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The CoCrFeNiMnX (X = 5, 20, and 35 at.%) alloys, reinforced with 5 at.% SiC powder, were prepared by mechanical alloying and spark plasma sintering. This preparation method resulted in microstructural refinement of the FCC solid solution grains, while the SiC addition reacted with residual oxygen to form homogeneously distributed ultrafine SiO2 particles. Additionally, the alloys contained Cr7C3 carbides, which were significantly larger than the SiO2 particles and enriched with the alloy's elements, including Mn. Among the tested materials, the reinforced CoCrFeNiMn20 alloy exhibited the highest hardness and compressive yield strength (CYS), achieving 392 ± 9 HV30 or 476 ± 3 HVIT1 and 1024 ± 18 MPa, respectively. This alloy also maintained superior CYS (956 ± 35 MPa) even after 100 h of annealing at 800 °C. The reduction in CYS after annealing was smallest for the CoCrFeNiMn5 alloy (35 MPa) and increased with higher Mn content, highlighting Mn's significant role in diffusion-related processes. At elevated temperatures (600 and 800 °C), the CoCrFeNiMn5 alloy had the highest CYS of 190 ± 33 MPa, while the CoCrFeNiMn35 alloy had the lowest at 80 ± 6 MPa. This trend was also observed in wear rate tests, where the CoCrFeNiMn5 alloy had the lowest specific wear rate coefficient of 3.54 ± 0.09 × 10-4 mm³ N⁻1 m⁻1. This was due to matrix softening and oxide lubrication without significant spalling. Thus, the CoCrFeNiMn5 alloy demonstrated superior mechanical properties and wear resistance under various conditions, making it a promising candidate for applications requiring high strength and durability.

IMPORTANCE: The 2022 Barcelona Clinic Liver Cancer algorithm currently discourages liver resection (LR) for patients with multinodular hepatocellular carcinoma (HCC) presenting with 2 or 3 nodules that are each 3 cm or smaller. OBJECTIVE: To compare the efficacy of liver resection (LR), percutaneous radiofrequency ablation (PRFA), and transarterial chemoembolization (TACE) in patients with multinodular HCC. DESIGN, SETTING, AND PARTICIPANTS: This cohort study is a retrospective analysis conducted using data from the HE.RC.O.LE.S register (n = 5331) for LR patients and the ITA.LI.CA database (n = 7056) for PRFA and TACE patients. A matching-adjusted indirect comparison (MAIC) method was applied to balance data and potential confounding factors between the 3 groups. Included were patients from multiple centers from 2008 to 2020; data were analyzed from January to December 2023. INTERVENTIONS: LR, PRFA, or TACE. MAIN OUTCOMES AND MEASURES: Survival rates at 1, 3, and 5 years were calculated. Cox MAIC-weighted multivariable analysis and competing risk analysis were used to assess outcomes. RESULTS: A total of 720 patients with early multinodular HCC were included, 543 males (75.4%), 177 females (24.6%), and 350 individuals older than 70 years (48.6%). There were 296 patients in the LR group, 240 who underwent PRFA, and 184 who underwent TACE. After MAIC, LR exhibited 1-, 3-, and 5-year survival rates of 89.11%, 70.98%, and 56.44%, respectively. PRFA showed rates of 94.01%, 65.20%, and 39.93%, while TACE displayed rates of 90.88%, 48.95%, and 29.24%. Multivariable Cox survival analysis in the weighted population showed a survival benefit over alternative treatments (PRFA vs LR: hazard ratio [HR], 1.41; 95% CI, 1.07-1.86; P = .01; TACE vs LR: HR, 1.86; 95% CI, 1.29-2.68; P = .001). Competing risk analysis confirmed a lower risk of cancer-related death in LR compared with PRFA and TACE. CONCLUSIONS AND RELEVANCE: For patients with early multinodular HCC who are ineligible for transplant, LR should be prioritized as the primary therapeutic option, followed by PRFA and TACE when LR is not feasible. These findings provide valuable insights for clinical decision-making in this patient population.

Nearly equiatomic AlCoCrFeNi alloy samples were prepared by induction melting and mechanical alloying (MA) combined with spark plasma sintering (SPS). The cast sample showed a dendritic microstructure composed of spinodally decomposed nanometric constituents of the B2 and BCC phases. The spark plasma sintered sample exhibited an ultrafine-grained microstructure of B2 phase and FCC solid solution and Cr23C6carbides. The MA + SPS sample was strengthened by compressive stress-strain test up to a yield strength of 2029 ± 5 MPa, resulting significantly higher compared to 1366 ± 32 MPa of the cast sample. In addition to the higher compressive yield strength, the sintered sample exhibited a hardness of more than 130 HV higher compared to the cast alloy. On the other hand, the cast alloy showed high plastic deformation (29%) and significantly high ultimate compressive strength of 3072 ± 122 MPa. Together with these mechanical characteristics, the MA + SPS sample showed good thermal stability while preserving the mechanical properties even after annealing at 800 °C. This was not the case with the cast sample, in which ductility and ultimate strength significantly decreased upon annealing at 800 °C. A substantial yield strength reduction of both MA + SPS and cast samples was recorded when tested at 800 °C. Nevertheless, stress-strain curve trends were observed to be quite different between the two samples, thus suggesting dissimilar deformation mechanisms under high-temperature compression.

Introduction:The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab (A + B) is equally effective in viral and nonviral patients. Methods:We retrospectively analyzed 885 HCC patients treated with the first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% nonviral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multivariate models to explore potential differences on overall survival (OS), time-to-progression (TTP), disease control rates (DCRs) based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to the second-line treatments and outcomes were also reported and compared between etiologies. Results:Overall, no statistically significant differences were found in median OS (mOS: viral 15.9 months; nonviral 16.3 months), TTP (mTTP: viral 8.3 months; nonviral 7.2 months), and DCRs (viral 78.1%; nonviral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and nonviral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e., NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of the second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups. Conclusion:Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and nonviral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.

In metal additive manufacturing (AM), inert gases are traditionally used to achieve a controlled atmosphere and mitigate the effects of residual reactive gases. However, the interaction between gases and laser processes, particularly in reactive laser powder bed fusion (RL-PBF) technology, offers the possibility of opening up new avenues for material synthesis. In this experimental work, the authors observed the presence of C3N4in the residual powder during the manufacture of AISI 1070 steel parts by L-PBF, indicating a reactive process occurred during parts production. This investigation revealed the formation in the working chamber of a waste product containing C3N4carbon nitride, due to the reaction between the carbon released from the steel and the nitrogen in the chamber. Remarkably, despite carbon depletion, the final product of AISI 1070 steel complies with the specifications of use. Hence, the L-PBF machine was modified to allow black powder sampling from various locations in the chamber. Authors attempted to enhance the production of the C3N4material by increasing the SED up to 7143 J/mm2to sublimate a pure graphite rod and concurrently manufacture parts in AISI 1070, in a nitrogen atmosphere. The results obtained at higher SED values showed that in both cases (graphite rod or AISI 1070 steel) a C3N4compound in the black powder is formed in the investigated atmosphere by reaction of nitrogen atoms with the carbon atoms vaporized by the laser beam. Thus, the study highlights the novel achievement of synthesizing carbon nitride as a high-value by-product while producing functional AISI 1070 steel parts via L-PBF through reaction with nitrogen atmosphere.

Our paper describes the production and characterization of inhalable microparticles loaded with nanoparticles for the lung administration of rapamycin (Rapa). In detail, core–shell lipid/polymer hybrid nanoparticles loaded with Rapa (Rapa@Man-LPHNPs) were produced with mean size of about 128 nm and slightly negative ζpotential (−13.8 mV). A fluorescent graft polyaspartamide-poly(lactic-co-glycolic acid) copolymer (PHEA-g-RhB-g-PLGA) for use as the polymeric core was obtained by nanoprecipitation, while an appropriate mixture of DPPC and mannosylated phospholipid (DSPE-PEG2000-Man) was used to provide the macrophage-targeting lipid shell. The successful formation of Rapa@Man-LPHNPs was confirmed by TEM and DSC analyses. The loaded drug (4.3 wt% of the total weight) was slowly released from the polymeric core and protected from hydrolysis, with the amount of intact drug after 24 h of incubation in the medium being equal to 74 wt% (compared to 40% when the drug is freely incubated at the same concentration). To obtain a formulation administrable by inhalation, Rapa@Man-LPHNPs were entrapped inside PVA : LEU microparticles by using the nano into micro (NiM) strategy, specifically by spray drying (SD) in the presence of a pore-forming agent. In this way, NiM particles with geometric and theoretical aerodynamic diameters equal to 4.52 μm and 3.26 μm, respectively, were obtained. Furthermore, these particles showed optimal nebulization performance, having an FPF and an MMAD equal to 27.5% and 4.3 μm, respectively.

Dynamic modulus vs. temperature was measured in different alloys (stainless steels, Al alloys, Ti alloys, Ni-base superalloys) prepared by additive manufacturing and an anomalous trend was observed in some of them. Dynamic modulus, measured in successive mechanical spectroscopy test runs with heating-cooling cycles, exhibits an anomalous trend in the first test run that is no longer present in the successive runs. The phenomenon consists in the inversion of the decreasing trend of modulus occurring during heating and gives rise to its permanent increase at the end of the complete heating-cooling cycle. The temperature range where the modulus anomaly takes place and the permanent increase observed after cooling depend on the specific alloy. Scanning electron microscopy (SEM) observations and density measurements revealed that the irreversible process causing the anomalous behavior is the closure of pores of nanometric size leading to material densification. This result has been discussed by considering lattice diffusion.

Background:Atezolizumab + bevacizumab represent the current standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, direct comparison with other combination treatments including immune checkpoint inhibitors (ICI) + tyrosine kinase inhibitors (TKIs) are lacking. Objectives:This network meta-analysis (NMA) aims to indirectly compare the efficacy and the safety of first-line systemic therapies for unresectable advanced HCC. Method:A literature search of MEDLINE, Embase, and SCOPUS databases was conducted up to October 31, 2022. Phase 3 randomized controlled trials (RCTs) testing TKIs, including sorafenib and lenvatinib, or ICIs reporting overall survival (OS) and progression-free survival (PFS) were included. Individual survival data were extracted from OS and PFS curves to calculate restricted mean survival time. A Bayesian NMA was performed to compare treatments in terms of efficacy (15- and 30-month OS, 6-month PFS) and safety, represented by grade ≥3 (severe) adverse events (SAEs). The incremental safety-effectiveness ratio as measure of net health benefit was calculated as the difference in SAE probability divided by survival difference between the 2 most effective treatments. Results:Nine RCTs enrolling 6,600 patients were included. Atezolizumab plus bevacizumab showed the highest probability (88%) of achieving the 30-month OS landmark. Lenvatinib showed a probability of 86% of achieving best PFS outcomes. ICI monotherapies ranked as most tolerable. Atezolizumab plus bevacizumab showed the best net health benefit for OS, compared to durvalumab plus tremelimumab. When evaluating the net health benefit for PFS, at a willingness-to-risk threshold of 10% of SAEs for life-month gained, atezolizumab plus bevacizumab was favoured in 78% of cases, while at threshold of 30% of SAEs for life-month gained, lenvatinib was favoured in 76% of cases. Conclusions:Atezolizumab plus bevacizumab is the best treatment in terms of net benefit and therefore it should be recommended as standard of care. Compared to atezolizumab plus bevacizumab, lenvatinib monotherapy had the best net benefit for PFS when physicians and patients are available to accept a higher risk of toxicity.

Introduction:Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies. Methods:A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences. Results:ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases. Conclusion:Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC.

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort.MethodsWe analysed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centres to compare epidemiological and future trends in three subgroups: pure, single aetiology MAFLD (S-MAFLD); mixed aetiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC.ResultsMAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002–2003, to 77.3% and 28.9% in 2018–2019, respectively, p<0.001). In Italy S-MAFLD HCC is expected to overcome M-MAFLD HCC in about 6 years. Patients with S-MAFLD HCC were older, more frequently men and less frequently cirrhotic with clinically relevant portal hypertension and a surveillance-related diagnosis. They had more frequently large tumours and extrahepatic metastases. After weighting, and compared with patients with non-MAFLD, S-MAFLD and M-MAFLD HCC showed a significantly lower overall (p=0.026, p=0.004) and HCC-related (p<0.001, for both) risk of death. Patients with S-MAFLD HCC showed a significantly higher risk of non-HCC-related death (p=0.006).ConclusionsThe prevalence of MAFLD HCC in Italy is rapidly increasing to cover the majority of patients with HCC. Despite a less favourable cancer stage at diagnosis, patients with MAFLD HCC have a lower risk of HCC-related death, suggesting reduced cancer aggressiveness.

Introduction:In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. Methods:The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. Results:We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0–1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). Conclusions:Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

Carbon quantum dots (CQD) were prepared from three different precursors and by three bottom-up synthesis methods: classical pyrolysis of citric acid (CAP), microwave irradiation of glucose (GM), and hydrothermal treatment of glucosamine hydrochloride (GAH). CQD were further functionalized using various nitrogen-containing compounds: 6-aminohexanoic acid, 1,6-diaminohexane, N-octylamine, dimethylamine, and tryptophan. Special attention was dedicated to investigate how the combination of synthetic method and starting material affected the nature and properties of CQD. The analysis indicated that CAP were good candidates for covalent post-functionalization, GM allowed an easy passivation, and GAH permitted the direct introduction of nitrogen into the core. The size distribution showed a core–shell structure for CQD functionalized with an aminoacid by microwave irradiation, whereas the thermal decomposition evidenced the degradation of functionalizing molecules and the presence of pyridinic and pyrrolic nitrogen after hydrothermal synthesis. Photoluminescence spectra revealed important differences between the synthesis techniques, related to the occurrence of surface states, and the highest fluorescence quantum yield for hydrothermally prepared CQD. These approaches led to CQD with properties that can be exploited in many fields from energy conversion to sensing.

The creep behaviour of an AM50 alloy modified by the addition of different proportions of Si was investigated at 125 °C. Increases from 0.3 to 1.5 wt.% Si led to a significant reduction in secondary creep rate. The time to rupture under 100 MPa increased with Si content and peaked with Si = 0.5 – 0.8 wt.%; further increases in Si content did not induce significant variations in creep strength, since the reduction in creep rate was offset by a parallel reduction in ductility. Microstructural investigations led to the identification of the major strengthening phases: β-Mg17Al12and Mg2Si. Results are discussed and analysed in the light of the more recent data on the creep response of other Mg– Al alloys.

ObjectiveThe benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration.DesignWe pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson.ResultsRecurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1).ConclusionEffects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

High-entropy alloys are known to show exceptionally high mechanical properties, both compression and tensile strength, and unique physical properties, such as their phase stability. These quite unusual properties are primarily due to the microstructure generated by mechanical alloying processes, such as conventional induction arc melting, powder metallurgy, or mechanical alloying. In the present study, an equiatomic CoCrFeNiNb high-entropy alloy was prepared by a sequence of conventional induction melting, powder metallurgy, and compaction via spark plasma sintering. The high-entropy alloys showed uniform sub-micrometer grain microstructure consisted by a mixture of an fcc solid solution strengthened by a hcp Laves phase and a third intergranular oxide phase. The as-cast high-entropy alloys showed an ultimate compression strength (UCS) of ∼1400 MPa, which after sintering and compaction at 1273 K increased up to ∼2400 MPa. Extensive transmission electron microscopy quantitative analyses were carried out to model the UCS. A quite good agreement between the microstructure-strengthening model and the experimental UCS was found.

Background: Hepatocellular carcinoma prognosis depends on both liver and tumor determinants, especially on maximum tumor diameter, multifocality, and presence of portal vein thrombosis, despite apparently complete tumor removal by resection or liver transplantation.Aims: To examine parameters of hepatocellular carcinoma aggressiveness as tumor size increases.Methods: A large hepatocellular carcinoma database was examined for trends in serum alpha-fetoprotein and the percentage of patients with macroscopic portal vein thrombosis or tumor multifocality.Results: A total of 13,016 hepatocellular carcinoma patients were identified having full tumor and survival data. Of these, 76.56% were male and 23.44% were female, with a median age of 64.4 years. We found that as the maximum tumor diameter increased, there was a significant trend for increased alpha-fetoprotein levels (P<0.001) and an increased percentage of patients with either portal vein thrombosis or tumor multifocality, each P<0.0001. Furthermore, the increases of both alpha-fetoprotein and portal vein thrombosis were proportionately greater than the related maximum tumor diameter increases. These trends of increased alpha-fetoprotein, portal vein thrombosis, and multifocality with increasing maximum tumor diameter had non-linear patterns. Within alpha-fetoprotein and multifocality trends, there were identifiable sub-trends associated with specific maximum tumor diameter ranges.Conclusions: The greater fold-increases in alpha-fetoprotein and portal vein thrombosis compared with increases in maximum tumor diameter imply that hepatocellular carcinoma characteristics may change with increasing size to a more aggressive phenotype, suggesting that follow-up tumor sampling might be useful, in addition to baseline tumor sampling, for optimal therapeutic choices to be made.

The properties of anodized aluminum, and wear resistance in particular, are of high interest for the scientific community. In this study, discs of AA6082 were subjected to a peculiar hard anodizing process leading to anodized samples having different thicknesses. In order to investigate the wear mechanism of samples, unidirectional tribological tests were performed against alumina balls (corundum) under different loading conditions. Surface and microstructure of all the samples were characterized before and after the tribological tests, using different characterization techniques. The tribological tests showed remarkable differences in the friction coefficient and wear behavior of the anodized AA6082 samples, related to the microstructure modifications and to the specific applied sliding conditions.

Introduction:The prognosis of patients undergoing transarterial chemoembolization (TACE) is extremely variable, and a confounding factor is that TACE is often repeated several times. We retrospectively evaluated the accuracy of different prognostic scores and staging systems in estimating overall survival (OS) in patients with hepatocellular carcinoma (HCC). Methods:An analysis considering prognostic models as time-varying variables was performed, calculating OS from the time of TACE to the time of the subsequent treatment. Total follow-up time for each patient was therefore split into several observation times accounting for each TACE procedure. Values of the likelihood ratio test (LRT) and Akaike information criterion (AIC) were used to compare different systems. Univariable and multivariable analyses were conducted to identify additional factors predictive of OS. We analyzed 1,610 TACE performed in 1,058 patients recorded in the Italian Liver Cancer database from 2008 through 2016. Results:The median OS of the enrolled patients was 41 months. According to LRT χ2 and AIC values based on the time-varying analysis, mHAP-III achieved the best values (41.72 and 4,625.49, respectively, p< 0.0001), indicating the highest predictive performance compared with all other scores (HAP, mHAP-II, ALBI, and pALBI) and staging systems (MELD, ITALICA, CLIP, MESH, MESIAH, JIS, HKLC, and BCLC). In the multivariable Cox proportional hazards model, mHAP-III maintained an independent effect on OS (hazard ratio 1.31, 95% CI: 1.10–1.55, p< 0.0001). Time-varying age, alcoholic etiology, radiologic response to TACE, and performing ablation or surgery after TACE were additional significant variables resulting from the multivariable model. Conclusion:An innovative time-varying analysis revealed that mHAP-III was the most accurate model in predicting OS in patients with HCC undergoing TACE. Other clinical pre- and post-TACE variables were also found to be relevant for this prediction.

Introduction:Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. Methods:We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. Results:Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4–14.8) and 5.1 (3.3–6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3–4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. Conclusions:In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials.

ABSTRACTIntroduction: Concerns were raised about a high occurrence of hepatocellular carcinoma (HCC) after successful treatment of chronic hepatitis C (CHC) by direct-acting antivirals (DAAs).Areas covered: The authors summarize the clinical studies reporting the occurrence rate and risk factors of HCC after DAAs in CHC.Expert opinion: The recent introduction of all-oral DAAs has substantially changed the scenario of CHC, achieving a sustained virological response (SVR) in >90% of cases. Earlier concerns raised about an increasing incidence of HCC post-DAAs were flawed by large heterogeneity of patients, the limited number of well-designed prospective studies (only nine, up to date) and the inclusion of a large number of patients with advanced liver disease, previously excluded from interferon-based studies. Current data on DAAs have shown a lower risk of HCC development; however, they were unable to identify patients at greater risk for HCC occurrence after SVR. Surveillance strategy, likely lifelong, is mandatory in these patients according to general expert opinion.

AbstractPorous materials are playing an increasingly relevant role in several fields and industrial sectors with structural and functional applications. Their properties critically depend on the relative density and pore morphology thus it is of great importance monitoring the variations of such structural features. Among the experimental techniques commonly used for investigating the microstructure evolution of porous materials, Mechanical Spectroscopy (MS) provides damping and dynamic modulus of the material during heat treatments. In this work three cases of possible pore structure evolution in different metallic alloys have been examined by MS: (i) growth and coalescence of pores, (ii) closure of pores of nanometric size and (iii) no change of porosity.The results show how dynamic modulus measurements can be successfully employed for a direct monitoring of porosity variations during heating. The technique is quite sensitive and allows to identify the temperature range where pore evolution takes place providing information useful to orientate heat treatments of porous materials.

The NA48/2 experiment collected data in 2003 and 2004 with the main purpose to study direct CP violation in charged kaons decaying in three pions. Thanks to the huge statistics collected, other studies are also possible. In this paper two recent results, in the framework of QCD studies, are reported: the measurement of the K±→ π0e±νForm Factors and the first observation of the rare decay K±→ π±π0e+e−.

An innovative method of tool wear assessment, based on the digitization of the cutting tool performed by a piezoelectric 3D scanner and on the analysis of the surfaces of a 3D model generated using the Reverse Engineering technique, has been developed. To this purpose, face milling experiments were carried out under dry cutting condition on AISI 420 B stainless steel using inserts in cemented carbide, with a two-layers coating (TiN and TiAlN). The time dependence of the insert wear was analysed by interrupting milling at predetermined time values. The proposed approach has been validated by comparing the output provided by the reverse engineering method to that measured experimentally by analysing the worn insert images obtained using a stereo microscope. An excellent agreement between the results given by the two different methodologies has been found. The worn tools have also been analysed using the scanning electron microscopy technique in order to understand the wear mechanisms operating during dry milling.

A high-pressure die-cast magnesium alloy plate was friction stir processed at high rotation rates with different advancing speeds. The stirred zone was very narrow around the tool and this made the friction stir process difficult to occur in the whole thickness of the plate. Intermetallic-phase network at grain boundaries was refined due to partial dissolution and fragmentation of Mg17Al12 β-phase during the friction stir process; the likely increment of solute content in solid solution was exploited for aging to improve hardness. The ductility of friction stir processed samples deformed at 300° and 350°C substantially increased compared to the base material and to room temperature strained samples.

Nowadays, cutting tools, designed to be used for machining without lubricants, are developed to improve the high working speed capabilities. With this respect, quaternary Ti-and N-based coatings are able to significant increase hardness, wear resistance and high temperature oxidation resistance. One of the major drawbacks still consists on the limited thermal stability of such coatings, which is reported to be about 600°C. In the present study, thermal stability studies of a nanostructured multi-layered N-based (AlTiCrxN1-x) coating on a HSS 6-5-2 tool steel were carried out. Two quantities were calculated out of the hardness and elastic modulus of the coatings. One is the ratio H/E that represents the coating resistance to compression without failure; another one is H3/E2, which provides information on the specific contact pressure limit without failure. It was found that, by using the less demanding thermal cycling mode, the coating ability to plastically deform without damage, is retained up to 800-1000°C. The highest, and more effective coating plasticity index was obtained by using the less demanding cycling mode, while, the other two modes induced a continuous index decrease with temperature.

In this paper, the hot working behaviour of X30 CrMoN 15 1 high N steel was investigated by torsion testing. A new constitutive model based on the Garofalo equation was used to describe the flow stress dependence on temperature, strain and strain rate. Adiabatic heating was accounted for in the modelling of the flow curves. An excellent description of the experimental data was obtained by the model, which suggests that in isothermal condition the flow curves are characterised by a peak, followed by a moderate softening to a steady state. The high values of the activation energy for hot working were rationalised by considering the strengthening effect of undissolved particles hindering dislocation motion.This paper is part of a Themed Issue on Recent developments in bearing steels.

An innovative welding methodology, defined as double-side friction stir welding, was developed in order to obtain joints in 2-mm-thick sheets in AA6082 aluminium alloy. Such approach consists in performing the friction stir welding process on both sheet surfaces: the first welding operation is followed by a second one performed by putting the rotating tool in contact with the sheet surface opposite to the one welded by the first pass. The effect of the welding parameters, tool configuration and sheet positioning on the mechanical properties, microstructure and post-welding formability was analysed and discussed in detail. In order to evaluate the advantages offered by the new welding methodology, the experimental results obtained using the double-side friction stir welding were compared with those given by the conventional process.

Effects of new physics in flavor could be found both in Flavor Changing Neutral Current (FCNC) processes and in Lepton Flavor Violation (LFV) modes. The former offer the possibility to deeply test the standard model in a clean environment, while the latter are sensitive to contribution from several models beyond the standard model. In the Kaon sector both FCNC and LFV will be investigated in the NA62 experiment. In addition the kaons sector is an ideal place where to look for new particles and tiny effects, in the region of hundreds of MeV/c2. In this paper prospects for exotic searches in NA62 will be presented, together with recent results from NA48/2 and NA62-RK on LFV kaon decays modes.

The chalcogenide material Ge2Sb2Te5is the prototype phase-change material, with widespread applications for optical media and random access memory. However, the full set of its independent elastic properties has not yet been published. In this study, we determine the elastic constants of the rocksalt Ge2Sb2Te5, experimentally by X-ray diffraction (XRD) and residual stress and computationally by density functional theory (DFT). The stiffnesses (XRD-stress/DFT) in GPa are C11= 41/58, C12= 7/8, and C44= 8/12, and the Zener ratio is 0.46/0.48. These values are important to understand the effect of elastic distortions and nonmelting processes on the performances of increasingly small phase change data bits.

OBJECTIVES:The Barcelona Clinic Liver Cancer (BCLC) intermediate stage (BCLC B) includes a heterogeneous population of patients with hepatocellular carcinoma (HCC). Recently, in order to facilitate treatment decisions, a panel of experts proposed to subclassify BCLC B patients. In this study, we aimed to assess the prognostic capability of the BCLC B stage reclassification in a large cohort of patients with untreated HCC managed by the Italian Liver Cancer Group.METHODS:We assessed the prognosis of 269 untreated HCC patients observed in the period 1987–2012 who were reclassified according to the proposed subclassification of the BCLC B stage from stage B1 to stage B4. We evaluated and compared the survival of the various substages.RESULTS:Median survival progressively decreased from stage B1 (n=65, 24.2%: 25 months) through stages B2 (n=105, 39.0%: 16 months) and B3 (n=22, 8.2%: 9 months), to stage B4 (n=77, 28.6%: 5 months; P<0.0001). Moreover, we observed a significantly different survival between contiguous stages (B1 vs. B2, P=0.0002; B2 vs. B3, P<0.0001; B3 vs. B4, P=0.0219). In multivariate analysis, the BCLC B subclassification (P<0.0001), MELD score (P=0.0013), and platelet count (P=0.0252) were independent predictors of survival.CONCLUSIONS:The subclassification of the intermediate-stage HCC predicts the prognosis of patients with untreated HCC. The prognostic figures identified in this study may be used as a benchmark to assess the efficacy of therapeutic intervention in the various BCLC B substages, whereas it remains to be established whether incorporation of the MELD score might improve the prognosis of treated patients.

In the present work, the strengthening effect of the Fe-rich intermetallic phases in a 2219 aluminium alloy subjected to equal channel angular pressing (ECAP) has been studied. Three different deformation conditions, corresponding to the as-extruded, ECAP route A—1 pass and ECAP route A—2 passes were considered. Microstructural characterization has been performed by light microscopy, transmission electron microscopy and scanning electron microscopy observations. All the contributions to the alloy strengthening, including solid solution, dislocation boundary, very fine particle precipitation induced by the adiabatic heating, equilibrium θ = Al2Cu secondary phase particles and the effect of the Fe-rich intermetallics, are discussed in this work. The resulting strengthening was evaluated and modelled in Part II.

In the present work, the strengthening effect of the Fe-rich intermetallic phases in a 2219 aluminum alloy subjected to equal channel angular pressing (ECAP) has been studied. Three different deformation conditions, corresponding to the as-extruded, ECAP route A—1 pass, and ECAP route A—2 passes, were considered. Mechanical characterizations have been performed by microhardness tests and tensile tests. All the contributions to the strengthening due to solid solution affects, dislocation boundaries, fine particles, and intermetallics have been quantitatively determined using transmission electron microscopy and field-emission scanning electron microscopy. The microstructure strengthening terms were combined, and the resulting value was shown to be fully consistent with the experimental yield strength obtained either by tensile tests or by microhardness measurements. These were (i) solution hardening; (ii) dislocation hardening through grain, cell, and very-low angle (misorientation angles within 4°, and typically showing Moiré fringes on TEM) boundaries; (iii) strengthening due to the equilibrium θ (Al2Cu), either through shearable (i.e., anti-phase) or by bowing (i.e., Orowan) mechanism; (iv) GP-I, GP-II (θ″) zones, and semi-coherent θ′ pre-precipitate, generated along tangle dislocations by the combined effect of the severe plastic deformation and the adiabatic heating; and (v) coarser intermetallic particle strengthening. In particular, the effect of the Fe-rich intermetallics on the alloy has been evaluated by calculating all the characteristic terms: the so-called parameter of intermetallic appearance index, according to Shabestari, the strengthening due to the load transfer (ΔσLT), and the strengthening due to the presence of the intermetallic phases (ΔσIntermet). Very good agreement was obtained between the strengthening model developed in this study and the experimentally measured yield stress.

Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance. It is associated with a high rate of mortality and its prevalence in the United States and in Western Europe is increasing. Cirrhosis is the strongest and the most common known risk factor for HCC, usually due to hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. However, different lines of evidence identify in non-alcoholic fatty liver disease (NAFLD) a possible relevant risk factor for occurrence of HCC. Given the continuing increase in the prevalence of obesity and diabetes, the incidence of non-alcoholic steatohepatitis–related HCC may also be expected to increase, and a potential role of behavior treatment and/or insulin-sensitizing drugs can be envisaged. Vaccination against HBV is the most efficient primary prevention measure currently available to reduce the HCC incidence and mortality in high-incidence areas, while data on the role of interferon (IFN) and nucleos(t)ide analogues (NUC) are still controversial. The pooling of data from the literature suggests a slight preventive effect of antiviral therapy on HCC development in patients with HCV-related cirrhosis, but the preventive effect is limited to sustained virological responders.

Magnesium alloys containing rare earth elements are known to have high specific strength and corrosion resistance. The addition of SiC ceramic particles makes the metal matrix composite stronger with better wear and creep resistance and a still good machinability. The role of the reinforcement particles to the enhanced strength can be quantitatively evaluated using transmission electron microscopy (TEM). This paper presents a quantitative strengthening evaluation in a SiC Mg-RE composite alloy. The different contributions were determined by TEM inspections. The microstructure strengthening mechanism was studied after room temperature compression specimens. The way of combining the different contributions and the comparison to the measured yield stress, is also discussed and justified.

This paper is a review of the thermal stability of nanostructured nitride coatings synthesised by reactive magnetron sputtering technique. In the last three decade, nitride based coatings have been widely applied as hard wear-protective coatings in mechanical components. More recently, a larger interest has been addressed to evaluate the thermal stability of such coatings, as their mechanical and tribological properties are deteriorated at high working temperatures. This study describes the microstructural, mechanical and compositional stability of nano-crystalline Cr-N and nano-composited Ti-N based coatings (Ti-Al-Si-B-N and Ti-Cr-B-N) after air and vacuum annealing. For Cr-N coatings annealing in vacuum induces phase transformation from CrN to Cr2N, while after annealing in air only Cr2O3 phase is present. For Ti-N based coatings, a well-definite multilayered structure was shown after air annealing. Degradation of mechanical properties was observed for all the nitride coatings after thermal annealing in air.

Intra- and postoperative bleeding represents an extremely serious and frequent complication of hepatic surgery. In this study, we evaluated the effectiveness of a radiofrequency (RF) device using heat to cause coagulative necrosis of the hepatic parenchyma to control hemostasis in minor hepatic resection. Between December 2005 and November 2007, a study was conducted of 21 patients undergoing 22 hepatic resections with the RF-assisted technique. Sixteen of these were affected by hepatocellular carcinoma and five had liver metastases from colorectal cancer. Intraoperative blood loss, the need for blood transfusion, the complication rates, operating times, and the duration of postoperative hospitalization were evaluated. Four segmentectomies and 18 tumorectomies were performed. The average blood loss was of 15.7 mL (range, 0-40 mL); the average operating time was 25.7 minutes (range, 12-43 minutes); the mean postoperative hospital stay was 8.2 days (range, 3-49 days) with a median of 6.0 days. The authors concluded that the RF-assisted technique can be a useful method not only for reducing blood loss and avoiding blood transfusions, but also for reducing operating time and postoperative hospitalization for minor liver resections.

The prevalence of hepatocellular carcinoma in Europe and the US is increasing and is currently the leading cause of death in patients with cirrhosis. Surveillance programs for patients with cirrhosis aim to detect tumors at an early stage, when the greatest therapeutic benefits can be achieved. Curative treatments for early-stage tumors include liver transplantation, resection and percutaneous ablation. Transarterial chemoembolization (TACE) and sorafenib can improve survival for patients with intermediate and advanced tumors, respectively. In clinical practice, combination therapies are often used, despite limited evidence to support this approach from randomized controlled trials. Combination therapy with radiofrequency ablation (RFA) plus percutaneous ethanol injection can, however, improve survival for selected patients compared with RFA alone. Combined treatment with TACE and RFA also improves patients' survival compared with TACE or RFA monotherapy. TACE performed before or after surgical resection, however, is not beneficial. Prevention of tumor progression in patients awaiting liver transplantation requires nonsurgical treatments; however, the real advantages of the available treatment modalities are yet to be defined. The role of sorafenib administration in combination with TACE after the use of potentially curative treatments, for the treatment of intermediate hepatocellular carcinoma, or in selective settings after liver transplantation, requires further study.

Here, novel lipid–polymer hybrid nanoparticles (LPHNPs), targeted to lung macrophages, were realized as potential carriers for Roflumilast administration in the management of chronic obstructive pulmonary disease (COPD). To achieve this, Roflumilast-loaded fluorescent polymeric nanoparticles, based on a polyaspartamide-polycaprolactone graft copolymer, and lipid vesicles, made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-distearoyl-sn-glycero-phosphoethanolamine-N-(polyethylene glycol)-mannose, were properly combined using a two-step method, successfully obtaining Roflumilast-loaded hybrid fluorescent nanoparticles (Man-LPHFNPs@Roflumilast). These exhibit colloidal size and a negative ζ potential, 50 wt % phospholipids, and a core–shell-type morphology; they slowly release the entrapped drug in a simulated physiological fluid. The surface analysis also demonstrated their high surface PEG density, which confers mucus-penetrating properties. Man-LPHFNPs@Roflumilast show high cytocompatibility toward human bronchial epithelium cells and macrophages and are uptaken by the latter through an active mannose-mediated targeting process. To achieve an inhalable formulation, the nano-into-micro strategy was applied, encapsulating Man-LPHFNPs@Roflumilast in poly(vinyl alcohol)/leucine-based microparticles by spray-drying.

Spark Plasma Sintering (SPS) of nanostructured FeMo powder produces samples with satisfactory density, however the final grain size critically depends on the sintering temperature. Two groups (sets A and B) of samples have been examined by means of internal friction (IF) and dynamic modulus measurements carried out in successive test runs on the same samples to assess their structural stability. Set A and B had been sintered at 1113 and 1128 K and had an average grain size of 100 nm and 1 µm, respectively. TEM and XRD have been performed on the samples in as-prepared condition and after IF measurements cycles. The samples with smaller grains are more stable and substantially are not affected by grain coarsening which, on the contrary, occurs in those with grains of larger size. The heating up to 923 K during the tests diminishes dislocation density in both the groups. An anomalous trend of resonance frequency during the first test run in samples of set A has been ascribed to the formation of small cracks relaxing internal stresses.

This paper presents a transmission electron microscopy study of two Fe-1.5wt.%Mo steels stabilized with 1.5wt.%SiO2 and 1.5wt.%TiO2,respectively, and compacted through spark plasma sintering. The microstructure inspections revealed that sintered FeMo+SiO2 is able to maintain a nanometric scale grained structure up to a sintering temperature of 815°C, while the steel modified with TiO2 retained its nanometric scale microstructure up to 900°C. The ultra-fine grained structure (within 100-150 nm) was also directly correlated to the grain boundary stability through systematic extinction contours survey. Local nano-welding phenomena shows the effective compacting process of the Fe-Mo powders during sintering. Residual nano-porosity was found to decorate most of the grain boundaries and the triple grain junctions in all the sintering conditions examined, although this nano-porosity accounted for values within 0.26% in volume fraction.

Thin nanostructured Ti-B-N-based films are known for their excellent mechanical properties and their stability at high temperature in oxidizing atmosphere. In the present work, nanostructured Ti-Al-Si-B-N and Ti-Cr-B-N coatings deposited on AISI 304 stainless steel by ion implantation have been characterized. To evaluate the oxidation resistance and thermal stability, the coatings were annealed at 900°C in vacuum and in air for 4 hours. The mechanical properties, phase composition and micro-structure of as-deposited and annealed coatings were addressed. The coatings showed a complex multilayered structure and a substantial change of their mechanical properties, due to the new structure and to the phases formed after air annealing.

Microstructure evolution with equal channel angular pressing (ECAP) using route Bc, that is a 90° axial rotation of the billet between passes, up to 8 passes, was investigated by transmission electron microscopy. The study has been focused on the induced development of boundary misorientation and spacing toward microstructure refinement. Cell (low-angle) and grain (high-angle) misorientation and spacing were determined from about 250 boundaries per pass of ECAP, systematically using whether Kikuchi patterns or Moiré fringes, these latter where possible. The average cell size and misorientation saturate within the first two passes. Misorientation and spacing of high-angle boundaries decrease with the number of passes. After 8 passes, mean cell size is ≈ 1.3 µm and the fraction of high-angle boundaries is ≈ 0.7. Differences in rate of grain structure evolution per pass are linked to differences in ability of dislocations introduced in new passes to recombine with the existing ones. As ECAP strain rises, the misorientation distribution develops strong deviations from the MacKenzie distribution for statistical grain orientation. This is interpreted as a result of the tendency to form equiaxed grains in a textured grain structure.

The tensile properties and the microstructure of an Al-7%Si-0.6%Mg-0.5%Cu rheo-cast component were investigated. The material underwent a T5 treatment, consisting in ageing at 160, 175 and 190°C for durations ranging from 0.5 to 48h. Tensile testing indicated that the T5 treatment resulted in a relatively good level of strength and in a comparatively low ductility. In order to improve ductility, maintaining as low as possible the cost of the final component, a single solution treatment at 500°C for 4h was subsequently applied. The tensile strength and ductility of the solution treated and aged material were higher than in the T5 condition. These differences were attributed to the microstructural evolution occurring during exposure at 500°C, in particular to the spheroidization of eutectic-Si and to a more homogeneous distribution of the precipitates.

The microstructural evolution with strain was investigated either in a Zr-modified 6082 Al-Mg-Si alloy and in the same alloy added with 0.117wt.% Sc, subjected to severe plastic deformations. Materials were deformed by equal-channel angular pressing using route BC, up to a true strain of ∼12. A strain of ~4 produced a sub-micrometer scale microstructure with very fine cells (nanometer scale) in the grain interior. The role of fine dispersoids (Al3(Sc1-x,Zrx)) was investigated by transmission electron microscopy techniques and discussed. Dispersoids were responsible for a more complex dislocation substructure with strain. Compared to the commercial parent alloy, block wall formation and propagation were favored by the presence of Sc-Zr containing dispersoids, while cell boundary evolution was less affected, compared to the commercial parent alloy. Mean misorientation across block walls increased with strain much more in the Sc-Zr containing alloy, reaching a plateau, starting from a true strain of ∼8. Misorientation across cell boundaries continuously increased to ∼8° and ∼5° for the Sc-Zr and Zr containing alloy, respectively.

Mechanical spectroscopy was employed to investigate the microstructure evolution of a Zr-modified 6082 Al-Mg-Si alloy and the same alloy with Sc addition after ageing and following severe plastic deformation through equal channel angular pressing. Measurements of the internal friction and dynamic young modulus have been performed in isothermal and isochronal runs in the frequency range 0.1 - 104 Hz. The anelasticity spectra reveal in the temperature range 470-870 K both structural and anelastic relaxation processes. Two structural damping maxima connected with inverse temperature trend of the modulus occur in the alloys submitted to equal channel angular pressing, the first one is strongly suppresed by Sc and Zr addition. An anelastic relaxation peak whose strength depends on the nature and morphology of precipitates and dispersoids and on the deformation and ageing condition was observed in all samples investigated. The high background damping occurring before the first structural damping maximum is analyzed with reference to a superplastic behavior of the equal channel angular pressing processed alloys.

Chronic hepatitis C virus infection is currently the most common cause of end stage liver disease worldwide. Although the conclusions of the last National Institutes of Health Consensus Development Conferences on Hepatitis C have recently been published, several important issues remain unanswered. This paper reviews the available data using an evidence-based approach. Current evidence is sufficient to recommend IFN treatment for all patients with acute hepatitis. A later initiation of therapy yields the same likelihood of response as early treatment. A daily induction dose during month 1 is the best treatment option. The current gold standard of efficacy for treatment-naive patients with chronic hepatitis C is the combination of pegylated IFN and ribavirin. The overall sustained viral response rate to these regimens is 54 – 56% following a 48-week course of therapy. Patients with genotype 1 infection will have a 42 – 51% likelihood of response to 48weeks of therapy. Those with genotypes 2 or 3 infection will respond to 24weeks in 78 – 82% of cases. Debate continues regarding the optimal dose and duration of peginterferon (PEG-IFN), not only in patients infected with genotype 2 or 3 but also in those infected with genotype 1. The optimal dose of ribavirin has yet to be determined. Available data show the need to give the highest tolerable doses (1000–1200mg/day) to the difficult-to-treat patients (genotype 1, cirrhotics, obese), although there is a greater likelihood of intolerance. Genotypes 2 and 3 may receive 800mg/day, which is also the most appropriate lower dose for those patients who require dosage modification for anaemia or other side effects. Tolerability and compliance to therapy are still a problem, as ∼15– 20% of patients within trials and > 25% in clinical practice withdraw from therapy. New PEG-IFNs are more effective than conventional IFN in improving liver histology. Monotherapy with PEG-IFN induces a marked reduction in staging in virological sustained responders, and to a lesser degree in relapsers, but provides no benefit to nonresponders after 24–48weeks of treatment. The use of maintenance therapy in virological nonresponders aiming to improve histology should be considered experimental and of unproven benefit. Pooling data from the literature suggests a slight preventive effect of IFN on hepatocellular carcinoma development in patients with HCV-related cirrhosis. The magnitude of this effect is low and the observed benefit may be due to spurious associations. The preventive effect is more evident among sustained responders to IFN.

Abstract: We discuss interference effects between different particles, starting with the pioneering work by Abraham Pais and Oreste Piccioni in 1955 on K L →K S regeneration and $$K^0 - \overline K ^0 $$ oscillations. The ramifications of this work include quark mixing and neutrino oscillation phenomena.

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