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As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved.As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved.
We have identified a mistake in how Fig. 1 is referenced in the text of the article Eur. Phys. J. C 77 (2017) no. 8, 569 which affected three paragraphs of the results section. The corrected three paragraphs as well as the unmodified accompanying figure are reproduced in this document with the correct labeling.
In addition, an editing issue led to a missing acknowledgements section. The missing section is reproduced at the end of this document in the manner in which it should have appeared in the published article.
Background: The effects of blood flow restriction (training) may serve as a model of peripheral artery disease. In both conditions, circulating micro RNAs (miRNAs) are suggested to play a crucial role during exercise-induced arteriogenesis. We aimed to determine whether the profile of circulating miRNAs is altered after acute resistance training during blood flow restriction (BFR) as compared with unrestricted low- and high-volume training, and we hypothesized that miRNA that are relevant for arteriogenesis are affected after resistance training.
Methods: Eighteen healthy volunteers (aged 25 ± 2 years) were enrolled in this three-arm, randomized-balanced crossover study. The arms were single bouts of leg flexion/extension resistance training at (1) 70% of the individual single-repetition maximum (1RM), (2) at 30% of the 1RM, and (3) at 30% of the 1RM with BFR (artificially applied by a cuff at 300 mm Hg). Before the first exercise intervention, the individual 1RM (N) and the blood flow velocity (m/s) used to validate the BFR application were determined. During each training intervention, load-associated outcomes (fatigue, heart rate, and exhaustion) were monitored. Acute effects (circulating miRNAs, lactate) were determined using pre-and post-intervention measurements.
Results: All training interventions increased lactate concentration and heart rate (p < 0.001). The high-intensity intervention (HI) resulted in a higher lactate concentration than both lower-intensity training protocols with BFR (LI-BFR) and without (LI) (LI, p = 0.003; 30% LI-BFR, p = 0.008). The level of miR-143-3p was down-regulated by LI-BFR, and miR-139-5p, miR-143-3p, miR-195-5p, miR-197-3p, miR-30a-5p, and miR-10b-5p were up-regulated after HI. The lactate concentration and miR-143-3p expression showed a significant positive linear correlation (p = 0.009, r = 0.52). A partial correlation (intervention partialized) showed a systematic impact of the type of training (LI-BFR vs. HI) on the association (r = 0.35 remaining after partialization of training type).
Conclusions: The strong effects of LI-BFR and HI on lactate- and arteriogenesis-associated miRNA-143-3p in young and healthy athletes are consistent with an important role of this particular miRNA in metabolic processes during (here) artificial blood flow restriction. BFR may be able to mimic the occlusion of a larger artery which leads to increased collateral flow, and it may therefore serve as an external stimulus of arteriogenesis.
First results on K/π, p/π and K/p fluctuations are obtained with the ALICE detector at the CERN LHC as a function of centrality in Pb--Pb collisions at sNN−−−√=2.76 TeV. The observable νdyn, which is defined in terms of the moments of particle multiplicity distributions, is used to quantify the magnitude of dynamical fluctuations of relative particle yields and also provides insight into the correlation between particle pairs. This study is based on a novel experimental technique, called the Identity Method, which allows one to measure the moments of multiplicity distributions in case of incomplete particle identification. The results for p/π show a change of sign in νdyn from positive to negative towards more peripheral collisions. For central collisions, the results follow the smooth trend of the data at lower energies and νdyn exhibits a change in sign for p/π and K/p.
Background: Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters. Methods: 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment. Results: 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 ± 6.1 to 2.5 ± 1.9, p < 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 ± 17.3 to 11.7 ± 8.7; p = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time (p = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: r = 0.45; p = 0.003, pSWE: r = 0.35; p = 0.02, APRI: r = 0.44; p = 0.003, FIB-4: r = 0.41; p < 0.001). Conclusion: Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.
Members of the ATP‐binding cassette (ABC) transporter superfamily translocate a broad spectrum of chemically diverse substrates. While their eponymous ATP‐binding cassette in the nucleotide‐binding domains (NBDs) is highly conserved, their transmembrane domains (TMDs) forming the translocation pathway exhibit distinct folds and topologies, suggesting that during evolution the ancient motor domains were combined with different transmembrane mechanical systems to orchestrate a variety of cellular processes. In recent years, it has become increasingly evident that the distinct TMD folds are best suited to categorize the multitude of ABC transporters. We therefore propose a new ABC transporter classification that is based on structural homology in the TMDs:
Purpose: Physical activity is associated with altered levels of circulating microRNAs (ci-miRNAs). Changes in miRNA expression have great potential to modulate biological pathways of skeletal muscle hypertrophy and metabolism. This study was designed to determine whether the profile of ci-miRNAs is altered after different approaches of endurance exercise. Methods: Eighteen healthy volunteers (aged 24 ± 3 years) participated this three-arm, randomized-balanced crossover study. Each arm was a single bout of treadmill-based acute endurance exercise at (1) 100% of the individual anaerobic threshold (IANS), (2) at 80% of the IANS and (3) at 80% of the IANS with blood flow restriction (BFR). Load-associated outcomes (fatigue, feeling, heart rate, and exhaustion) as well as acute effects (circulating miRNA patterns and lactate) were determined. Results: All training interventions increased the lactate concentration (LC) and heart rate (HR) (p < 0.001). The high-intensity intervention (HI) resulted in a higher LC than both lower intensity protocols (p < 0.001). The low-intensity blood flow restriction (LI-BFR) protocol led to a higher HR and higher LC than the low-intensity (LI) protocol without BFR (p = 0.037 and p = 0.003). The level of miR-142-5p and miR-197-3p were up-regulated in both interventions without BFR (p < 0.05). After LI exercise, the expression of miR-342-3p was up-regulated (p = 0.038). In LI-BFR, the level of miR-342-3p and miR-424-5p was confirmed to be up-regulated (p < 0.05). Three miRNAs and LC show a significant negative correlation (miR-99a-5p, p = 0.011, r = − 0.343/miR-199a-3p, p = 0.045, r = − 0.274/miR-125b-5p, p = 0.026, r = − 0.302). Two partial correlations (intervention partialized) showed a systematic impact of the type of exercise (LI-BFR vs. HI) (miR-99a-59: r = − 0.280/miR-199a-3p: r = − 0.293). Conclusion: MiRNA expression patterns differ according to type of activity. We concluded that not only the intensity of the exercise (LC) is decisive for the release of circulating miRNAs—as essential is the type of training and the oxygen supply.
Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called coronavirus disease 2019 (COVID-19). While control of the SARS-CoV-2 spread partly depends on vaccine-induced or naturally acquired protective herd immunity, antiviral strategies are still needed to manage COVID-19. Enisamium is an inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. In vitro, enisamium acts through metabolite VR17-04 and inhibits the activity of the influenza A virus RNA polymerase. Here we show that enisamium can inhibit coronavirus infections in NHBE and Caco-2 cells, and the activity of the SARS-CoV-2 RNA polymerase in vitro. Docking and molecular dynamics simulations provide insight into the mechanism of action and indicate that enisamium metabolite VR17-04 prevents GTP and UTP incorporation. Overall, these results suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis in vitro.
Background and aims: One reason for the controversial discussion of whether the dual task (DT) walking paradigm has an added value for diagnosis in clinical conditions might be the use of different gait measurement systems. Therefore, the purpose was 1) to detect DT effects of central gait parameters obtained from five different gait analysis devices in young and old adults, 2) to assess the consistency of the measurement systems, and 3) to determine if the absolut and proportional DT costs (DTC) are greater than the system-measurement error under ST. Methods: Twelve old (72.2 ± 7.9y) and 14 young adults (28.3 ± 6.2y) walked a 14.7-m distance under ST and DT at a self-selected gait velocity. Interrater reliability, precision of the measurement and sensitivity to change were calculated under ST and DT. Results: An age effect was observed in almost all gait parameters for the ST condition. For DT only differences for stride length (p < .029, ɳ2p = .239) as well as single and double limb support (p = .036, ɳ2p = .227; p = .034, ɳ2p = .218) remained. The measurement systems showed a lower absolute agreement compared to consistency across all systems. Conclusions: When reporting DT effects, the real changes in performance and random measurement errors should always be accounted for. These findings have strong implications for interpreting DT effects.