Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding

Background: The real-world, long-term benefits of sustained virologic response (SVR) on the risk of variceal bleeding remain unclear. Aim: To assess the association between DAA-induced SVR and post-treatment variceal bleeding. Methods: We identified patients who initiated DAA-only anti-viral treatments in the United States Veterans Affairs healthcare system from 2013 to 2015. We followed patients until 1 January 2019 for the development of gastro-oesophageal variceal bleeding defined by diagnostic codes. We used multivariable Cox proportional hazards regression to assess the association between SVR and development of variceal bleeding, adjusting for potential confounders. Results: Among 33 582 DAA-treated patients, 549 (1.6%) developed variceal bleeding after treatment (mean follow-up 3.1 years). Compared to no SVR, SVR was associated with a significantly lower incidence of variceal bleeding among all patients (0.46 vs 1.26 per 100 patient-years, adjusted hazard ratio [AHR] 0.66, 95% CI 0.52-0.83), among patients with pre-treatment cirrhosis (1.55 vs 2.96 per 100 patient-years, AHR 0.73, 95% CI 0.57-0.93) and among patients without pre-treatment cirrhosis (0.07 vs 0.29 per 100 patient-years, AHR 0.33, 95% CI 0.17-0.65). The risk of variceal bleeding after treatment was lower in those who achieved SVR vs no SVR among patients who had non-bleeding varices (3.5 vs 4.9 per 100 patient-years) or bleeding varices (12.9 vs 16.4 per 100 patient-years) diagnosed before treatment, but these differences were not statistically significant in adjusted analyses. Conclusion: DAA-induced SVR is independently associated with a lower risk of variceal bleeding during long-term follow-up in patients with and without pre-treatment cirrhosis. These findings demonstrate an important real-world benefit of DAA treatment

The effect of respiration buffer composition on mitochondrial metabolism and function

<div><p>Functional studies on isolated mitochondria critically rely on the right choice of respiration buffer. Differences in buffer composition can lead to dramatically different respiration rates leading to difficulties in comparing prior studies. The ideal buffer facilities high ADP-stimulated respiratory rates and minimizes substrate transport effects so that the ability to distinguish between various treatments and conditions is maximal. In this study, we analyzed a variety of respiration buffers and substrate combinations to determine the optimal conditions to support mitochondrial function through ADP-stimulated respiration and uncoupled respiration using FCCP. The buffers consisted of a standard KCl based buffer (B1) and three modified buffers with chloride replaced by the K-lactobionate, sucrose, and the antioxidant taurine (B2) or K-gluconate (B3). The fourth buffer (B4) was identical to B2 except that K-lactobionate was replaced with K-gluconate. The substrate combinations consisted of metabolites that utilize different pathways of mitochondrial metabolism. To test mitochondrial function, we used isolated cardiac guinea pig mitochondria and measured oxygen consumption for three respiratory states using an Oroboros Oxygraph-2k. These states were the leak state (energized mitochondria in the absence of adenylates), ADP-stimulated state (energized mitochondria in the presence of saturating ADP concentrations), and uncoupled state (energized mitochondria in the presence of FCCP). On average across all substrate combinations, buffers B2, B3, and B4 had an increase of 16%, 26%, and 35% for the leak state, ADP-simulated state, and uncoupled state, respectively, relative to rates using B1. The common feature distinguishing these buffers from B1 is the notable lack of high chloride concentrations. Based on the respiratory rate metrics obtained with the substrate combinations, we conclude that the adenine nucleotide translocase, the dicarboxylate carrier, and the alpha-ketoglutarate exchanger are partially inhibited by chloride. Therefore, when the goal is to maximize ADP-stimulated respiration, buffers containing K-lactobionate or K-gluconate are superior choices compared to the standard KCl-based buffers.</p></div

Mitochondrial respiration data for various common substrates^a.

<p>Mitochondrial respiration data for various common substrates<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0187523#t002fn001" target="_blank">^a</a>.</p