Securing sustainable funding for viral hepatitis elimination plans

The majority of people infected with chronic hepatitis C virus (HCV) in the European Union (EU) remain undiagnosed and untreated. During recent years, immigration to EU has further increased HCV prevalence. It has been estimated that, out of the 4.2 million adults affected by HCV infection in the 31 EU/ European Economic Area (EEA) countries, as many as 580 000 are migrants. Additionally, HCV is highly prevalent and under addressed in Eastern Europe. In 2013, the introduction of highly effective treatments for HCV with direct‐acting antivirals created an unprecedented opportunity to cure almost all patients, reduce HCV transmission and eliminate the disease. However, in many settings, HCV elimination poses a serious challenge for countries’ health spending. On 6 June 2018, the Hepatitis B and C Public Policy Association held the 2nd EU HCV Policy summit. It was emphasized that key stakeholders should work collaboratively since only a few countries in the EU are on track to achieve HCV elimination by 2030. In particular, more effort is needed for universal screening. The micro‐elimination approach in specific populations is less complex and less costly than country‐wide elimination programmes and is an important first step in many settings. Preliminary data suggest that implementation of the World Health Organization (WHO) Global Health Sector Strategy on Viral Hepatitis can be cost saving. However, innovative financing mechanisms are needed to raise funds upfront for scaling up screening, treatment and harm reduction interventions that can lead to HCV elimination by 2030, the stated goal of the WHO.     

Diagnostic utility of CD10 in benign and malignant extrahepatic bile duct lesions

CD10, a cell surface enzyme with neutral metalloendopeptidase activity, is a marker for intestinal epithelial brush border. It is also present in normal bile ducts and gallbladder epithelia but is absent in cholangiocarcinomas. However, the expression profile of CD10 in benign and malignant extrahepatic biliary lesions has not been studied. In this study, 69 biopsies, 9 resections, and 9 cell blocks prepared from fine-needle aspirations of the extrahepatic bile ducts from 86 patients were studied immunohistochemically for CD10 expression. The majority of cases contained normal biliary epithelium (NL, n=64), along with foci of benign or malignant lesions in various combinations. Benign lesions included reactive atypia (n=35), low-grade dysplasia of unknown significance (n=21), and bile duct adenoma (BDA, n=1). Malignant lesions included high-grade dysplasia (HGD, n=45) and invasive adenocarcinoma (IC, n=30). As expected, the NL showed strong continuous staining at the apical surface in all cases. Benign lesions were also CD10 positive in all but 3 cases; however, the staining pattern was discontinuous, with positive cells varying from 20% to 80%. None of the malignant lesions showed CD10 immunoreactivity, except for 2 HGD cases and 1 IC case, which exhibited focal staining. The Pearson χ2 and Fisher exact tests showed significant statistical difference in CD10 expression among the study groups (P<0.001). Our findings suggest that absence of CD10 expression in strips of atypical biliary epithelial cells may be a phenotype associated with malignant transformation and may serve as a useful marker to aid in the evaluation of bile duct biopsies, in which distinction between benign and malignant lesions on biopsies or cytology specimens can be extremely challenging because of limited sampling, crush artifact, and frequent inflammatory/reactive changes.     

Is There any Benefit from Expanding the Criteria for the Resection of Hepatocellular Carcinoma in Cirrhotic Liver? Experience from a Developing Country

Background

Patients with large-size (>10?cm) hepatocellular carcinoma (HCC) in Child B cirrhosis are usually excluded from curative treatment, i.e., hepatic resection, because of marginal liver function and poor outcome. This study was designed to evaluate the feasibility of the radiofrequency (RF)-assisted sequential “coagulate-cut liver resection technique” in expanding the criteria for resection of large HCC in cirrhotic livers with impaired liver function.

Methods

Forty patients with Child-Pugh A or B cirrhosis underwent liver resection from December 1, 2001 to December 31, 2008. Of these, 20 patients (13 Child-Pugh A and 7 Child-Pugh B) with advanced stage HCC (stage B and C according to Barcelona-Clinic Liver Cancer Group) underwent major liver resection. The two groups were comparable in terms of patient age, liver cirrhosis etiology, tumor number, and size.

Results

All resections were performed without the Pringle maneuver. There was no significant difference found between the two groups regarding resection time, perioperative transfusion, postoperative complications, hospital stay, and day 7 values of hemoglobin and liver enzymes. Likewise, there was no significant difference found in the overall survival between Child A and Child B patients who underwent major liver resection

Conclusions

RF-assisted sequentional “coagulate-cut liver resection technique“ may be a viable alternative for management of patients with advanced HCC in cirrhotic liver with impaired function.     

Processing complex pseudo-words in mild cognitive impairment: The interaction of preserved morphological rule knowledge with compromised cognitive ability

Mild cognitive impairment (MCI) affects the cognitive performance of elderly adults. However, the level of severity is not high enough to be diagnosed with dementia. Previous research reports subtle language impairments in individuals with MCI specifically in domains related to lexical meaning. The present study used both off-line (grammaticality judgment) and on-line (lexical decision) tasks to examine aspects of lexical processing and how they are affected by MCI. 21 healthy older adults and 23 individuals with MCI saw complex pseudo-words that violated various principles of word formation in Slovenian and decided if each letter string was an actual word of their language. The pseudo-words ranged in their degree of violability. A task effect was found, with MCI performance to be similar to that of healthy controls in the off-line task but different in the on-line task. Overall, the MCI group responded slower than the elderly controls. No significant differences were observed in the off-line task, while the on-line task revealed a main effect of Violation type, a main effect of Group and a significant Violation × Group interaction reflecting a difficulty for the MCI group to process pseudo-words in real time. That is, while individuals with MCI seem to preserve morphological rule knowledge, they experience additional difficulties while processing complex pseudo-words. This was attributed to an executive dysfunction associated with MCI that delays the recognition of ungrammatical formations.     

Monthly or weekly bisphosphonate? Evaluation of satisfaction in patients with postmenopausal osteoporosis using OPSAT-Q questionnaire during the BOOSTER study in Croatia

A prospective, open-labelled, multicentre 6-month study was designed to assess three categories that have high impact on Health-Related Quality of Life (HR-QoL). These categories were: satisfaction, preference and drug tolerability in postmenopausal patients with osteoporosis in Croatia, at first treated with weekly oral bisphosphonates, followed by monthly oral ibandronate. Three hundred eighty-five postmenopausal women who were treated with one of the weekly bisphosphonates for at least 6?months were included into the study and after they had signed written informed consent, the therapy was changed to monthly ibandronate. Satisfaction with the treatment was assessed with the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q). Patients completed OPSAT-Q at the baseline visit before the change of therapy (visit 1) and 6?months after the change of therapy (visit 2). Following 6?months ibandronate therapy, the values in all four domains of the OPSAT-Q (convenience, confidence with daily activities, overall satisfaction, side effects) as well as in the Composite Satisfaction Score were higher in visit 2 (p?相似文献   

Development of Novel Water‐Soluble Phytostanol Analogs: Disodium Ascorbyl Phytostanyl Phosphates (FM‐VP4): Preclinical Pharmacology,Pharmacokinetics and Toxicology

FM‐VP4 is a novel inhibitor of cholesterol absorption that has lipid lowering and body weight reducing properties. In vitro and in vivo studies were performed to investigate the lipid‐lowering effects, mechanism of action, pharmacokinetics, and toxicity of FM‐VP4. FM‐VP4 decreased cholesterol accumulation in Caco‐2 cells by approximately 50%; its activity appeared to be independent of pancreatic lipase, p‐glycoprotein, or cholesterol incorporation in micelles. In animal studies, FM‐VP4 was added to the diet or drinking water and the following results were obtained. In gerbils 2% FM‐VP4 produced mean 56 and 53% reduction in total cholesterol (TC) after 4 and 8 weeks, respectively. This reduction was entirely due to the loss of the low‐density lipoprotein (LDL) pool, which was reduced to undetectable levels at either time point. At 8 weeks, high‐density lipoprotein (HDL) concentration had risen by a mean of 34% whereas total triglyceride (TG) concentrations had decreased by a mean of 60%. FM‐VP4 also had a profound effect on body weight in these animals. At 8 weeks, the mean body weight was in the 4% FM‐VP4 treatment group 25% lower than in the control group. No hepatic or renal toxicity was associated with these changes. In Apo E‐deficient mice, after 4‐ and 8‐week treatments FM‐VP4 caused a significant decrease in both TC and TG concentrations compared to controls. After 12 weeks, the areas of atherosclerotic lesion involvement in the aortic roots were decreased by a mean of 80% in the 0.5, 1, and 2% FM‐VP4 treatment groups compared to controls. Taken together, these results suggest that FM‐VP4 is a potential new drug with lipid‐lowering and weight loss potential, without apparent toxicity.     

The effect of alcohols as the third component on diffusion in mixtures of aromatics and ketones

With laboratory and numerical work, we demonstrate that one of the main diffusion coefficients and the smaller eigenvalue of the Fick diffusion matrix are invariant to the number of methylene groups of the alcohol in ternary mixtures composed of an aromatic (benzene), a ketone (acetone) and one of three different alcohols (methanol, ethanol or 2-propanol). A critical analysis of the relationship between the kinetic and thermodynamic contributions to the diffusion coefficients allows us to explain this intriguing behaviour of this class of mixture. These findings are reflected by the diffusive behaviour of the according binary subsystems. Our approach provides a promising systematic framework for future investigations into the important and challenging problem of transport diffusion in multicomponent liquids.

The Fick diffusion coefficient matrix of three ternary mixtures composed of an aromatic (benzene), a ketone (acetone) and one of three different alcohols (methanol, ethanol or 2-propanol) is investigated with laboratory and numerical work.

Multicomponent diffusion plays a crucial role in various natural and industrial processes involving mass transfer.^1–3 Liquids appearing in nature and technical applications are essentially multicomponent. However, only data on binary diffusion coefficients are relatively abundant because the diffusion behavior of ternary and higher mixtures is much more complex.^4,5 Describing the isothermal–isobaric diffusion of a ternary mixture by Fick’s law requires four different diffusion coefficients that are composition dependent. The presence of cross diffusion coefficients aggravates the interpretation and data processing in experimental work, resulting in large uncertainties.^6,7 Thus, efforts are being made to develop new methods for analysis of multicomponent diffusion explicitly addressing various degrees of complexity.^8–10 Predictive equations for multicomponent diffusion of liquids mostly rely on extensions of the Darken relation,^11–13 which is only valid for ideal mixtures.¹⁴ The underlying physical phenomena in non-ideal mixtures are not well understood and the lack of experimental data impedes the development and verification of new predictive equations.The objective of this study was not only to measure and predict the Fick diffusion coefficient matrix for a series of ternary liquid mixtures, rather, the emphasis lied on understanding common features and whether they can be related to the behavior of the pure components and binary subsystems. Three ternary mixtures that are composed of organic compounds were selected, i.e. an aromatic, a ketone and an alcohol. Throughout, the first two components were benzene (1) and acetone (2) and the third component was one of the alcohols, methanol, ethanol or 2-propanol. For each mixture, nine state points along a composition path with a constant content of benzene, x₁ = 0.33 mol mol⁻¹, were studied under ambient conditions (298.15 K and 0.1 MPa). Seven of the state points were ternary mixtures and two were binary subsystems. To obtain reliable results for the Fick diffusion coefficient matrix, two complementary approaches were used, i.e. experiments and predictive molecular simulations. This combination allows for a critical analysis and leads to a deeper understanding of the underlying phenomena.^14,15The Taylor dispersion technique was utilized for the experiments.^16,17 In this method, a small quantity of mixture with a slightly different composition is injected into a laminar stream. It disperses due to convection and diffusion while flowing through a capillary tube and the refractive index is measured at its end to sample the concentration distribution. We have used the same apparatus as in previous works.^6,7 The Fick diffusion matrix is obtained by fitting working equations to the measured signal, i.e. the Taylor peak. The mathematical model of the Taylor dispersion technique was originally developed on the basis of Fick’s law in the volume reference frame. In a ternary mixture, two molar fluxes J^v_i relative to a volume averaged velocity are related to gradients of molar concentration ∇C_i with four diffusion coefficients D^v_ij. Alternatively, fluxes expressed in the molar reference frame J_i are relative to a molar averaged velocity and the mole fraction gradients ∇x_i act as a driving force1with molar density ρ. The fluxes of all three components are constrained by ΣJ_i = 0. The main diffusion coefficients D₁₁ and D₂₂ relate the flux of one component to its own mole fraction gradient and the cross diffusion coefficients D₁₂ and D₂₁ describe the coupling of the flux of one component with the gradient of the other. The third component does not appear in eqn (1) explicitly, but in general it affects all four diffusion coefficients. The transformation of experimental data from the volume to the molar reference frame (D^v_ij to D_ij) could be done here on the basis of the pure component volumes (see the ESI^†).Equilibrium molecular dynamics (MD) simulations were employed in this work, allowing for examination at the microscopic scale. The underlying molecular models were rigid, non-polarizable force fields of united atom type, consisting of a varying number of Lennard–Jones, point charge, dipole and quadrupole sites (see the ESI^†). Note that the force field parameters were adjusted to pure fluid properties only so that all simulation results for the mixtures are strictly predictive. Diffusion coefficients were sampled with the Green–Kubo formalism, based on integrated correlation functions of net velocities of the contained species.^11,15 Thereby, phenomenological coefficients Δ_ij were obtained, associating the diffusive fluxes with the chemical potential gradients ∇μ_i2with gas constant R and temperature T. Fluxes J_i correspond to the molar reference frame as in eqn (1).The diffusion coefficients from experiment and simulation are related to different driving forces so that the chemical potential gradients have to be transformed to the mole fraction gradients for their comparison.¹⁸ This transformation is contained in the thermodynamic factor matrix Γ3with the activity coefficient of species i being γ_i, which expresses the non-ideality of a mixture with respect to the composition. This relationship shows that the Fick diffusion coefficients are actually the product of two contributions, a kinetic Δ_ij and a thermodynamic Γ_ij. The separate observation of these two contributions promotes understanding of the underlying physical phenomena. In the present study, the thermodynamic factor was calculated using the Wilson excess Gibbs energy (g^E) model, using parameters fitted to experimental vapor–liquid equilibrium data of the binary subsystems (see the ESI^†). This combination of MD simulation results with a g^E model was successfully used in previous work to predict Fick diffusion coefficients, including several binary subsystems of the ternary mixtures studied here.¹⁹The four elements of the Fick diffusion coefficient matrix were determined for the three ternary mixtures, benzene + acetone + methanol/ethanol/2-propanol, for nine different compositions, each at ambient temperature and pressure.Results for the first main element of the diffusion matrix D₁₁, which relates the flux of benzene to its own mole fraction gradient, are shown in Fig. 1(a). The experimental data agree quantitatively with the molecular simulation data. D₁₁ increases with the acetone content in the ternary mixture. Since mixtures with a constant mole fraction of benzene (x₁ = 0.33 mol mol⁻¹) were studied throughout, the left edge of Fig. 1(a) corresponds to the binary limit of benzene + alcohol, while the right edge corresponds to that of benzene + acetone. Analysis of the ternary diffusive fluxes implies the following asymptotic behavior of the diffusion coefficients towards the binary limits:⁷ (i) at the infinite dilution limit, x₂ → 0, the ternary coefficient D₁₁ tends to the binary Fick diffusion coefficient of benzene + alcohol; (ii) at the other limit, x₃ → 0, D₁₁ − D₁₂ = D₂₂ − D₂₁ → D_bin (benzene + acetone) should hold. The present experimental and simulation results for D₁₁ are consistent with these asymptotic limits.Open in a separate windowFig. 1Top: The main Fick diffusion coefficient (molar reference frame) of benzene D₁₁ in the three ternary mixtures benzene (1) + acetone (2) + alcohol (3) at a constant benzene mole fraction x₁ = 0.33 mol mol⁻¹ from experiment (triangles) and MD simulation combined with the Wilson g^E model (circles). Both data sets were sampled at the same compositions, but are slightly shifted in the plot for visibility reasons. The symbols at the edges of this plot are the binary diffusion coefficients of benzene + alcohol (x₂ → 0) and of benzene + acetone (x₃ → 0). Bottom: The binary Fick diffusion coefficient of the subsystems benzene + alcohol and benzene + acetone. Most of the binary experimental data were taken from the literature.^20–27An inspection of Fig. 1(a) provides an unexpected finding: the main element D₁₁ is almost identical for all three mixtures along the examined composition path, i.e. it is independent of the contained type of alcohol. To explain this intriguing behavior of D₁₁, the properties of the pure components are considered first (see