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Background: Donor hepatitis-C (HCV) infection has historically represented a barrier to kidney transplantation (KT). However, direct-acting antiviral (DAA) medications have revolutionised treatment of chronic HCV infection. Recent American studies have demonstrated that DAA regimes can be used safely peri-operatively in KT to mitigate HCV transmission risk. Methods: To formulate this narrative review, a comprehensive literature search was performed to analyse results of existing clinical trials examining KT from HCV-positive donors to HCV-negative recipients with peri-operative DAA regimes. Results: 13 studies were reviewed (11 single centre, four retrospective). Outcomes for 315 recipients were available across these studies. A sustained virological response at 12 weeks (SVR12) of 100% was achieved in 11 studies. One study employed an ultra-short DAA regime and achieved an SVR12 of 98%, while another achieved SVR12 of 96% due to treatment of a missed mixed genotype. Conclusion: HCV+ KT is safe and may allow increased utilisation of organs for transplantation from HCV+ donors, who often have other favourable characteristics for successful donation. Findings from US clinical trials can be applied to the United Kingdom transplant framework to improve organ utilisation as suggested by the NHSBT vision strategy "Organ Donation and Transplantation 2030: meeting the need"., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Doherty, Athwal, Moinuddin, Augustine, Prince, van Dellen and Khambalia.)

Chronic liver disease (CLD) is an ignored epidemic. Premature mortality is considerable and in the United Kingdom (UK) liver disease is in the top three for inequitable healthcare alongside heart and respiratory disease. Fifty percentage of patients with CLD are first diagnosed with cirrhosis after an emergency presentation translating to poorer patient outcomes. Traditional models of care have been based in secondary care when the need is at community level. Investigating patients for disease based on their risk factors at a population level in the community will identify its presence early when there is potential reversibility. Innovation is needed in three broad areas to improve clinical care in this area: better access to diagnostics within the community, integrating diagnostics across primary and secondary care and utilizing digital healthcare to enhance patient care. In this article, we describe how the Integrated Diagnostics for Early Detection of Liver Disease (ID-LIVER) project, funded by UK Research and Innovation, is developing solutions in Greater Manchester to approach the issue of diagnosis of liver disease at a population level. The ambition is to build on innovative pathways previously established in Nottingham by bringing together NHS organizations, academic partners and commercial organizations. The motivation is to co-create and implement a commercial solution that integrates multimodal diagnostics via cutting edge data science to drive growth and disrupt the currently inadequate model. The ambitious vision is for this to be widely adopted for early diagnosis and stratification of liver disease at a population level within the NHS., Competing Interests: ING and JM have received investigator led funding research from Gilead Sciences. Gilead had no intellectual input into the study concept or design, interpretation of the results or editing the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bennett, Purssell, Street, Piper Hanley, Morling, Hanley, Athwal and Guha.)

Background: Prescription information for many drugs entering the market lacks dosage guidance for hepatic impairment. Dedicated studies for assessing the fate of drugs in hepatic impairment commonly stratify patients using Child-Pugh score. Child-Pugh is a prognostic clinical score with limitations in reflecting the liver's metabolic capacity., Aims: To demonstrate the need for better drug dosing approaches in hepatic impairment, summarise the current status, identify knowledge gaps related to drug kinetic parameters in hepatic impairment, propose solutions for predicting the liver disease impact on drug exposure and discuss barriers to dosing guidance in those patients., Methods: Relevant reports on dosage adjustment in hepatic impairment were analysed concerning the prediction of the impairment impact on drug kinetics using physiologically-based pharmacokinetic (PBPK) modelling., Results: PBPK models are suggested as a potential framework to understand drug clearance changes in hepatic impairment. Quantifying changes in abundance and activity of drug-metabolising enzymes and transporters, understanding the impact of shunting, and accounting for interindividual variations in drug absorption could help in extending the success of these models in hepatically-impaired populations. These variables might not correlate with Child-Pugh score as a whole. Therefore, new metabolic activity markers, imaging techniques and other scoring systems are proposed to either support or substitute Child-Pugh score., Conclusions: Many physiological changes in hepatic impairment determining the fate of drugs do not necessarily correlate with Child-Pugh score. Quantifying these changes in individual patients is essential in future hepatic impairment studies. Further studies assessing Child-Pugh alternatives are recommended to allow better prediction of drug exposure., (© 2021 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

In vitro to in vivo extrapolation (IVIVE) enables prediction of in vivo clinical outcomes related to drug exposure in various populations from in vitro data. Prudent IVIVE requires scalars specific to the biologic characteristics of the system in each population. This study determined experimentally for the first time scalars in liver samples from patients with varying degrees of cirrhosis. Microsomal and cytosolic fractions were extracted from 13 noncirrhotic and 32 cirrhotic livers (six mild, 13 moderate, and 13 severe, based on Child-Pugh score). Fractional protein content was determined, and cytochrome P450 reductase activity was used to correct for microsomal protein loss. Although the median microsomal protein per gram liver (MPPGL) in mild, moderate, and severe cirrhosis (26.2, 32.4, and 30.8 mg⋅g -1 , respectively) seemed lower than control livers (36.6 mg⋅g -1 ), differences were not statistically significant (Kruskal-Wallis test, P > 0.05). Corresponding values for cytosolic protein per gram liver were 88.2, 67.9, 62.2, and 75.4 (mg⋅g -1 ) for mild, moderate, and severe cirrhosis and control livers, respectively, with statistically lower values for severe versus controls (Mann-Whitney P = 0.006). Cirrhosis associated with cancer showed lower MPPGL (24.8 mg⋅g -1 ) than cirrhosis associated with cholestasis (38.3 mg⋅g -1 , P = 0.003). Physiologically based pharmacokinetic simulations with disease-specific scalars captured cirrhosis impact on exposure to alfentanil, metoprolol, midazolam, and ethinylestradiol. These experimentally-determined scalars should alleviate the need for indirect scaling using functional liver volume. Scaling factors in cirrhosis might be a reflection of the etiology rather than the disease severity. Hence, bundling various cirrhotic conditions under the same umbrella when predicting hepatic impairment impact should be revisited. SIGNIFICANCE STATEMENT: Cirrhosis-specific scalars required for extrapolation from microsomal or cytosolic in vitro systems to liver tissue are lacking. These scalars can help in predicting drug clearance and selection of dosage regimens for cirrhosis populations. Attempts to consider potential changes have been empirical and ignored the potential impact of the cause of cirrhosis. We obtained experimental values for these scalars for the first time and assessed their impact on predicted exposure to various substrate drugs using physiologically-based pharmacokinetics simulations., Competing Interests: A.R.-H. holds shares in Certara, a company focusing on model‐informed drug development, and declares no support from any organization for the submitted work. All other authors declare that they have no conflicts of interest., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Autophagy and the unfolded protein response (UPR) both promote activation of hepatic stellate cells (HSC), however the link between the two stimuli remains unclear. Here we have explored the role of X-box binding protein 1 (XBP1), one of three UPR effector pathways and sought to establish the interdependence between autophagy and the UPR during HSC activation. XBP1 induction accompanied both culture-based HSC activation and ER stress induced by tunicamycin. Ectopic overexpression of XBP1 induced collagen 1-alpha expression in HSCs, which was inhibited by knockdown of ATG7, a critical autophagy mediator. Genome-wide transcriptomic profiling indicated an upregulation of collagen synthesis pathways, but not of the transforming growth factor (TGF)-b pathway, a canonical fibrogenic driver, suggesting that XBP1 activates a specific subset of fibrogenesis pathways independent of TGF-β1. XBP1 target gene signatures were significantly induced in rodent liver fibrosis models (n = 3-5) and in human samples of non-alcoholic fatty liver disease (NAFLD) (n = 72-135). Thus, XBP1-mediated UPR contributes to fibrogenic HSC activation and is functionally linked to cellular autophagy.

Background: To ensure patient safety, rigorous quality assurance (QA) measures for colonoscopy were introduced for the Bowel Cancer Screening Programme (BCSP) in England. The impact of these high QA measures on patient experience and satisfaction is unknown., Aims: To determine the impact of this high-level QA of colonoscopy on patient satisfaction., Methods: A case controlled study using a retrospective audit & telephone interview patient survey was performed between 1/1/07-01/10/08 on patients that underwent colonoscopy. Data were analyzed by comparing quantitative and qualitative performance colonoscopy indicators in patients within the BCSP with those outside the programme (NON-BCSP)., Participants: 720 patients that had undergone day case colonoscopy., Setting: Accredited BCSP centre: University Hospitals Aintree, UK., Intervention: Comparing patient satisfaction between BCSP to NON-BCSP populations., Results: Uptake was 68% (n=488). Caecal intubation rate (CIR) was higher (99 v 91%; p=0.001), and sedation doses lower in BCSP compared to NON-BCSP (Midazolam dose Median [IQR] (1 [0, 2] v 2 [1, 3] mg; respectively p=0.0001). For patient satisfaction and experience, scores were high and pain scores were low in both groups; with no statistically significant difference between groups. However, willingness to have a repeat procedure was higher in BCSP (p=0.001)., Conclusions: Whilst superior CIR with less sedation within BCSP, overall scores were similar for patient satisfaction, both in and outside the programme. With the higher 'willingness for repeat' within BCSP, a positive impact of higher level of QA is suggested and that good patient experience can be achieved with minimal conscious sedation in expert hands.