Baseline MELD score predicts hepatic decompensation during antiviral therapy in patients with chronic hepatitis C and advanced cirrhosis

Background and Aims: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined. Methods: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks). Results: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001). Conclusions: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis

Size, shape, and stability of organic particles formed during freeze-thaw cycles : model experiments with tannic acid

Hypothesis: Freeze-thaw cycles (FTC) in soils can cause the aggregation of dissolved organic matter but controlling factors are little understood. Experiments: In freeze–thaw experiments with tannic acid (TA) as model substance, we studied the effect of TA concentration, pH, electrolytes (NaCl, CaCl2, AlCl3), and number of FTC on particle formation. Tannic acid (0.005 to 10 g L 1) was exposed to 1–20 FTC at pH 3 and 6. The size and shape of particles was determined by confocal laser scanning microscopy. Particle stability was deduced from the equivalent circle diameter (ECD) obtained in dry state and the hydrodynamic diameter measured in thawing solutions. Findings: Tannic acid particles occurred as plates and veins, resembling the morphology of ice grain boundaries. Low pH and presence of electrolytes favored the formation of large particles. The freeze-concentration effect was most intense at low TA concentrations and increased with the number of FTC. While ECD of particles formed at low TA concentrations were smaller than at high concentrations, it was vice versa in the thawed state. At low TA concentrations, higher crystallization pressure of ice caused enhanced stability of large particles. We conclude that FTC can strongly alter the physical state of dissolved organic matter, with likely consequences for its bioavailability

Size, shape, and stability of organic particles formed during freeze–thaw cycles: Model experiments with tannic acid

Hypothesis: Freeze-thaw cycles (FTC) in soils can cause the aggregation of dissolved organic matter but controlling factors are little understood. Experiments: In freeze–thaw experiments with tannic acid (TA) as model substance, we studied the effect of TA concentration, pH, electrolytes (NaCl, CaCl2, AlCl3), and number of FTC on particle formation. Tannic acid (0.005 to 10 g L−1) was exposed to 1–20 FTC at pH 3 and 6. The size and shape of particles was determined by confocal laser scanning microscopy. Particle stability was deduced from the equivalent circle diameter (ECD) obtained in dry state and the hydrodynamic diameter measured in thawing solutions. Findings: Tannic acid particles occurred as plates and veins, resembling the morphology of ice grain boundaries. Low pH and presence of electrolytes favored the formation of large particles. The freeze-concentration effect was most intense at low TA concentrations and increased with the number of FTC. While ECD of particles formed at low TA concentrations were smaller than at high concentrations, it was vice versa in the thawed state. At low TA concentrations, higher crystallization pressure of ice caused enhanced stability of large particles. We conclude that FTC can strongly alter the physical state of dissolved organic matter, with likely consequences for its bioavailability

Unsichtbar wirksam : Bodenmikroaggregate: kleine Strukturen mit großer Wirkung

In der Bodenforschung spielen Mikroaggregate eine besondere Rolle. Sie haben eine komplexe innere Architektur in der mikrobielle, biogeochemische und physikalische Prozesse in Wechselwirkung stehen, die bisher noch sehr wenig untersucht, aber von fundamentaler Bedeutung für die Funktionsfähigkeit von Böden sind. Wissenschaftler vom Institut für Bodenkunde versuchen daher, einen Beitrag zum mechanistischen Verständnis der Bildung und Funktion von Mikroaggregaten zu leisten

Permafrost degradation and its consequences for carbon storage in soils of Interior Alaska

Permafrost soils in the northern hemisphere are known to harbor large amounts of soil organic matter (SOM). Global climate warming endangers this stable soil organic carbon (SOC) pool by triggering permafrost thaw and deepening the active layer, while at the same time progressing soil formation. But depending, e.g., on ice content or drainage, conditions in the degraded permafrost can range from water-saturated/anoxic to dry/oxic, with concomitant shifts in SOM stabilizing mechanisms. In this field study in Interior Alaska, we investigated two sites featuring degraded permafrost, one water-saturated and the other well-drained, alongside a third site with intact permafrost. Soil aggregate- and density fractions highlighted that permafrost thaw promoted macroaggregate formation, amplified by the incorporation of particulate organic matter, in topsoils of both degradation sites, thus potentially counteracting a decrease in topsoil SOC induced by the permafrost thawing. However, the subsoils were found to store notably less SOC than the intact permafrost in all fractions of both degradation sites. Our investigations revealed up to net 75% smaller SOC storage in the upper 100 cm of degraded permafrost soils as compared to the intact one, predominantly related to the subsoils, while differences between soils of wet and dry degraded landscapes were minor. This study provides evidence that the consideration of different permafrost degradation landscapes and the employment of soil fractionation techniques is a useful combination to investigate soil development and SOM stabilization processes in this sensitive ecosystem

Real-world effectiveness of voxilaprevir/velpatasvir/sofosbuvir in patients following DAA failure

Background &amp; Aims: Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is highly effective for re-treatment of direct-acting antiviral (DAA)-experienced patients with chronic HCV infection. In the present study, predictors of virologic treatment response were analyzed in an integrative analysis of three large real-world cohorts. Methods: Consecutive patients re-treated with VOX/VEL/SOF after DAA failure were enrolled between 2016 and 2021 in Austria, Belgium, Germany, Italy, Spain and Switzerland. Results: A total of 746 patients were included: median age was 56 (16-88) years and 77% were male. Most patients were infected with HCV genotype 1 (56%) and 3 (32%). 86% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Overall, 95.4% (683/716) of patients achieved a sustained virologic response. Treatment effectiveness was significantly affected by advanced liver disease (p &lt;0.001), hepatocellular carcinoma (p &lt;0.001), higher baseline ALT levels (p = 0.02), HCV genotype 3 (p &lt;0.001), and prior VEL/SOF treatment (p = 0.01). In a multivariate analysis, only HCV genotype 3, hepatocellular carcinoma and cirrhosis turned out to be independent predictors of treatment failure. Resistance-associated substitutions, as well as the presence of rare genotypes, did not impact treatment outcome. The effectiveness of rescue therapy with glecaprevir/pibrentasvir and SOF, with or without ribavirin, for 12 to 24 weeks was found to be high (100%). Conclusions: Infection with HCV genotype 3, the presence of liver cancer and cirrhosis are independently associated with failure of VOX/VEL/SOF re-treatment. It is unclear whether the addition of ribavirin and/or extension of treatment duration may be effective to avoid virologic relapse on VOX/VEL/SOF. However, rescue treatment with glecaprevir/pibrentasvir+SOF seems to be effective. Impact and implications: Representative data on the effectiveness of voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) in clinical practice are still scarce and the collection of a larger number of patients with difficult-to-treat cofactors including the assessment of resistance-associated substitution profiles is required before more specific recommendations for optimal re-treatment in these patients can be given. Thus, we aimed to analyze treatment effectiveness and predictors of virologic response to VOX/VEL/SOF in an integrative analysis of three large real-word cohorts. The study results, derived from a multicenter cohort consisting of 746 patients, demonstrated that re-treatment with VOX/VEL/SOF is an effective salvage therapy associated with an overall per protocol sustained virologic response rate of 95%. Hepatocellular carcinoma onset, cirrhosis and HCV genotype 3 were identified as independent negative predictors of treatment response, whereas resistance-associated substitutions, as well as rare genotypes and chimera, did not impact sustained virologic response rates following re-treatment with VOX/VEL/SOF

Process sequence of soil aggregate formation disentangled through multi-isotope labelling

Microaggregates (250 µm) that resisted 60 J mL−1 ultrasonic dispersion. Afterwards, we assessed the C, N, Fe, and Si stable isotope composition in each size fraction. After four weeks we found a rapid build-up of stable macroaggregates comprising almost 50 % of soil mass in the treatment with plants and respective soil rooting, but only 5 % when plants were absent. The formation of these stable macroaggregates proceeded with time. Soil organic carbon (SOC) contents were elevated by 15 % in the large macroaggregates induced by plant growth. However, the recovery of EPS-derived 13C was below 20 % after 4 weeks, indicating rapid turnover in treatments both with and without plants. The remaining EPS-derived C was mainly found in macroaggregates when plants were present and in the occluded small microaggregates (<20 µm) when plants were absent. The excess of bacterial 15N closely followed the pattern of EPS-derived 13C (R2 = 0.72). In contrast to the organic gluing agents, the goethite-57Fe and montmorillonite-29Si were relatively equally distributed across all size fractions. Overall, microaggregates were formed within weeks. Roots enforced this process by stabilizing microaggregates within stable macroaggregates. As time proceeded the labelled organic components decomposed, while the labelled secondary oxides and clay minerals increasingly contributed to aggregate stabilization and turnover at the scale of months and beyond. Consequently, the well-known hierarchical organization of aggregation follows a clear chronological sequence of stabilization and turnover processes

Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients

BACKGROUND AND AIMS Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. METHODS A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. RESULTS Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. CONCLUSIONS In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. IMPACT AND IMPLICATIONS Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed