Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry.

Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post-treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1- and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.

[Expert opinion on boceprevir- and telaprevir-based triple therapies of chronic hepatitis C]. / Expertenempfehlungen zur Triple-Therapie der HCV-Infektion mit Boceprevir und Telaprevir.

With the approval of boceprevir and telaprevir the standard treatment of chronic hepatitis C virus (HCV) genotype 1 infection will be the triple therapy of a HCV protease inhibitor together with pegylated interferon alfa and ribavirin. In clinical studies a significant increase of sustained virological response rates from 38 - 44 % to 63 - 75 % for treatment-naïve and from 17 - 21 % to 59 - 66 % in treatment-experienced patients in comparison to the dual combination therapy with pegylated interferon alfa and ribavirin alone has been demonstrated. In addition, a large number of treatment-naïve patients and relapsers benefit from shorten treatment durations to 24 - 28 weeks. However, important differences exist between the administration of boceprevir and telaprevir in terms of a pegylated interferon alfa/ribavirin lead-in phase, the duration of dosing of the protease inhibitor, the overall treatment duration, HCV RNA measurements for response guided treatment durations and stopping rules. Furthermore, triple therapies with boceprevir and telaprevir may be associated with selection of resistant viral variants, new adverse events and clinically relevant drug-drug interactions. The present review gives an overview on the results of underlying clinical studies together with a guideline for the practical management of boceprevir- and telaprevir-based triple therapies.

The use of otolith microstructure to estimate age in adult Atlantic cod Gadus morhua.

Transverse sections of otoliths from Atlantic cod Gadus morhua from the Baltic Sea revealed narrow growth increments. The widths of these increments corresponded to daily increments from fish with known otolith growth rates and were therefore assumed to be daily increments. They exhibited a distinct pattern with increasing distance from the primary primordium. A series of zones with clearly distinguishable increments, first with increasing then with decreasing widths in a dome-shaped pattern, were separated by zones where no regular increment structure was visible. Increment width seemed to be tightly coupled to the annual cycle in environmental temperature at a depth of 30-60 m, where G. morhua predominantly reside. Between 135 and 200 increments occurred within the different zones, with a non-significant trend towards lower increment numbers and widths with distance from the primary primordium of the otolith. Increment formation apparently ceased at temperatures < 5-6 degrees C, but growth during the cold months corresponded closely with estimated growth rates. The increment patterns seemed to reflect annual cycles in environmental temperature, and the count of the increment cycles may thus be a promising tool for the determination of the true age of Baltic G. morhua.

Expert opinion on the treatment of patients with chronic hepatitis C.

The current preferred treatment for patients with hepatitis C virus (HCV) is combination therapy consisting of pegylated interferon alfa and ribavirin (RBV) for 24-48 weeks. Although this approach appears to be highly effective for patients with HCV genotypes 2 or 3, who have a sustained virological response (SVR) of approximately 80%, the treatment algorithm is less effective for patients with HCV genotype 1, as these patients have SVR rates of just 40-50%. In order to improve treatment outcomes, this article explores potential approaches for the optimization of treatment for patients with HCV genotype 1: considering shorter treatment periods for patients with a rapid virological response (RVR), increasing treatment periods for slow responders, and increasing RBV dose are all suggestions. Results from clinical trials suggest that approximately 20% of the HCV genotype 1-infected population are slow responders, and around 15% of all HCV genotype-1 infected patients could benefit from a shorter treatment duration without compromising the SVR rate. Interest has also focused on whether treatment duration could be individualized in some patients with genotype 2 and 3 infection. Here all the findings from recent studies are translated into practical advice, to help practitioners make evidence-based treatment decisions in everyday clinical practice. Although there are areas where currently available data do not provide conclusive evidence to suggest amending treatment approaches, there is clearly potential for individualized treatment in all aspects of hepatitis treatment in the future.

Simplest nonequilibrium phase transition into an absorbing state.

We study in further detail particle models displaying a boundary-induced absorbing state phase transition [Deloubrière and van Wijland Phys. Rev. E 65, 046104 (2002) and Barato and Hinrichsen, Phys. Rev. Lett. 100, 165701 (2008)]. These are one-dimensional systems consisting of a single site (the boundary) where creation and annihilation of particles occur, and a bulk where particles move diffusively. We study different versions of these models and confirm that, except for one exactly solvable bosonic variant exhibiting a discontinuous transition and trivial exponents, all the others display nontrivial behavior, with critical exponents differing from their mean-field values, representing a universality class. Finally, the relation of these systems with a (0+1)-dimensional non-Markovian process is discussed.

The German Hep-Net acute hepatitis C cohort: impact of viral and host factors on the initial presentation of acute hepatitis C virus infection.

INTRODUCTION: The impacts of viral load, genotype, age, sex and BMI on the clinical course of acute hepatitis C are poorly defined. Here we studied 259 patients with acute HCV infection recruited in the German Hep-Net data base between 1998 and 2008. Antiviral treatment with interferon alpha was initiated in 171 patients (66 %) within 4 months after the diagnosis of acute hepatitis C. RESULTS: In this cohort (i) the mode of infection was associated with age as iv-drug users were significantly younger than non-iv-drug users while the proportion of patients who acquired HCV by medical procedures increased with age; (ii) patients younger than 30 years were more often infected with genotype 3 (26 % versus 8 % for patients older than 50 years; p = 0.03); (iii) 51 % of patients were icteric and 28 % presented with a 30-fold elevation of liver enzymes, however, no fulminant hepatic failure occurred; (iv) HCV genotype was not associated with disease severity and time to onset of symptoms; (v) low HCV viremia was associated with lower serum AST levels and a longer time from exposure to onset of symptoms; (vi) disease severity was independent from the mode of infection, age, sex and body mass index (BMI). CONCLUSIONS: In this large cohort of patients admitted for antiviral therapy, acute hepatitis C took a rather mild course of disease in the majority of patients. Disease severity was not associated with HCV genotype, viral load, age, sex and BMI.

Some Atlantic cod Gadus morhua in the Baltic Sea visit hypoxic water briefly but often.

Individual behaviour of Atlantic cod Gadus morhua in the presence of hypoxic water was measured in situ in the vertically stratified Bornholm Basin of the Baltic Sea. Considering all recaptured individuals, the use of hypoxic habitat was comparable to data derived by traditional survey data, but some G. morhua had migrated towards the centre of the c.100 m deep basin and spent about a third of their time at oxygen saturation <50%, possibly to forage on zoobenthos. Maximal residence time per visit in such hypoxic water was limited to a few hours, allowing for the digestion of consumed prey items in waters with sufficient dissolved oxygen.

Rate equations and scaling in pulsed laser deposition.

We study a simplified model for pulsed laser deposition [Hinnemann, Phys. Rev. Lett. 87, 135701 (2001)] by rate equations. We consider a set of equations where islands are assumed to be pointlike, as well as an improved one that takes the size of the islands into account. The first set of equations is solved exactly but its predictive power is restricted to a few pulses. The improved set of equations is integrated numerically, is in excellent agreement with simulations, and fully accounts for the crossover from continuous to pulsed deposition. Moreover, we analyze the scaling of the nucleation density and show numerical results indicating that a previously observed logarithmic scaling does not apply.

Numerical study of a model for nonequilibrium wetting.

We revisit the scaling properties of a model for nonequilibrium wetting [Phys. Rev. Lett. 79, 2710 (1997)], correcting previous estimates of the critical exponents and providing a complete scaling scheme. Moreover, we investigate a special point in the phase diagram, where the model exhibits a roughening transition related to directed percolation. We argue that in the vicinity of this point evaporation from the middle of plateaus can be interpreted as an external field in the language of directed percolation. This analogy allows us to compute the crossover exponent and to predict the form of the phase transition line close to its terminal point.

[Transjugular intrahepatic portosystemic shunt: evaluation of the impact of the stent's configuration on the patency rate]. / Transjugulärer intrahepatischer portosystemischer Shunt: Untersuchung des Einflusses der Stentkonfiguration auf die Offenheitsrate.

PURPOSE: To evaluate the impact of the configuration of the stent on the patency rate after transjugular intrahepatic portosystemic shunt with a self-expanding stent. MATERIALS AND METHODS: In total, 80 patients (60 male, 20 female; mean age 56 +/- 9.6, range 37 - 81) with a transjugular intrahepatic portosystemic shunt were evaluated. The primary technical success rate, interventional revision rate, and mean patency rate according to Kaplan-Meier were calculated. The angle of deviation of the blood flow at the portal venous inflow and central venous outflow were measured on projected angiograms (valid cases, n = 78). The following five angle groups were established: 1. portal venous inflow, 2. central venous outflow, 3. maximum, angle, 4. minimum angle, and 5. sum of both angles in the shunt system. Within each group, the Mann-Whitney Test and after dichotomic partition using the median Pearson's Chi-Square Test and Fisher's Exact Test were carried out to prove the dependency of the patency on the stent's configuration. RESULTS: The primary technical success rate was 93 %, the interventional revision rate was 28 %, and the mean patency rate was 17.5 months. The mean/standard deviation/median angle were as follows: 1. portal venous inflow 66.5 degrees / 19.2 degrees / 65 degrees , 2. central venous outflow 43.7 degrees / 14.0 degrees / 40 degrees , 3. maximum angle 69.1 degrees / 16.3 degrees / 65 degrees , 4. minimum angle 40.6 degrees / 13.3 degrees / 40 degrees , and 5. sum of both angles 110.2 degrees / 21.8 degrees / 110 degrees . The 2-sided values of significance in the Mann-Whitney Test/Chi-Square Test/Exact-Fisher Test were as follows: 1. portal venous inflow 0.112 / 0.066 / 0.083, 2. central venous outflow 0.960 / 0.919 / 1.000, 3. maximum angle 0.151 / 0.042 / 0.056, 4. minimum angle 0.578 / 0.622 / 0.632, and 5. sum of both angles 0.104 / 0.111 / 0.140. CONCLUSION: The shunt's patency rate when using a self-expanding stent is not dependent on the stent's configuration regarding the deviation of the blood flow at the portal venous inflow and central venous outflow, and the maximum, minimum and total deviation in the shunt.

Core beliefs and social anxiety in the eating disorders.

Social anxiety is a common comorbid problem in the eating disorders. The present study investigated whether specific types of core beliefs are common in eating-disordered individuals presenting with high levels of social anxiety. The participants were a group of 191 women meeting Diagnostic and Statistical Manual-IV (DSM-IV) criteria for an eating disorder. Young's Schema Questionnaire (YSQ-S) was used as a measure of core beliefs, while a brief version of the Fear of Negative Evaluation scale (Brief FNE) was used as a measure of social anxiety. The results showed that eating-disordered individuals with high levels of comorbid social anxiety report higher levels of socially-oriented core beliefs (abandonment; defectiveness/shame) than those who experience low levels of social anxiety. The findings highlight the potential importance of addressing core beliefs in specific groups of eating-disordered individuals. Implications for future research and clinical practice are discussed.

Influence of diffusion on models for nonequilibrium wetting.

It is shown that the critical properties of a recently studied model for nonequilibrium wetting are robust if one extends the dynamic rules by single-particle diffusion on terraces of the wetting layer. Examining the behavior at the critical point and along the phase transition line, we identify a special point in the phase diagram where detailed balance of the dynamical processes is partially broken.

Oxygen depletion in coastal seas and the effective spawning stock biomass of an exploited fish species.

Environmental conditions may have previously underappreciated effects on the reproductive processes of commercially exploited fish populations, for example eastern Baltic cod, that are living at the physiological limits of their distribution. In the Baltic Sea, salinity affects neutral egg buoyancy, which is positively correlated with egg survival, as only water layers away from the oxygen consumption-dominated sea bottom contain sufficient oxygen. Egg buoyancy is positively correlated to female spawner age/size. From observations in the Baltic Sea, a field-based relationship between egg diameter and buoyancy (floating depth) could be established. Hence, based on the age structure of the spawning stock, we quantify the number of effective spawners, which are able to reproduce under ambient hydrographic conditions. For the time period 1993-2010, our results revealed large variations in the horizontal extent of spawning habitat (1000-20 000 km(2)) and oxygen-dependent egg survival (10-80%). The novel concept of an effective spawning stock biomass takes into account offspring that survive depending on the spawning stock age/size structure, if reproductive success is related to egg buoyancy and the extent of hypoxic areas. Effective spawning stock biomass reflected the role of environmental conditions for Baltic cod recruitment better than the spawning stock biomass alone, highlighting the importance of including environmental information in ecosystem-based management approaches.

Directed percolation with long-range interactions: Modeling nonequilibrium wetting.

It is argued that some phase transitions observed in models of nonequilibrium wetting phenomena are related to contact processes with long-range interactions. This is investigated by introducing a model where the activation rate of a site at the edge of an inactive island of length l is 1+a l(-sigma) . Mean-field analysis and numerical simulations indicate that for sigma>1 the transition is continuous and belongs to the universality class of directed percolation, while for 0

Hemodynamic effects of different H2-receptor antagonists.

In a randomized, placebo-controlled, double-blind study, 10 healthy volunteers were treated orally once a day for 1 week each with placebo, 800 mg cimetidine, 300 mg ranitidine, and 40 mg famotidine. On the seventh treatment day, heart rate, blood pressure, systolic time intervals, and impedance cardiography were measured before the morning dose and at 2, 6, 12, and 24 hours after the morning dose. Heart rate and blood pressure were not markedly altered by any of the H2-receptor antagonists compared with the findings for placebo. Cimetidine and ranitidine did not markedly alter parameters of systolic time interval and impedance cardiography compared with placebo in contrast to famotidine, which significantly decreased stroke volume, cardiac output, and the Heather Index in impedance cardiography (p less than 0.05) and also significantly increased the ratio of the preejection period to the left ventricular ejection time in systolic time interval (p less than 0.05) 2 hours after the morning dose. Six hours after administration, most of these alterations could no longer be detected. The observed changes in hemodynamic parameters confirm that famotidine exerts negative effects on cardiac performance, whereas such influences could not be shown for cimetidine and ranitidine.

Hemodynamic effects of quinidine and famotidine in patients with congestive heart failure.

In a randomized, placebo-controlled, double-blind study, 12 patients with congestive heart failure (New York Heart Association class II) were successively treated for 1 week each with placebo, 40 mg famotidine, and 1000 mg quinidine. On the seventh treatment day, heart rate, blood pressure, systolic time intervals, impedance cardiography, and Doppler ultrasound were measured. Heart rate and blood pressure were not markedly altered by either drug. By contrast, quinidine and famotidine significantly decreased stroke volume and cardiac output in impedance cardiography and Doppler ultrasound (p less than 0.05). A high correlation between both noninvasive methods was found for cardiac output and stroke volume (r = 0.93 and r = 0.97 for stroke volume 1 1/2 hours after quinidine and placebo administration, respectively). In addition, the mechanocardiographic ratio of the preejection period to the left ventricular ejection time in systolic time intervals increased significantly 1 1/2 and 3 hours after administration of quinidine and famotidine (p less than 0.05). In conclusion, both quinidine and famotidine exert similar negative effects on cardiac performance, with no significant differences in hemodynamic parameters emerging between the antiarrhythmic agent and the H2-receptor antagonist.

Clinical aspects of cardiovascular effects of H2-receptor antagonists.

In vitro studies and animal experiments as well as clinical observations in humans concerning cardiovascular effects of H2-receptor antagonists have been published shortly after the development. Thus, clinical studies were performed to investigate these effects. The following review summarizes the results from in vitro studies up to the clinical investigations performed.