Trace-element XAFS sensitivity: a stress test for a new XRF multi-detector.

X-ray absorption fine-structure (XAFS) spectroscopy can assess the chemical speciation of the elements providing their coordination and oxidation state, information generally hidden to other techniques. In the case of trace elements, achieving a good quality XAFS signal poses several challenges, as it requires high photon flux, counting statistics and detector linearity. Here, a new multi-element X-ray fluorescence detector is presented, specifically designed to probe the chemical speciation of trace 3d elements down to the p.p.m. range. The potentialities of the detector are presented through a case study: the speciation of ultra-diluted elements (Fe, Mn and Cr) in geological rocks from a calcareous formation related to the dispersal processes from Ontong (Java) volcanism (mid-Cretaceous). Trace-elements speciation is crucial in evaluating the impact of geogenic and anthropogenic harmful metals on the environment, and to evaluate the risks to human health and ecosystems. These results show that the new detector is suitable for collecting spectra of 3d elements in trace amounts in a calcareous matrix. The data quality is high enough that quantitative data analysis could be performed to determine their chemical speciation.

Effect of a common missense variant in LIPA gene on fatty liver disease and lipid phenotype: New perspectives from a single-center observational study.

Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disease characterized by hypoalphalipoproteinemia, mixed hyperlipemia, and fatty liver (FL) due to mutations in LIPAse A, lysosomal acid type (LIPA) gene. The rs1051338 single-nucleotide polymorphism (SNP) in LIPA gene, in vitro, could adversely affect the LAL activity (LAL-A). Nonalcoholic fatty liver disease (NAFLD) is often associated with metabolic syndrome, and the diagnosis requires the exclusion of excess of alcohol intake and other causes of hepatic disease. The aim of the study was to evaluate the impact of rs1051338 rare allele on lipid phenotype, severity of FL, and LAL-A in patients suffering from dyslipidemia associated with NAFLD. We selected 74 subjects with hypoalphalipoproteinemia or mixed hyperlipemia and evaluated transaminases, liver assessment with controlled attenuation parameter (CAP), LAL-A, rs1051338 SNP genotype. The presence of rare allele caused higher levels of triglycerides and hepatic transaminase and lower levels of high-density lipoprotein cholesterol (HDL-C). Multivariate analysis highlighted independent association between rare allele and FL severity in subjects with NAFLD. The rs1051338 SNP may modulate FL severity and atherogenic dyslipidemia in patients suffering from NAFLD.

Real-world experience with obeticholic acid in patients with primary biliary cholangitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. METHODS: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. RESULTS: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). CONCLUSIONS: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. LAY SUMMARY: Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.

Accuracy of Transient Elastography in Assessing Fibrosis at Diagnosis in Naïve Patients With Primary Biliary Cholangitis: A Dual Cut-Off Approach.

BACKGROUND AND AIMS: Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Noninvasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis (AF) at disease presentation in PBC. APPROACH AND RESULTS: We collected data from 167 consecutive treatment-naïve PBC patients who underwent liver biopsy (LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to the Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for AF (Ludwig stage ≥III). Effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. The derivation cohort consisted of 126 patients with valid LSM and LB; VCTE identified patients with AF with an AUROC of 0.89. LSM cutoffs ≤6.5 and >11.0 kPa enabled to exclude and confirm, respectively, AF (negative predictive value [NPV] = 0.94; positive predictive value [PPV] = 0.89; error rate = 5.6%). These values were externally validated in an independent cohort of 91 PBC patients (NPV = 0.93; PPV = 0.89; error rate = 8.6%). Multivariable analysis found that the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. CONCLUSIONS: In a multicenter study of treatment-naïve PBC patients, we identified two cutoffs (LSM ≤6.5 and >11.0 kPa) able to discriminate at diagnosis the absence or presence, respectively, of AF in PBC patients, with external validation. In patients with LSM between these two cutoffs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

MEMS Membranes with Nanoscale Holes for Analytical Applications.

Micro-electro-mechanical membranes having nanoscale holes were developed, to be used as a nanofluidic sample inlet in novel analytical applications. Nanoscopic holes can be used as sampling points to enable a molecular flow regime, enhancing the performance and simplifying the layout of mass spectrometers and other analytical systems. To do this, the holes must be placed on membranes capable of consistently withstanding a pressure gradient of 1 bar. To achieve this goal, a membrane-in-membrane structure was adopted, where a larger and thicker membrane is microfabricated, and smaller sub-membranes are then realized in it. The nanoscopic holes are opened in the sub-membranes. Prototype devices were fabricated, having hole diameters from 300 to 600 nm, a membrane side of 80 µm, and a simulated maximum displacement of less than 150 nm under a 1 bar pressure gradient. The obtained prototypes were tested in a dedicated vacuum system, and a method to calculate the effective orifice diameter using gas flow measurements at different pressure gradients was implemented. The calculated diameters were in good agreement with the target diameter sizes. Micro-electro-mechanical technology was successfully used to develop a novel micromembrane with nanoscopic holes, and the fabricated prototypes were successfully used as a gas inlet in a vacuum system for mass spectrometry and other analytical systems.

Optimization of a Low-Power Chemoresistive Gas Sensor: Predictive Thermal Modelling and Mechanical Failure Analysis.

The substrate plays a key role in chemoresistive gas sensors. It acts as mechanical support for the sensing material, hosts the heating element and, also, aids the sensing material in signal transduction. In recent years, a significant improvement in the substrate production process has been achieved, thanks to the advances in micro- and nanofabrication for micro-electro-mechanical system (MEMS) technologies. In addition, the use of innovative materials and smaller low-power consumption silicon microheaters led to the development of high-performance gas sensors. Various heater layouts were investigated to optimize the temperature distribution on the membrane, and a suspended membrane configuration was exploited to avoid heat loss by conduction through the silicon bulk. However, there is a lack of comprehensive studies focused on predictive models for the optimization of the thermal and mechanical properties of a microheater. In this work, three microheater layouts in three membrane sizes were developed using the microfabrication process. The performance of these devices was evaluated to predict their thermal and mechanical behaviors by using both experimental and theoretical approaches. Finally, a statistical method was employed to cross-correlate the thermal predictive model and the mechanical failure analysis, aiming at microheater design optimization for gas-sensing applications.

Hepatic Elastometry and Glissonian Line in the Assessment of Liver Fibrosis.

The aim of this study was to identify a method for staging hepatic fibrosis using a non-invasive, rapid and inexpensive technique based on ultrasound morphologic hepatic features. A total of 215 patients with different liver diseases underwent B-mode (2-D brightness mode) ultrasonography, vibration-controlled transient elastography, 2-D shear wave elastography and measurement of the controlled attenuation parameter with transient elastography. B-Mode images of the anterior margin of the left lobe were obtained and processed with automatic Genoa Line Quantification (GLQ) software based on a neural network for staging liver fibrosis. The accuracy of GLQ was 90.6% during model training and 78.9% in 38 different patients with concordant elastometric measures. Receiver operating characteristic curve analysis of GLQ performance using vibration-controlled transient elastography as a reference yielded areas under the curves of 0.851 for F ≥ F1, 0.793 for F ≥ F2, 0.784 for F ≥ F3 and 0.789 for F ≥ F4. GLQ has the potential to be a rapid, easy-to-perform and tolerable method in the staging of liver fibrosis.

Strengthening of Wood-Like Materials via Densification and Nanoparticle Intercalation.

Recently, several chemical and physical treatments were developed to improve different properties of wood. Such treatments are applicable to many types of cellulose-based materials. Densification leads the group in terms of mechanical results and comprises a chemical treatment followed by a thermo-compression stage. First, chemicals selectively etch the matrix of lignin and hemicellulose. Then, thermo-compression increases the packing density of cellulose microfibrils boosting mechanical performance. In this paper, in comparison with the state-of-the-art for wood treatments we introduce an additional nano-reinforcemeent on densified giant reed to further improve the mechanical performance. The modified nanocomposite materials are stiffer, stronger, tougher and show higher fire resistance. After the addition of nanoparticles, no relevant structural modification is induced as they are located in the gaps between cellulose microfibrils. Their peculiar positioning could increase the interfacial adhesion energy and improve the stress transfer between cellulose microfibrils. The presented process stands as a viable solution to introduce nanoparticles as new functionalities into cellulose-based natural materials.

High-current stream of energetic α particles from laser-driven proton-boron fusion.

The nuclear reaction known as proton-boron fusion has been triggered by a subnanosecond laser system focused onto a thick boron nitride target at modest laser intensity (∼10^{16}W/cm^{2}), resulting in a record yield of generated α particles. The estimated value of α particles emitted per laser pulse is around 10^{11}, thus orders of magnitude higher than any other experimental result previously reported. The accelerated α-particle stream shows unique features in terms of kinetic energy (up to 10 MeV), pulse duration (∼10 ns), and peak current (∼2 A) at 1 m from the source, promising potential applications of such neutronless nuclear fusion reactions. We have used a beam-driven fusion scheme to explain the total number of α particles generated in the nuclear reaction. In this model, protons accelerated inside the plasma, moving forward into the bulk of the target, can interact with ^{11}B atoms, thus efficiently triggering fusion reactions. An overview of literature results obtained with different laser parameters, experimental setups, and target compositions is reported and discussed.

Treatment of hepatitis C virus infection with direct-acting antiviral drugs is safe and effective in patients with hemoglobinopathies.

Progression of liver fibrosis in patients with hemoglobinopathies is strongly related to the severity of iron overload and the presence of chronic hepatitis C virus (HCV) infection. Effective iron chelation therapy and HCV infection eradication may prevent liver complications. The European Association for the Study of the Liver guidelines recommend interferon-free regimens for the treatment of HCV infection in patients with hemoglobinopathies. However, data regarding the use of direct-acting antiviral drugs (DAAs) in this patient population are few. This observational study evaluated the safety and efficacy of therapy with DAAs in an Italian cohort of patients with hemoglobinopathies, chronic HCV infection and advanced liver fibrosis. Between March 2015 and December 2016, 139 patients received DAAs and completed 12 weeks of follow up after the end of treatment for the evaluation of sustained virological response (12SVR). The 12SVR (93.5%) was comparable with that typically observed in cirrhotic patients without hemoglobinopathies. Three patients died during the period of observation of causes unrelated to DAAs. One patient did not achieve a virological response and five (3.6%) relapsed during 12 weeks of follow-up after the end of therapy. In addition, patients showed significant reductions in serum ferritin at 12 weeks to levels similar to those observed in a control group of 39 patients with thalassemia major without HCV infection, who adhered to chelation therapy and had no overt iron overload. In conclusion, the use of DAAs appears to be safe and effective in patients with hemoglobinopathies and advanced liver disease due to HCV.

Biopsychosocial predictors of interferon-related depression in patients with Hepatitis C.

OBJECTIVES: The aim of this study is to examine the role of different bio-psycho-social risk factors for the onset of depression among patients with Hepatitis C (HCV) treated with Interferon alpha (IFN). MATERIAL AND METHODS: Patients with HCV were recruited and assessed prospectively at baseline and after 4, 8, and 24 weeks since the start of IFN treatment. Assessments included the Hamilton Depression and Anxiety Rating Scales (HAM-D and HAM-A), Toronto Alexithymia Scale, Temperament Evaluation of the Memphis, Pisa, Paris and San Diego, 110 item version (TEMPS-A), Young Mania Rating Scale and other assessment tools. Sociodemographic and clinical factors were entered as predictors in logistic regression models, with early-onset depression (4 weeks) or persistent depression (24 weeks) as the outcomes. RESULTS: Early-onset depression was predicted by preexisting depressive symptoms' severity (baseline HAM-D scores: OR=1.24; 95% CI: 1.03, 1.50; p=0.03) and by the presence of additional physical comorbidities (OR=3.74; 95% CI: 1.12, 12.5; p=0.03). Persistent depression was predicted by additional physical comorbidities (OR=7.75; 95% CI: 1.33, 45.0, p=0.02), depressive temperament (OR=8.95; 95% CI: 1.32, 60.6; p=0.03) and, at trend-level, by unknown mode of HCV contagion (OR=5.21; 95% CI: 0.89, 30.4; p=0.07). CONCLUSIONS: The incidence of IFN-related depression is associated with factors related to patients' physical and temperamental characteristics. Further research should include comprehensive biopsychosocial assessments to improve the early detection and treatment of vulnerable patients in the real clinical world.

Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies.

BACKGROUND & AIMS: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures. METHODS: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N=200) and whenever possible at baseline (N=70). RESULTS: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P<.001). Interestingly, 57.1% of DAA IFN-free non-responders had a misclassified genotype, and 3/4 sofosbuvir breakthroughs showed the major-RAS-S282T, while RAS-L159F was frequently found in sofosbuvir relapsers (18.2%). Notably, 9.0% of patients showed also extra target RASs, and 47.4% of patients treated with ≥2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure. CONCLUSIONS: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.

Behavior of soluble HLA-A, -B, -C and HLA-G molecules in patients with chronic hepatitis C virus infection undergoing pegylated interferon-α and ribavirin treatment: potential role as markers of response to antiviral therapy.

The serum levels of soluble HLA class I antigens (sHLA-A, -B, -C and sHLA-G) were determined in 40 HCV genotype 1-infected patients before (T 0), after 3, 6, and 12 months (T 3, T 6, and T 12) of pegylated-IFN-α plus ribavirin therapy and 6 months (T 18) after the end of treatment. Twenty patients were sustained virological responders (SVR), and 20 were non-responders (NR). sHLA-A, -B, -C levels at T 0 were significantly higher in both SVR (mean 10.48 µg/ml) and NR (mean 11.87 µg/ml) patients as compared to healthy controls (mean 0.34 µg/ml, p < 0.0001) and HIV-infected subjects (mean 1.22 µg/ml, p < 0.0001). sHLA-G levels at T 0 were significantly higher in SVR (mean 24.78 ng/ml) and NR (mean 24.93 ng/ml) patients as compared to healthy controls (mean 10.34 ng/ml, p = 0.015 and p = 0.014, respectively) but were lower as compared to HIV-infected subjects (mean 48.00 ng/ml, p < 0.0001). The levels of sHLA-A, -B, -C and sHLA-G significantly decreased in SVR from T 0 to T 18 (mean 1.64 and 1.43 ng/ml, respectively, p < 0.0001) and correlated with HCV-RNA, AST, ALT, γGT, and ALP levels. The determination of soluble HLA class I levels could be proposed as a surrogate marker to discriminate SVR and NR HCV-infected patients during PEG-IFN-α plus ribavirin therapy.

'Emergency exit' of bone-marrow-resident CD34(+)DNAM-1(bright)CXCR4(+)-committed lymphoid precursors during chronic infection and inflammation.

During chronic inflammatory disorders, a persistent natural killer (NK) cell derangement is observed. While increased cell turnover is expected, little is known about whether and how NK-cell homeostatic balance is maintained. Here, flow cytometric analysis of peripheral blood mononuclear cells in chronic inflammatory disorders, both infectious and non-infectious, reveals the presence of a CD34(+)CD226(DNAM-1)(bright)CXCR4(+) cell population displaying transcriptional signatures typical of common lymphocyte precursors and giving rise to NK-cell progenies with high expression of activating receptors and mature function and even to α/ß T lymphocytes. CD34(+)CD226(bright)CXCR4(+) cells reside in bone marrow, hardly circulate in healthy donors and are absent in cord blood. Their proportion correlates with the degree of inflammation, reflecting lymphoid cell turnover/reconstitution during chronic inflammation. These findings provide insight on intermediate stages of NK-cell development, a view of emergency recruitment of cell precursors, and upgrade our understanding and monitoring of chronic inflammatory conditions.

Inherent transcriptional signatures of NK cells are associated with response to IFNα + rivabirin therapy in patients with Hepatitis C Virus.

BACKGROUND: Differences in the expression of Natural Killer cell receptors have been reported to reflect divergent clinical courses in patients with chronic infections or tumors. However, extensive molecular characterization at the transcriptional level to support this view is lacking. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNα/RBV in patients chronically infected with HCV. METHODS: To this end we here studied by flow cytometer and gene expression profile, phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with HCV genotype-1 virus who were subsequently treated with PEG-IFNα/RBV. Results were further correlated with divergent clinical response obtained after treatment. RESULTS: The pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients. A set of 476 transcripts, including molecules involved in RNA processing, ubiquitination pathways as well as HLA class II signalling were differently expressed among divergent patients. In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D. A complex relationship was observed that suggested for extensive post-transcriptional editing. Only a small number of the NK cell transcripts identified were correlated with chronic HCV infection/replication indicating that inherent transcriptional activity prevails over environment effects such as viral infection. CONCLUSIONS: Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.

HOMA, BMI, and Serum Leptin Levels Variations during Antiviral Treatment Suggest Virus-Related Insulin Resistance in Noncirrhotic, Nonobese, and Nondiabetic Chronic Hepatitis C Genotype 1 Patients.

Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders. Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment. Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P = 0.033 and 0.048, resp.) in patients who achieved an early viral load decay (EVR), a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR. Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype.

Epidemiological and clinical features of hepatitis delta in HBsAg-positive patients by HIV status.

BACKGROUND: The epidemiology of HBV-associated hepatitis has changed in recent years, especially after the introduction of anti-HBV vaccination, with a consequent decrease in the incidence of HDV-associated hepatitis. However, HDV remains of concern in non-vaccinated people and in immigrants. The aim of this retrospective survey has been to assess prevalence and clinical characteristics of HDV infection in Liguria, a region in Northern Italy, in both HIV-positive and negative patients. METHODS: During the year 2010, 641 patients chronically infected with HBV entered an observational study of HBV infection conducted in eight tertiary care centres belonging to the 'Ligurian HBV Study Group'. RESULTS: Of 641 patients, 454 (70.8%) were evaluated for HDV serology and 26 (5.7%) were found positive. Among them, 16 were also HIV-positive and 10 were not. Of the 428 HDV-negative patients, only 313 were tested for HIV and 33 (10.5%) were positive. At the time point of study entry there was no age difference between HIV-positive or negative patients, but HIV-positive patients were 10 years younger than HIV-negative (mean age 34.25 ±6.16 versus 41.50 ±8.89 years; P=0.021) at the time point of their first visit in each centre and they were also more frequently intravenous drug users (P=0.009). Despite a similar rate of cirrhosis in the two groups, no HIV-positive patient received an HDV-active therapy (that is, interferon), versus 4 of 10 HIV-negative patients (P=0.014). CONCLUSIONS: HDV infection is still a problem in patients not covered by HBV vaccination. Both HDV and HIV testing were frequently overlooked in our setting.

Therapeutic management of chronic hepatitis B in clinical practice: a region-wide survey.

GOALS: To characterize the clinical and treatment pattern in a large population of hepatitis B virus (HBV) patients managed at tertiary referral centers in clinical practice. BACKGROUND: Successful treatment, either with interferon (IFN) or nucleos(t)ide analogs (NUCs), of chronic HBV infection is associated with improved long-term patient outcome. However, in clinical practice, the actual management of these patients is not well characterized, and data regarding treatment pattern in this setting are lacking. METHODS: In this cross-sectional study, we evaluated 505 patients chronically infected with HBV alone and who had at least 1-year follow-up. We assessed indication to, rate of, and type of treatment as well as the characteristics of treated patients. RESULTS: Overall prevalence of positivity for HBe antigen was 19.3%, and the majority of patients had chronic hepatitis (47.5%). Non-Italian patients represented approximately one third of the population (27.1%). Among patients with indication to antiviral therapy (n=318), treatment was actually carried out in 264 patients (83.0%), prevalently with NUCs (65.9%). IFN-treated patients were younger (P<0.001), more frequently male (P=0.025) and HBeAg positive (P=0.003), and less frequently cirrhotics (P<0.001) as compared with patients treated with NUCs. CONCLUSIONS: In a geographical area with a low positivity for HBe antigen, antiviral therapy is actually carried out in the majority of patients who have indication to treatment, prevalently with NUCs, whereas IFN treatment is more frequently carried out in young, HBe antigen-positive patients who do not have advanced liver disease.

Measurement of sorafenib plasma concentration by high-performance liquid chromatography in patients with advanced hepatocellular carcinoma: is it useful the application in clinical practice? A pilot study.

Pharmacokinetics and dose-finding studies on sorafenib were conducted on heterogeneous groups of patients with solid tumors. Portal hypertension, gut motility impairment and altered bile enterohepatic circulation may explain different sorafenib toxicological profile in cirrhotic patients. This study evaluated sorafenib plasma concentration in a homogeneous group of cirrhotic patients with hepatocellular carcinoma (HCC). Sorafenib concentrations were determined by liquid chromatography in 12 consecutive patients. Data have been evaluated by the generalized estimating equations method (p value statistical level was set at α = 0.05). (1) There were not significant differences between sorafenib concentrations in patients who tolerate the full dose versus patients with reduced dose due to toxicity; (2) the average sorafenib concentrations measured 3 h after the morning dosing were lower than those measured 12 h after the evening dosing (p = 0.005); (3) sorafenib concentrations decrease overtime (p < 10(-4)); (4) it has been found an association between the development of severe adverse reactions and sorafenib concentrations (p < 10(-5)). The relationship between dose and concentration of sorafenib in HCC patients is poor and not clinically predictable, confirming the variability both in the maximum tolerated dose and in plasma concentrations. Several factors may influence the pharmacokinetics in patients with liver disease. This may explain the inter-patient variability of concentrations and the lack of differences in concentration at different dosages. It could be interesting to extend the series of HCC patients to enhance information on the kinetics of the drug; furthermore, to establish a threshold of plasma sorafenib concentrations to predict severe adverse reactions would be clinically useful.