Background/Aims:Renal dysfunction is a frequent and life-threatening complication of advanced cirrhosis and is particularly common in acute-on-chronic liver failure (ACLF), where it is associated with high mortality and poor clinical outcomes. This study aimed to (1) elucidate the role of the renal asymmetric dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH)-endothelial nitric oxide synthase (eNOS) axis in cirrhosis ± superimposed inflammation (mimicking ACLF) with renal dysfunction, and (2) evaluate the effects of CC on this pathway. Methods:Male Wistar rats were administered carbon tetrachloride (15% v/v in corn oil, 0.5 mL/kg, twice weekly for 14 weeks) to induce cirrhosis with renal dysfunction. After 14 weeks, rats were randomized to receive CC (8 mg/kg orally for 2 weeks) before an acute lipopolysaccharide (LPS) challenge. All animals were sacrificed at week 16. Results:CCl4-induced cirrhotic rats showed decreased mean arterial pressure (MAP), renal blood flow (RBF), and increased renal vascular resistance (RVR), and elevated kidney injury markers neutrophil gelatinase-associated lipocalin, blood urea nitrogen , and kidney injury molecule-1 along with heightened renal inflammation. Acute LPS administration further exacerbated these abnormalities. CC treatment markedly reduced renal injury and inflammatory markers in cirrhotic ± LPS-challenged rats, although MAP, RBF, and RVR remained unchanged. In ACLF rats with renal dysfunction, CC significantly lowered renal ADMA levels and increased phosphorylated eNOS and DDAH-1 expression, while DDAH-2 expression decreased. CC also restored renal nitric oxide (NO) levels, enhanced antioxidant enzyme activity, and reduced oxidative stress. Conclusion:This study provides the first evidence that CC enhances renal NO bioavailability by upregulating DDAH-1 and eNOS expression and reducing ADMA accumulation, thereby improving renal endothelial function in cirrhosis with renal dysfunction. Targeting DDAH-1-mediated NO restoration may represent a promising therapeutic strategy for managing renal dysfunction in cirrhosis.

Background:Adult solid organ transplant recipients (SOTRs) have decreased responsiveness to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination and higher incidence of infection, but there are few data on the serological response in pediatric SOTR. The aim of this study was to determine serological response to SARS-CoV-2 vaccination in pediatric liver (LT) and kidney transplant (KT) recipients and compare it with adult SOTR. Methods:A European, prospective, multicenter study was performed. Samples were taken at 7 and 32 wk following COVID-19 vaccination and serological endpoints were measured by ELISA. Results:A total of 42 pediatric (16 post-LT and 26 post-KT) and 117 adult (all post-LT) were included. All pediatric participants and 94% adult participants received mRNA vaccines. Paediatric SOTR patients had significantly higher anti-Spike IgG levels than adult participants at week 7 (114 220.7 [59 285.92-220 058.55] versus 8756.7 [5643.69-13 586.71], P < 0.0001) and week 32 (46 113.2 [10 992.91-193 436.14] versus 8207.0 [3561.20-18 913.43], P = 0.0032). No significant difference in week 7 anti-Spike IgG response was found between pediatric LT and KT (129 434.4 [51 888.64-322 869.69] versus 105 304.5 [39 910.20-277 849.50], P = 0.9854). No differences were seen between children and adults in the rate of decline of anti-Spike IgG between weeks 7 and 32 (P = 0.8000). Male sex and hemolytic-uremic syndrome or postischemic kidney disease were associated with lower anti-Spike IgG levels at week 7 in pediatric SOTR. Conclusions:Paediatric SOTR demonstrate greater SARS-CoV-2 vaccine responses than comparable adult SOTR patients. These data support efficacy and safety of SARS-CoV-2 vaccination in child SOTR and may alleviate vaccine hesitancy in this patient group.

Liver disease is a major, and increasing, cause of death in the UK. The UK Chronic Liver Failure network (UK-CLIF) was developed as a multi-stakeholder network with the aim to advance cirrhosis research, with emphasis on geographical areas of high disease prevalence or limited research activity. The process involved network development through dissemination and snowball sampling techniques, with monitoring of network development and connections between participants, developed over two online meetings. Network membership included representatives from patients, carers, clinicians, researchers, R&D professionals, industry representatives, and the third sector. Subsequently, two facilitated in-person workshops were conducted with network participants. World Café methodology and participant dot voting was used to develop areas of priority and consensus in: (i) research infrastructure for cirrhosis clinical trials, (ii) clinical factors affecting research delivery, and (iii) research priorities for future trials. Thematic analysis demonstrated that the need for patient-centric trial materials, a lack of resource for clinicians to participate in research, and variability in the standard of inpatient care for cirrhosis, were barriers for cirrhosis clinical trials. Future activities for UK-CLIF include participation in a process of quality standard setting for inpatient care for cirrhosis, and coordination of a James Lind Alliance Priority Setting Partnership to develop research questions for liver cirrhosis.

Why have white, less educated voters left the Democratic Party over the past few decades? Scholars have proposed ethnocentrism, social issues and deindustrialization as potential answers. We highlight the role played by the 1994 North American Free Trade Agreement (NAFTA). In event-study analysis, we demonstrate that counties whose 1990 employment depended on industries vulnerable to NAFTA suffered large and persistent employment losses relative to other counties. These losses begin in the mid-1990s and are only modestly offset by transfer programs. While exposed counties historically voted Democratic, in the mid-1990s they turn away from the party of the president (Bill Clinton) who ushered in the agreement and by 2000 vote majority Republican in House elections. Employing a variety of micro-data sources, including 1992-1994 respondent-level panel data, we show that protectionist views predict movement toward the GOP in the years that NAFTA is debated and implemented. This shift among protectionist respondents is larger for whites (especially men and those without a college degree) and those with conservative social views, suggesting an interactive effect whereby racial identity and social-issue positions mediate reactions to economic policies.

Long-term outcome and ‘health-related quality of life’ (HRQoL) following hospitalisation for COVID-19-related severe acute respiratory infection (SARI) is limited.ObjectiveTo assess the impact of HRQoL in patients hospitalised with COVID-19-related SARI at 1 year post discharge, focusing on the potential impact of age, frailty, and disease severity.MethodRoutinely collected outcome data on 1207 patients admitted with confirmed COVID-19 related SARI across all three secondary care sites in our NHS trust over 3 months were assessed in this retrospective cohort study. Of those surviving 1 year, we prospectively collected 36-item short form (SF-36) HRQoL questionnaires, comparing three age groups (<49, 49–69, and the over 69-year-olds), the relative impact of frailty (using the Clinical Frailty Score; CFS), and disease severity (using National Early Warning Score; NEWS) on HRQoL domains.ResultsOverall mortality was 46.5% in admitted patients. In our SF-36 cohort (n=169), there was a significant reduction in all HRQoL domains versus normative data; the most significant reductions were in thephysical component(p<0.001) across all ages and theemotional component(p<0.01) in the 49–69 year age group, with age having no additional impact on HRQoL. However, there was a significant correlation between physical well-beingversus CFS (the correlation coefficient=−0.37, p<0.05), though not NEWS, with no gender difference observed.ConclusionThere was a significant reduction in all SF-36 domains at 1 year. Poor CFS at admission was associated with a significant and prolonged impact on physical parameters at 1 year. Age had little impact on the severity of HRQoL, except in the domains ofphysical functioningand the overallphysical component.

Background Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. Methods In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30 g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. Findings Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P = 0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. Interpretations Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. Funding Wellcome Trust and Department of Health and Social Care. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background Nonselective B-blockers (NSBBs) are believed to have pleiotropic effects beyond reducing portal pressure. However, studies also report potential harm in patients hospitalized with cirrhosis and ascites. We therefore investigated whether NSBB use at ATTIRE trial entry (Albumin to prevent infection in chronic liver failure, 2016-19) was associated with increased renal or cardiovascular dysfunction, compared the incidence of infection and plasma markers of systemic inflammation, and examined mortality at 28-days, 3 and 6-months. Methods In ATTIRE patients grouped by NSBB use at trial entry, we studied infection at baseline, hospital acquired infection and organ dysfunction during trial treatment period and mortality, with propensity score matching to account for differences in disease severity. Findings There were no differences in renal or cardiovascular dysfunction between patients treated with NSBBs or not, during days 3-15 of hospitalization, despite elevated serum creatinine in NSBB patients at hospitalisation. Use of NSBBs was associated with a significant reduction in infection at hospitalization (p = 0.006), lower white cell counts throughout hospital stay (p < 0.001) and reduced plasma procalcitonin (p = 0.009) and interlukin-8 levels (p = 0.04) at baseline, but markers of bacterial translocation and systemic inflammation were the same in treatment groups. There was no reduction in hospital acquired infections in patients taking NSBBs and no beneficial impact on mortality at 28-days, 3 and 6-months. Interpretations Our real-world data from a completed randomised trial show that use of NSBBs in decompensated cirrhosis patients is safe during hospitalisation. We also show a potential anti-inflammatory role for NSBBs which may be mediated by a downregulation of IL-8 induced leucocytosis, that was associated with reduced infection at baseline but not a survival benefit. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.

In decompensated cirrhosis, the severity of portal hypertension (PHT) is associated with increased hepatic endothelial nitric oxide synthase (eNOS) trafficking inducer (Nostrin), but the mechanism remains unclear. AIM: To investigate: (1) Whether in cirrhosis-PHT models, ± superimposed inflammation to mimic acute-on-chronic liver failure (ACLF) modulates hepatic nitric oxide synthase trafficking inducer (NOSTRIN) expression, nitric oxide (NO) synthesis, and/or endothelial dysfunction (ED); and (2) Whether the "angiotensin II type 1 receptor blocker" candesartan cilexetil (CC) affects this pathway. CD-1 mice received intraperitoneal carbon tetrachloride injections (CCl4 15% v/v in corn oil, 0.5 mL/kg) twice weekly for 12 wk to induce cirrhosis. After 12 wk, mice were randomized to receive 2-wk oral administration of CC (8 mg/kg) ± LPS. At sacrifice, plasma (biochemical indicators, cytokines, and angiotensin II) and liver tissues (histopathology, Sirius-red stains, and molecular studies) were analysed. Moreover, Nostrin gene knockdown was tested in human umbilical vein endothelial cells (HUVECs). When compared to naïve animals, CCl4-treated animals showed markedly elevated hepatic Nostrin expression (P < 0.0001), while hepatic peNOS expression (measure of eNOS activity) was significantly reduced (P < 0.05). LPS challenge further increased Nostrin and reduced peNOS expression (P < 0.05 for both) in cirrhotic animals. Portal pressure and subsequent hepatic vascular resistance were also increased in all cirrhotic animals following LPS challenge. In CCl4 ± LPS-treated animals, CC treatment significantly reduced Nostrin (P < 0.05) and increased hepatic cGMP (P < 0.01). NOSIP, caveolin-1, NFκB, and iNOS protein expression were significantly increased in CCl4-treated animals (P < 0.05 for all). CC treatment non-significantly lowered NOSIP and caveolin-1 expression while iNOS and NFκB expression was significantly reduced in CCl4 + LPS-treated animals (P < 0.05 for both). Furthermore, Nostrin knockdown significantly improved peNOS expression and associated NO synthesis and reduced inflammation in HUVECs. This study is the first to indicate a potential mechanistic role for the Nostrin-eNOS-NO pathway in cirrhosis and ACLF development. Moreover, this pathway provides a potential therapeutic target given the ameliorative response to Candesartan treatment.

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage-and pathogen-associated molecular patterns. This first-in-man randomized -controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers.Methods: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre -specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). Results: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group.Conclusions: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and patho-physiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy.Clinical trial number: NCT03065699.& COPY; 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, and due to substantial morbidity and mortality, has proven a significant global health-economic burden.Treatment options are broad and include surgical approaches (i.e., transplantation and resection), radiological (i.e., percutaneous ablation, and trans arterial approaches) and systemic therapies, though treatment response often remains poor.As such, clinical decision making requires a multidisciplinary approach to improve treatment strategy after consideration of the patient's tumor stage, liver function, and performance status.Current systemic cytotoxic therapies for non-surgical candidates have largely remained unchanged over the last decade.Systemic therapies have extended life expectancy by up to 3 months but not without potential notable adverse effects that often limit their use.However, even if patients have necessary access to best treatment, survival outcomes remain concerningly poor.Improved understanding of the pathogenic role of advanced liver fibrosis and wider cancer biology is spearheading the development of targeted immunogenic therapies that appear to offer real promise.Importantly, limiting progression to cirrhosis and early detection of HCC in at risk groups, alongside best use of currently accessible therapeutic options, remains key across global healthcare systems.The focus of this review is to critically assess all current published literature, encapsulating the prevalence, diagnosis, and management of HCC, whilst looking ahead to the potential future therapeutic directions in HCC management.

Background: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. Methods: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4–10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. Results: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis ( p < 0.0001), AILD ( p < 0.0001), and control ( p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. Conclusions: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level.

Abstract Background Bacterial infection is a major cause of mortality in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP) is a serious and common infection in patients with cirrhosis and ascites. Secondary prophylactic antibiotic therapy has been shown to improve outcomes after an episode of SBP but primary prophylaxis to prevent the first episode of SBP remains contentious. The aim of this trial is to assess whether primary antibiotic prophylaxis with co-trimoxazole improves overall survival compared to placebo in adults with cirrhosis and ascites. Methods The ASEPTIC trial is a multicentre, placebo-controlled, double-blinded, randomised controlled trial (RCT) in England, Scotland, and Wales. Patients aged 18 years and older with cirrhosis and ascites requiring diuretic treatment or paracentesis, and no current or previous episodes of SBP, are eligible, subject to exclusion criteria. The trial aims to recruit 432 patients from at least 30 sites. Patients will be randomised in a 1:1 ratio to receive either oral co-trimoxazole 960 mg or an identical placebo once daily for 18 months, with 6 monthly follow-up visits thereafter (with a maximum possible follow-up period of 48 months, and a minimum of 18 months). The primary outcome is overall survival. Secondary outcomes include the time to the first incidence of SBP, hospital admission rates, incidence of other infections (including Clostridium difficile) and antimicrobial resistance, patients’ health-related quality of life, health and social care resource use, incidence of cirrhosis-related decompensation events, liver transplantation, and treatment-related serious adverse events. Discussion This trial will investigate the efficacy, safety, and cost-effectiveness of co-trimoxazole for patients with liver cirrhosis and ascites to determine whether this strategy improves clinical outcomes. Given there are no treatments that improve survival in decompensated cirrhosis outside of liver transplant, if the trial has a positive outcome, we anticipate widespread adoption of primary antibiotic prophylaxis. Trial registration ClinicalTrials.gov NCT043955365 . Registered on 18 April 2020. Research ethical approval was granted by the Research Ethics Committee (South Central – Oxford B; REC 19/SC/0311) and the Medicines and Healthcare products Regulatory Agency (MHRA).

: SARS-CoV-2 is a novel coronavirus that has been identified, in December 2019, in Wuhan, China, and since it has become a worldwide pandemic, it has imposed far-reaching impacts on global human health and socio-economic activity. Worldwide, over 4 million Covid-19 related deaths were reported until September 2021. Recently published case studies have reported that Covid-19 patients develop different degrees of liver dysfunction. Inevitably, in hospitalized Covid-19 patients who develop acute liver derangement, there are a plethora of potential pathogenic causes such as direct-viral, immune-driven, and drug-induced and/or ischaemic liver injury. Patients with advanced chronic liver diseases (e.g., cirrhosis) and/or autoimmune liver disease have a poor immune function and associated poorer outcomes compared to other critically ill cohorts. However, largely any immediate liver derangement tends to be relatively mild, and as such, any de novo liver injury may not be a significant feature of Covid-19. There is an immediate necessity, therefore, to better understand the liver-specific pathophysiology of COVID-19. This review focuses on the up-to-date information regarding Covid-19 and associated indices for liver dysfunction, possible mechanisms, and potential drug targeted therapies in Covid-19 patients with and without liver dysfunction. PubMed database was used to perform an extensive literature search using the keywords liver and SARS-CoV-2, liver and Covid-19, Covid 19 and treatment, etc.