic composition variation leads to a change in the ability of extracts to counteract lipid oxidation. Mature olive-leaf extracts exhibit higher antioxidant capacity than young olive-leaf extracts. This result enables us to hypothesize that two main bioconversion scenarios may occur during maturation of olive leaves, which could explain changes observed in antioxidant capacity: (1) a bioconversion of oleuropein and ligstroside into verbascoside isomers and oleuroside, and (2) a bioconversion of flavonoid aglycones into glucosylated forms of luteolin. Finally, this study leads to a better understanding of the relationship between phenolic profile and antioxidant capacity of olive leaves. [ABSTRACT FROM AUTHOR]

The death of dendritic cells (DCs) can potentially influence immune responses by affecting the duration of DC stimulation of lymphocytes. Here, we report that cultured mature monocyte-derived DCs manifest early mitochondrial damage ( i.e. within 24 hrs), characterized by mitochondrial membrane potential (ψΔm) disruption and mitochondrial release of pro-apoptotic factors, followed by reactive oxygen species (ROS) production and activation of caspases. Afterwards, DCs with mitochondrial alterations are condemned to undergo apoptosis and necrosis. Macroarray analysis results (validated by real time quantitative-PCR (QRT-PCR) and immunoblotting), showed up-regulation of the pro-apoptotic member of the Bcl-2 family, Bim, while expression of several anti-apoptotic molecules was down-regulated. Importantly, pre-apoptotic DCs (characterized by a low Δψm) showed a modified phenotype, with down-regulation.of HLA-DR and of the co-stimulatory molecules CD80 and CD86. Moreover, sorted viable low ψΔm DCs were unable to activate allogeneic T cells, indicating that pre-apoptotic DCs have already lost some of their immuno-stimulatory capabilities long before any detectable signs of death occur. Perturbations to mitochondrial respiration with rotenone identified the same modifications to DC immune functions. These data indicate a strong requirement for mitochondrial integrity for the immuno-stimulatory capacities of DC. Determining ΔΨm could be a useful parameter to select ‘fully’ functional DCs for anti-tumour vaccines. [ABSTRACT FROM AUTHOR]

The limitations of liver biopsy (invasive procedure, sampling errors, inter-observer variability and nondynamic fibrosis evaluation) have stimulated the search for noninvasive approaches for the assessment of liver fibrosis in patients with viral hepatitis. A variety of methods including the measurement of liver stiffness, using transient elastography, and serum markers, ranging from routine laboratory tests to more complex algorithms or indices combining the results of panels of markers, have been proposed. Among serum indices, Fibrotest has been the most extensively studied and validated. Transient elastography appears as a promising method but has been mostly validated in chronic hepatitis C with performance equivalent to that of serum markers for the diagnosis of significant fibrosis. The combination of both approaches as first-line assessment of liver fibrosis could avoid the performance of liver biopsy in the majority of patients with chronic hepatitis C, a strategy that deserves further evaluation in patients with hepatitis B or HIV-HCV coinfection. Transient elastography also appears to be an excellent tool for early detection of cirrhosis and may have prognostic value in this setting. Guidelines are now awaited for the use of noninvasive methods in clinical practice. [ABSTRACT FROM AUTHOR]

Hepatitis C virus genotype 4 (HCV-4) infection is progressing in Europe, where epidemiology and sustained virological response (SVR) seem to be different than in the Middle East. We analysed epidemiological features and SVR rates in a retrospective study of 1532 HCV-4-infected patients, including 1056 patients infected in France, 227 immigrants infected in Egypt and 249 in sub-Saharan Africa. SVR rates were assessed in 242 naive patients of the 1532, who received peginterferon plus ribavirin for 48 weeks. HCV subtype 4a or 4d was the most common among patients infected in France, where the predominant route of transmission was intravenous drug abuse. The 4a subtype was largely predominant (93%) among patients infected in Egypt, where transmission was mostly because of parenteral treatment for schistosomiasis. More than seven different subtypes and no predominant route of infection were found in patients infected in sub-Saharan Africa. Liver fibrosis was significantly less severe in patients infected in France and Africa than in patients infected in Egypt. SVR rates were higher in patients infected in Egypt, compared with those infected in France or Africa (54.9%, 40.3% and 32.4%, respectively, P < 0.05). An overall better response was observed in patients infected with the 4a subtype. In multivariate analysis, two factors were associated independently with SVR: the Egyptian origin of transmission and the absence of severe fibrosis. In conclusion, the distribution of HCV-4 subtypes varies with the geographical origin of transmission and affects the SVR following antiviral treatment. [ABSTRACT FROM AUTHOR]

Background The area under the receiver operating characteristic (ROC) curve is widely used as an estimate of the diagnostic value for fibrosis markers. Biopsy length and fragmentation are known as risk factors of false positive or false negative of biopsy but their quantitative impact on area under the receiver operating characteristic curve variability has not been assessed. Aim To assess these relationships to better compare the fibrosis markers. Methods The area under the ROC curves of FibroTest for the diagnosis of fibrosis was estimated in patients with chronic hepatitis C using an integrated database including 1312 patients with FibroTest and biopsy. To take into account the biopsy length, we used two adjustment factors: one in which an observed area under the ROC curve could be adjusted according to the relative area under the receiver operating characteristic curve of a biopsy of a given length vs. the entire liver and one taking into account the prevalence of each fibrosis stage defining advanced and non-advanced fibrosis. Results The mean biopsy length was smaller for cirrhosis (F4, 16 mm) vs. F3, (18 mm, P = 0.01) and F0 (19 mm, P = 0.01). The mean number of fragments was higher for cirrhosis (F4 = 4.1 fragments) vs. all the other stages (F0 = 1.9, F1 = 1.9, F2 = 1.9, F3 = 2.3; P < 0.001 vs. F4). The FibroTest area under the ROC curves for the diagnosis of advanced fibrosis, adjusted for stages’ prevalence, ranged from 0.80 to 0.98 depending on biopsy length and fragmentation, respectively. Conclusion The comparison of the area under the ROC curves of fibrosis markers should take into account the biopsy length and fragmentation. [ABSTRACT FROM AUTHOR]

We compared sustained virological response (SVR) in chronic hepatitis C patients with severe fibrosis treated with pegylated interferon (Peg-IFN) α-2b 1.5 μg/kg/week or 0.75 μg/kg/week in combination with ribavirin 800 mg/day for 48 weeks. This was a multicentre randomized controlled study. SVR was observed in 44.5% (45/101) of patients treated with the standard dose of Peg-IFN and 37.2% (38/102) of patients treated with the low dose (NS). In patients with genotypes 1, 4 and 5, SVR was observed in 25.0% of patients who received the standard dose and 16.9% of patients who received the low dose of Peg-IFN ( P = NS). In patients with genotypes 1, 4 and 5 and low viraemia, SVR was obtained in 27.3% of patients treated with the standard dose and 25.8% of patients treated with the low dose ( P = NS). In the high-viraemia subgroup, SVR was obtained in 24.0% and 9.1% of patients, respectively. In patients with genotypes 2 and 3, SVR was similar in both groups (73.2% vs 73.0%). Thus, (1) patients with genotypes 2 and 3 and severe fibrosis can be treated with low dose of Peg-IFN and ribavirin, (2) this study suggests that patients with genotypes 1, 4 and 5 and high viraemia could receive a standard dose of Peg-IFN associated with ribavirin for 48 weeks, (3) side effects limit the efficacy of the treatment with standard dose of Peg-IFN in patients with genotypes 1, 4 and 5 and low viraemia, (4) more studies are needed for patients with genotype 2 or 3 to define the optimal duration (24 or 48 weeks) in patients with severe fibrosis. [ABSTRACT FROM AUTHOR]

Background The psychiatric side effects of interferon, often responsible for dose reduction or treatment discontinuation, represent a major limitation in the treatment of chronic hepatitis C (CHC). Aim To prospectively assess the impact on adherence and sustained virological response (SVR) of the occurrence of psychiatric side effects during peginterferon and ribavirin therapy for CHC. Methods Ninety-eight consecutive treatment-naïve CHC patients receiving a standard course of peginterferon plus ribavirin were systematically screened for psychiatric side effects, using DSM-IV, at baseline and both during and after treatment. Results Psychiatric side effects occurred in 38 patients (39%), mostly within the first 12 weeks (87%), and always consisted of mood disorders. Overall, 68% of patients achieved an SVR (71% of patients with mood disorders and 68% of those without; P = N.S.). Peginterferon and ribavirin dose reductions did not differ between patients with mood disorders and those without (46% vs. 37%, respectively; P = N.S. and 13% vs. 22%, respectively; P = N.S.). Anti-viral therapy had to be discontinued in four patients (nonresponse: two, hyperthyroidism: one, psychiatric event: one). Conclusion Early detection and appropriate management of psychiatric side effects during peginterferon and ribavirin therapy for CHC allow optimizing adherence and virological efficacy. [ABSTRACT FROM AUTHOR]

The aim of this prospective study was to investigate beliefs regarding disease severity and lifestyle changes following hepatitis C diagnosis in patients with chronic hepatitis C (CHC). One hundred and eighty-five consecutive CHC patients were interviewed by means of self-questionnaires exploring several aspects of their disease. Most patients (93%) identified cirrhosis and liver cancer as the two main complications of CHC. More than half of patients (59%) thought that CHC was always associated with a fatal outcome whereas 3% thought that they would stay healthy. HCV viral load was the most commonly reported factor associated with disease severity. Sex life changes were reported by 107 patients (58%) whereas dietary intake changes were reported by 88 patients (48%). In multivariate analysis, changes in sex life were associated with male gender [odds ratio (OR): 2.57, 95% CI: 1.30–5.08, P < 0.007], perceived disease severity (OR: 1.02, 95% CI: 1.00–1.03, P < 0.03) and anxiety (OR: 1.05, 95% CI: 1.01–1.08, P < 0.003), whereas changes in dietary intake were associated with age (OR: 1.04, 95% CI: 1.02–1.08, P < 0.003) and anxiety (OR: 1.04, 95% CI: 1.01–1.08, P < 0.006). Our results show the considerable impact of CHC diagnosis on patients’ lifestyle. They emphasize the need for improving CHC patient counselling in order to avoid unnecessary sex life and dietary intake changes. [ABSTRACT FROM AUTHOR]

The antioxidant effect of lecithins was tested on several oils and fats varying in FA composition and tocopherol content. Standard lecithins, when added at a level of 1% w/w, exhibited a good protective effect against oxidation. This effect was observed to depend on the phospholipid content of the tested lecithins and the FA composition of the tested oils. Better results were obtained with lecithin samples containing high proportions of PC and PE. Indeed, the main antioxidant mechanism of lecithins was due to a synergistic effect between amino-alcohol phospholipids and γ- and δ-tocopherols. No synergism was observed with α-tocopherols, especially when the tested oil was rich in linoleic acid. Therefore, the antioxidant protection of lecithins was not effective for sunflower oil. Finally, the use of fractionated or enriched lecithins was not clearly advantageous compared to standard oil lecithins. [ABSTRACT FROM AUTHOR]

Objective To evaluate bladder function by conventional urodynamic investigations in young infants with primary vesico-ureteric reflux (VUR) who had undergone an initial temporary cutaneous vesicostomy followed by later antireflux surgery and vesicostomy closure. Patients and methods From 1983 to 1990, nine boys (10-360 days old) with primary VUR were treated with an initial vesicostomy, followed by delayed closure of the vesicostomy and the simultaneous surgical correction of reflux. Severe VUR was detected bilaterally in seven and unilaterally in two infants at the time of the initial diagnosis. The mean (SD, range) age at vesicostomy was 12.4 (8, 3-23) months and the duration of bladder defunctionalization 38.7 (25.5, 18-90) months. All patients were assessed urodynamically after closing the vesicostomy, using rapid-fill cystometry with normal saline solution at room temperature. The mean (range) age at the time of urodynamic testing was 7.3 (5-15) years; the mean (SD, range) follow-up was 10.1 (4.1, 5-17) years. Results Six boys with bilateral VUR underwent successful ureteroneocystostomy; nephroureterectomy was required in one patient. In two patients the VUR resolved with time. After re-functionalization, the mean (SD, range) maximum cystometric capacity, expressed as a percentage of the mean bladder capacity for age, was 1.4 (0.5, 0.6-2.2)%. In three patients the bladder capacity was higher (≥40%) than expected for age, while one had diminished (<70%) bladder capacity. The mean (range) endfilling detrusor pressure was 14.5 (5-42) cmH[sub 2]O and the mean (SD, range) compliance 24(13.9, 4-44) mL/cmH[sub 2]O. Two patients had a compliance of <10mL/cmH[sub 2]O, one of whom had associated unstable detrusor contractions of 90 cmH[sub 2]O. The mean (SD, range) detrusor voiding pressure at peak flow was 47.3 (16.8, 5-76) cmH[sub 2]O. One patient had a residual urine volume of 8% of bladder capacity. At the follow-up, only one patient (aged 5 years) with... [ABSTRACT FROM AUTHOR]

See Article on Page 2514 [ABSTRACT FROM AUTHOR]

Summary: A patient with hyperuricaemia and gouty arthritis due to a new variant of hypoxanthine–guanine phosphoribosyltransferase is described. The mutation (I136T, HPRT Marseille) is in the phosphoribosylpyrophosphate-binding region of the gene and leads to almost total loss of enzyme activity in erythrocytes, with 5% in lymphocytes. Nevertheless, the patient showed no neurological abnormality. [ABSTRACT FROM AUTHOR]

Objective To assess urodynamic and clinical data in patients with primary enuresis for potential prognostic indicators of detrusor instability. Patients and methods The records of 33 patients (mean age 8.8 years, range 5–14) with monosymptomatic primary enuresis (MPE, bedwetting as the sole symptom) and 47 patients (mean age 7.1 years, range 5–12) with complicated primary enuresis (CPE, bedwetting associated with diurnal urinary loss, squatting and urge incontinence) were reviewed. The children underwent urodynamic studies to detect detrusor instability and the prevalence was compared with the type of enuresis. Results Of 33 patients with MPE, 17 (49%) showed either typical unstable detrusor contractions (16) or low-compliance bladders (one); in the remaining 16 patients, filling cystometry was normal and micturition was normal in all. Of the 47 patients with CPE, 35 (79%) showed detrusor instability and two decreased bladder compliance; the remaining 10 had stable bladders and micturition was also normal in all patients. Conclusion The type of primary enuresis and the maximum cystometric bladder capacity were good indicators of bladder dysfunction. [ABSTRACT FROM AUTHOR]