Efficacy and Safety of Remdesivir in People With Impaired Kidney Function Hospitalized for COVID-19 Pneumonia: A Randomized Clinical Trial.

BACKGROUND: Few antiviral therapies have been studied in patients with COVID-19 and kidney impairment. Herein, efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-beta-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. METHODS: In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury (AKI), chronic kidney disease (CKD), or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on Day 1; 100 mg daily up to Day 5) or placebo (enrollment: March 2021-March 2022). The primary efficacy endpoint was the composite of all-cause mortality or invasive mechanical ventilation (IMV) through Day 29. Safety was evaluated through Day 60. RESULTS: Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 (37.0%) participants had AKI (remdesivir, 60; placebo, 30), 64 (26.3%) had CKD (remdesivir, 44; placebo, 20), and 89 (36.6%) had kidney failure (remdesivir, 59; placebo, 30); 31 (12.8%) were COVID-19 vaccinated. Composite all-cause mortality or IMV through Day 29 was 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = 0.61). Treatment-emergent adverse events were reported in 80.4% versus 77.5% and serious adverse events in 50.3% versus 50.0% of participants who received remdesivir versus placebo, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. CONCLUSIONS: Although underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in those with COVID-19 and severe kidney impairment. (EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351). TRIAL REGISTRATION: EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351.

Macrophage activation markers are associated with infection and mortality in patients with acute liver failure.

BACKGROUND AND AIMS: Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. METHODS: Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1-3) and late (>Day 3) time points were analysed for MAMs by enzyme-linked immunosorbent assay correlated to markers of illness severity and 21-day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. RESULTS: All MAMs serum concentrations were significantly higher in ALF compared to controls (p < .0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p = .002) and infection in general (p = .006). In MELD-adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p < .001) was higher in patients with ALF compared with controls and correlated with SOFA score (p = .018). sCD206 was independently validated as a predictor of infection in an external cohort. CONCLUSIONS: sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF.

Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial.

BACKGROUND: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD). METHODS/DESIGN: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival. DISCUSSION: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care. ETHICS AND DISSEMINATION: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation. TRIAL REGISTRATION: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

Liver transplantation for acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) occurs in the context of advanced liver disease and is associated with hepatic and extrahepatic organ failure, eventually leading to a major risk of short-term mortality. To date, there are very few effective therapeutic options for ACLF. In many cases, liver transplantation is the only life-saving treatment that has acceptable outcomes in carefully selected recipients. This Review addresses key aspects of the use of liver transplantation for patients with ACLF, providing an in-depth discussion of existing evidence regarding candidate selection, the optimal window for transplantation, potential prioritisation of liver grafts for this indication, and the global management of ACLF to bridge patients to liver transplantation.

Immunopathogenesis of acute on chronic liver failure.

Acute-on-chronic liver failure is a well-established description of a high-mortality syndrome of chronic liver disease (usually cirrhosis) with organ failure. While the exact definition is under refinement, the accepted understanding of this entity is in patients with chronic liver disease and various organs in failure and where systemic inflammation is a major component of the pathobiology. There are limited therapies for a disease with such a poor prognosis, and while improvements in the critical care management and for very few patients, liver transplantation, mean 50% can survive to hospital discharge, rapid application of new therapies is required. Here we explain the current understanding of the immunologic abnormalities seen in acute-on-chronic liver failure across the innate and adaptive immune systems, the role of the hepatic cell death and the gut-liver axis, and recommendations for future research and treatment paradigms.

Liver Elastography in Acute Liver Failure: A Pilot Study.

OBJECTIVES: We aimed to assess the feasibility and reliability of sequential ultrasonographic and elastographic monitoring in acute liver failure (ALF). DESIGN: Observational study. SETTING: ALF is a rare, life-threatening disease that requires intensive care admission and often liver transplant, where the accurate selection of patients is crucial. Liver elastography is a noninvasive tool that can measure hepatic stiffness, but previous results have been inconclusive in ALF. PATIENTS: Patients admitted between October 2021 and March 2023 to the Liver Intensive Therapy Unit at King's College Hospital with ALF were recruited, with healthy control (HC) individuals and acute-on-chronic liver failure (ACLF) used as controls. INTERVENTION: None. MEASUREMENTS: Average shear wave velocity was recorded with ElastPQ on the right and left liver lobes and the spleen. Portal vein flow, hepatic artery resistive index, and peak systolic velocity were also recorded. Physiologic and histologic data were used for comparison. MAIN RESULTS: Forty patients with ALF, 22 patients with ACLF, and 9 HC individuals were included in the study. At admission, liver stiffness measurement (LSM) of the right lobe was statistically different between HC individuals (5.6 ± 2 kPa), ALF (31.7 ± 17 kPa), and ACLF (76.3 ± 71 kPa) patients (ALF vs. ACLF, p = 0.0301). Spleen size and stiffness discriminated between ALF (10.4 ± 2 cm and 21.4 ± 16.6 kPa) and ACLF (14 ± 2.3 cm and 42.6 ± 26 kPa). At admission, LSM was not different between ALF patients who spontaneously survived versus patients who died or were transplanted in the following 90 days. However, the trend over the first 10 days of admission was different with a peak of LSM at day 5 in spontaneous survivors followed by reduction during the recovery phase. ALF patients with poor prognosis showed a persistently increased LSM. CONCLUSIONS: In ALF stiffness peaks at day 5 of admission with subsequent reduction in patients spontaneously surviving, showing significant difference according to the prognosis at day 7 of admission. LSM might be useful in distinguishing acute from acute-on-chronic liver failure together with spleen volume and stiffness.

Potential therapies for acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.

Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure.

BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis, which is associated with a high incidence of death from sepsis. Herein, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidylcholinic acid (LPA) pathway. METHODS: Ninety-six individuals with ALF, 104 with cirrhosis, 31 with sepsis and 71 healthy controls (HCs) were recruited. Pathways of interest were identified by multivariate statistical analysis of proton nuclear magnetic resonance spectroscopy and untargeted ultraperformance liquid chromatography-mass spectrometry-based lipidomics. A targeted metabolomics panel was used for validation. Peripheral blood mononuclear cells were cultured with LPA 16:0, 18:0, 18:1, and their immune checkpoint surface expression was assessed by flow cytometry. Transcript-level expression of the LPA receptor (LPAR) in monocytes was investigated and the effect of LPAR antagonism was also examined in vitro. RESULTS: LPC 16:0 was highly discriminant between ALF and HC. There was an increase in ATX and LPA in individuals with ALF compared to HCs and those with sepsis. LPCs 16:0, 18:0 and 18:1 were reduced in individuals with ALF and were associated with a poor prognosis. Treatment of monocytes with LPA 16:0 increased their PD-L1 expression and reduced CD155, CD163, MerTK levels, without affecting immune checkpoints on T and NK/CD56+T cells. LPAR1 and 3 antagonism in culture reversed the effect of LPA on monocyte expression of MerTK and CD163. MerTK and CD163, but not LPAR genes, were differentially expressed and upregulated in monocytes from individuals with ALF compared to controls. CONCLUSION: Reduced LPC levels are biomarkers of poor prognosis in individuals with ALF. The LPC-ATX-LPA axis appears to modulate innate immune response in ALF via LPAR1 and LPAR3. Further investigations are required to identify novel therapeutic agents targeting these receptors. IMPACT AND IMPLICATIONS: We identified a metabolic signature of acute liver failure (ALF) and investigated the immunometabolic role of the lysophosphatidylcholine-autotaxin-lysophosphatidylcholinic acid pathway, with the aim of finding a mechanistic explanation for monocyte behaviour and identifying possible therapeutic targets (to modulate the systemic immune response in ALF). At present, no selective immune-based therapies exist. We were able to modulate the phenotype of monocytes in vitro and aim to extend these findings to murine models of ALF as a next step. Future therapies may be based on metabolic modulation; thus, the role of specific lipids in this pathway require elucidation and the relative merits of autotaxin inhibition, lysophosphatidylcholinic acid receptor blockade or lipid-based therapies need to be determined. Our findings begin to bridge this knowledge gap and the methods used herein could be useful in identifying therapeutic targets as part of an experimental medicine approach.

General practitioner perspectives on factors that influence implementation of secondary care-initiated treatment in primary care: Exploring implementation beyond the context of a clinical trial.

BACKGROUND: The Beta-blockers Or Placebo for Primary Prophylaxis of oesophageal varices (BOPPP) trial is a 3-year phase IV, multi-centre clinical trial of investigational medicinal product (CTIMP) that aims to determine the effectiveness of carvedilol in the prevention of variceal bleeding for small oesophageal varices in patients with cirrhosis. Early engagement of General Practitioners (GPs) in conversations about delivery of a potentially effective secondary care-initiated treatment in primary care provides insights for future implementation. The aim of this study was to understand the implementation of trial findings by exploring i) GP perspectives on factors that influence implementation beyond the context of the trial and ii) how dose titration and ongoing treatment with carvedilol is best delivered in primary care. METHODS: This qualitative study was embedded within the BOPPP trial and was conducted alongside site opening. GP participants were purposively sampled and recruited from ten Clinical Commissioning Groups in England and three Health Boards across Wales. Semi-structured telephone individual interviews were conducted with GPs (n = 23) working in England and Wales. Data were analysed using reflexive thematic analysis. FINDINGS: Five overarching themes were identified: i) primary care is best placed for oversight, ii) a shared approach led by secondary care, iii) empower the patient to take responsibility, iv) the need to go above and beyond and v) develop practice guidance. The focus on prevention, attention to holistic care, and existing and often long-standing relationships with patients provides an impetus for GP oversight. GPs spoke about the value of partnership working with secondary care and of prioritising patient-centred care and involving patients in taking responsibility for their own health. An agreed pathway of care, clear communication, and specific, accessible guidance on how to implement the proposed treatment strategy safely and effectively are important determinants in the success of implementation. CONCLUSIONS: Our findings for implementing secondary care-initiated treatment in primary care are important to the specifics of the BOPPP trial but can also go some way in informing wider learning for other trials where work is shared across the primary-secondary care interface, and where findings will impact the primary care workload. We propose a systems research perspective for addressing implementation of CTIMP findings at the outset of research. The value of early stakeholder involvement is highlighted, and the need to consider complexity in terms of the interaction between the intervention and the context in which it is implemented is acknowledged. TRIAL REGISTRATION: ISRCTN10324656.

Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes.

Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-É£ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-É£ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-É£ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.

Systematic review and meta-analysis of the diagnostic accuracy of procalcitonin for post-operative sepsis/infection in liver transplantation.

BACKGROUND: Post-operative infection is a major cause of morbidity and mortality in Liver Transplantation (LT). Early diagnosis and antimicrobial treatment improves outcomes and ruling out sepsis aids immunosuppression decisions. Procalcitonin (PCT) has recently become part of such decision making in COVID-19 pneumonia but its role in LT is not established. We assessed the diagnostic accuracy of PCT as a diagnostic biomarker for infection or sepsis following LT. METHODS: A systematic search was conducted for studies reporting diagnostic performance of PCT for infection/sepsis following LT. Studies were assessed for reporting of diagnostic accuracy, relevance and quality. RESULTS: Eight studies with 363 participants reported data on the diagnostic accuracy of PCT, with pooled sensitivity, specificity, diagnostic odds ratio and summary receiver operator curve of 70% (95% CI 62-78), 77% (95% CI 73-83), 15.82 (95% CI 5.82-43.12) and 0.871 respectively. There was variability in the timing of sampling (post-operative day 1-8) and range of cut-off values (0.48 to 42.8 ng/mL). Heterogeneity was reduced when only studies with adult LT recipients were considered. CONCLUSIONS: PCT performs moderately well as a diagnostic test for postoperative infection/sepsis following LT. This marker is more suited for use in adult LT populations.

Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids.

Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.

Using a theory-informed approach to explore patient and staff perspectives on factors that influence clinical trial recruitment for patients with cirrhosis and small oesophageal varices.

OBJECTIVE: The success of pharmacological randomised controlled trials (RCTs) depends on the recruitment of the required number of participants. Recruitment to RCTs for patients with cirrhosis and small oesophageal varices raises specific additional challenges. The objectives of the study were 1) to explore patient perspectives on factors that influence RCT recruitment, 2) to understand factors that influence the success of recruitment from a staff perspective, and 3) to identify opportunities for tailored interventions to improve trial recruitment in this context. METHODS: The qualitative study was embedded in a multi-centre blinded RCT (BOPPP trial) and was conducted alongside site opening. Semi-structured interviews were conducted with patients who enrolled to participate in the trial (n = 13), patients who declined to take part (n = 5), and staff who were responsible for recruiting participants to the trial (n = 18). An open approach to data collection and analysis was adopted and the Theoretical Domains Framework (TDF) was used to provide a theoretical lens through which to view influences on behaviour. Data was analysed using thematic analysis. RESULTS: The findings consist of 5 overarching themes that outline trial recruitment influences at the patient, staff, team, organisational and trial levels: i) patient risks and benefits ii) staff attitudes, knowledge and capacity, iii) team-based approach, iv) organisational context and v) Trial collective. Patient-generated themes map onto thirteen of the fourteen TDF domains and staff-generated themes map onto all TDF domains. The overarching themes are not mutually exclusive; with evidence of direct interactions between patient and staff-level themes that influence recruitment behaviours. CONCLUSIONS: This study uses a theory-informed approach to gain new insights into improving clinical trial recruitment for patients with cirrhosis and small oesophageal varices. Although people with cirrhosis often display decreased healthcare-seeking behaviours, we found that patients used research to empower themselves to improve their health. Pragmatic trials involving unpredictable populations require staff expertise in building trust, and a deep knowledge of the patient group and their vulnerabilities. RCT recruitment is also more successful when research visits align with what staff identified as the natural rhythm of care. TRIAL REGISTRATION: ISRCTN10324656; https://clinicaltrials.gov/.

Variation in the Care of Acute Liver Failure: A Survey of Intensive Care Professionals.

INTRODUCTION: Acute liver failure (ALF) is a rare disease with potentially high mortality. We sought to assess the individual approach to ALF by intensive care unit (ICU) professionals. METHODS: Cross-sectional survey of ICU professionals. Web-based survey capturing data on respondents' demographics, characteristics of patients with ALF admitted to ICU, and their management. RESULTS: Among 204 participants from 50 countries, 140 (68.6%) worked in Europe, 146 (71.6%) were intensivists, 142 (69.6%) admitted <25 patients with ALF per year, and 166 (81.8%) reported <25% of patients had paracetamol-related ALF. On patients' outcomes, 126 (75.0%) reported an emergency liver transplantation (ELT) rate <25% and 140 (73.3%) a hospital mortality rate <50%. The approach to ALF in the ICU varied with age, region, level of training, type of hospital, and etiology (prescribing N-acetylcysteine for paracetamol toxicity, triggers for endotracheal intubation, measurement of and strategies for lowering serum ammonia, extracorporeal device deployment, and prophylactic antibiotics). CONCLUSIONS: The management of patients with ALF by ICU professionals differed substantially concerning the relevant clinical measures taken. Further education and high-quality research are warranted.

INTRODUÇÃO: A falência hepatica aguda (ALF) é uma doença rara potencialmente letal. Pretendeu-se avaliar a abordagem individual à ALF por profissionais da Unidade de Cuidados Intensivos (UCI). MÉTODOS: Inquérito transversal de profissionais da UCI. Inquérito online capturando informação da demografia dos respondedores, características dos doentes com ALF admitidos na UCI e sua abordagem. RESULTADOS: Entre 204 participantes de 50 países, 140 (68.6%) trabalhavam na Europa, 146 (71.6%) eram inten-sivistas, 142 (62.9%) admitiam <25 doentes com ALF por ano, e 166 (81.8%) reportaram <25% dos doentes com ALF relacionada com paracetamol. Quanto aos resultados dos doentes, 126 (75.0%) reportaram uma taxa de transplantação hepatica emergente (ELT) <25% e 140 (73.3%) uma taxa de mortalidade hospitalar <50%. A abordagem da ALF variou com a idade, região, nível de treino, tipo de hospital, ou etiologia nos seguintes tópicos: prescrição de N-acetil-cisteína, critérios de intubação orotraqueal, medição e estratégias de control da amoniémia, uso de técnicas extracorporais, e a prescrição de antibióticos profilácticos. CONCLUSÕES: A abordagem de doentes com ALF por profissionais da UCI diferiu substancialmente em aspectos clínicos importantes. Educação e investigação de qualidade adicionais serão necessárias.

Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis.

BACKGROUND AND AIMS: The "gut homing" hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine "the gut homing theory" in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases. APPROACH AND RESULTS: Expression of MAdCAM-1, CCL25, and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was up-regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of α4ß7, αEß7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. ß7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with ß7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver. CONCLUSIONS: These findings refute the widely accepted "gut homing" hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T cells is not unique to PSC, but is a panetiological feature of CLD.

The patient with cirrhosis in the intensive care unit and the management of acute-on-chronic liver failure.

Acute on chronic liver failure (ACLF) is a clinical syndrome characterised by acute hepatic decompensation, multi-organ failure and high mortality, in patients with cirrhosis. Organ dysfunction in ACLF is often reversible and when necessary these patients should be considered appropriate candidates for admission to an intensive care unit (ICU). The yearly increase in numbers of patients with ACLF admitted to ICU has been matched with an improvement in survival. ACLF has only been recently defined. In the absence of evidence-based guidelines we outline a systems-based approach to care which encompasses accepted ICU practice and evidence from trials in this cohort. We advocate for timely referral to specialist liver centres and consider the complexities of proceeding with liver transplantation. Equally, in a proportion of patients who continue to deteriorate, appropriate ceilings of care should be established. Future clinical trials may change treatment paradigms but care of patients with ACLF is undoubtedly becoming an integral part of an intensivist's practice. We hope that this review is a welcome starting point when managing this complex clinical syndrome.

Systematic review and meta-analysis of tumour microsatellite-instability status as a predictor of response to fluorouracil-based adjuvant chemotherapy in colorectal cancer.

PURPOSE: Colorectal cancer (CRC) can be classified according to the chromosomal-instability pathway (a microsatellite-stable (MSS) pathway) and the microsatellite-instability (MSI) pathway. Adjuvant therapy after surgery in advanced CRC is usually based on fluoropyrimidine 5-fluorouracil (5-FU) alone or combined with other agents. Controversy however remains on the use of 5-FU-based regimens in treating MSI-related tumours. AIMS: To systematically investigate the relationship between tumour microsatellite profile and 5-year overall survival in patients with CRC treated with 5-FU. METHODS: A systematic literature review of PubMed and Embase databases was conducted. Pre-specified criteria determined study inclusion/exclusion. The PRISMA and QUADAS-2 criteria were used to assess study suitability and quality respectively. Patients were categorised as having either MSI or MSS CRC. Overall 5-year survival was estimated from Kaplan-Meier curves. Publication bias was assessed using funnel-plots and Egger's test. RESULTS: 1807 studies were identified, with meta-analysis performed using nine studies. 5-FU treated individuals with CRC who died at 5 years were found to be 0.31 times less likely to have MSI than those who were alive, although this was not statistically significant. There was an insufficient number of studies to enable subgroup analysis by stage. CONCLUSIONS: In this meta-analysis, MSI status does not alter 5-year survival of patients with CRC patients treated with adjuvant 5-FU, however there is significant heterogeneity in the design of individual studies in the data synthesis. More studies are necessary to clarify whether CRC patients with MSI CRC, in particular early stage, should be offered 5-FU based adjuvant chemotherapy.

Rifaximin-α reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial.

BACKGROUND & AIMS: Rifaximin-α is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-α reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE. METHODS: In a placebo-controlled, double-blind, mechanistic study, 38 patients with cirrhosis and HE were randomised 1:1 to receive either rifaximin-α (550 mg BID) or placebo for 90 days. PRIMARY OUTCOME: 50% reduction in neutrophil oxidative burst (OB) at 30 days. SECONDARY OUTCOMES: changes in psychometric hepatic encephalopathy score (PHES) and neurocognitive functioning, shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolic profiling, whole blood bacterial DNA quantification, neutrophil toll-like receptor (TLR)-2/4/9 expression and plasma/faecal cytokine analysis. RESULTS: Patients were well-matched: median MELD (11 rifaximin-α vs. 10 placebo). Rifaximin-α did not lead to a 50% reduction in spontaneous neutrophil OB at 30 days compared to baseline (p = 0.48). However, HE grade normalised (p = 0.014) and PHES improved (p = 0.009) after 30 days on rifaximin-α. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-α (TNF-α) (p <0.001). Rifaximin-α suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α- and interleukin-17E-enriched intestinal microenvironment, augmenting antibacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection (odds ratio 0.21; 95% CI 0.05-0.96). CONCLUSION: Rifaximin-α led to resolution of overt and covert HE, reduced the likelihood of infection, reduced oralisation of the gut and attenuated systemic inflammation. Rifaximin-α plays a role in gut barrier repair, which could be the mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02019784. LAY SUMMARY: In this clinical trial, we examined the underlying mechanism of action of an antibiotic called rifaximin-α which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). We show that rifaximin-α suppresses gut bacteria that translocate from the mouth to the intestine and cause the intestinal wall to become leaky by breaking down the protective mucus barrier. This suppression resolves encephalopathy and reduces inflammation in the blood, preventing the development of infection.