Gavin Wright

King's College London

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Rajiv Jalan

The Royal Free Hospital

Nathan Davies

University College London

Vanessa Stadlbauer

Medical University of Graz

Rajeshwar P. Mookerjee

University College London

Debbie L. Shawcross

King's College London

Shilpa Chokshi

Foundation for Liver Research

Banwari Agarwal

The Royal Free Hospital

Natalie Zemon Davis

Princeton University

Vicente Arroyo

European Foundation for the Study of Chronic Liver Failure

Stephen Hodges

UiT The Arctic University of Norway

Cooperative Institutions

University College London

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European Foundation for the Study of Chronic Liver Failure

The Royal Free Hospital

University of Michigan–Ann Arbor

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

King's College London

Instituto de Salud Carlos III

King's College Hospital

Cambridge University Press

University of California, Davis

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Cardiovascular effects of whole-body heating in spontaneously hypertensive rats

Journal of Applied Physiology (1978)

Gavin Wright Edwin A. Knecht Mark Toraason

The cardiovascular response to severe whole-body heating was examined in anesthetized spontaneously hypertensive (SH) (mean BP = 140 Torr) and normotensive (N) rats (mean BP = 96 Torr). Elevation of colonic temperature to 44 degrees C resulted in an initial increase in arterial pressure (mean BP: SH = 199 Torr, N = 124 Torr) with a subsequent severe hypotension. There was little evidence to suggest that this collapse in systemic pressure was related to a direct heat impairment of cardiac function. It was more likely the result of a progressive venodilation which produced venous pooling and decreased venous return. The arterial blood pressure response to exogenous catecholamine challenge decreased at elevated temperatures. This suggests that there was a deterioration of the vasoconstrictor response and indicated a possible effect of heat at the receptor or effector level. There were significant differences between the responses of normotensive and hypertensive rats to whole-body heating suggesting an enhanced cardiovascular sensitivity in hypertensive rats that may partially explain earlier reports of inferior thermoregulation and heat intolerance in these animals.

Torr

Venous return curve

10.1152/jappl.1978.45.4.521

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Citations (17)

Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK

NIHR Open Research (2024)

Helen Crisp Oliver Tavabie Yvanne Enever Richard M. Allen Milton Silverman

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.

10.3310/nihropenres.13669.1

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Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure

Journal of Hepatology (2023)

Banwari Agarwal Rafael Bañares Faouzi Saliba María Pilar Ballester Dana Tomescu

•In a first-in-man, randomized-controlled trial of DIALIVE vs. standard of care, the primary endpoint of safety was met.•DIALIVE achieved acceptable performance characteristics for albumin exchange and reduction in endotoxin.•DIALIVE significantly reduced time to resolution of ACLF and improved prognostic scores compared with standard of care.•DIALIVE had a significantly greater impact on the pathophysiologically relevant biomarkers associated with ACLF. Background & AimsAcute-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.MethodsThirty-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).ResultsThere 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.ConclusionsThese data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy.Impact and implicationsThis is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy.Clinical trial numberNCT03065699. 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. 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). 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. These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy.

Standard of care

10.1016/j.jhep.2023.03.013

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Citations (36)

250 EVALUATION OF HAEMOSTASIS IN ACUTE LIVER FAILURE: A COMPREHENSIVE STUDY USING TRADITIONAL PLASMATIC TESTS AND WHOLE BLOOD THROMBOELASTOGRAPHY

Journal of Hepatology (2012)

Gavin Wright Vishwaraj Vemala A.K. Burroughs A. Gatt Anne Riddell

Monocyte

10.1016/s0168-8278(12)60263-3

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Citations (2)

33 INCREASED NEUTROPHIL TOLL-LIKE-RECEPTOR 2, 4 AND 9 EXPRESSION IN ALCOHOLIC HEPATITIS IS A RESULT OF ITS ACTIVATION RATHER THAN ITS CAUSE

Journal of Hepatology (2008)

Vanessa Stadlbauer Rajeshwar P. Mookerjee Gavin Wright Stephen Hodges Nathan Davies

Alcoholic Hepatitis

Expression (computer science)

10.1016/s0168-8278(08)60035-5

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Role of Toll-Like Receptor 4 in Modulating the Brain-Gut Axis in the Pathogenesis of Hepatic Encephalopathy

Journal of Hepatology (2016)

Yalda Sharifi Natalia Arias Gavin Wright Nihar Shah Marc Oria

Pathogenesis

Hepatic Encephalopathy

Gut–brain axis

10.1016/s0168-8278(16)01676-7

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A case of anastrazole-related drug-induced autoimmune hepatitis

Clinical Journal of Gastroenterology (2014)

Mohammad Saiful Islam Gavin Wright Peter A. Tanner Robert Lucas

Autoimmune Hepatitis

Hepatitis B

Liver disease

Liver function

10.1007/s12328-014-0512-4

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Citations (14)

Use of non-selective B-blockers is safe in hospitalised decompensated cirrhosis patients and exerts a potential anti-inflammatory effect: data from the ATTIRE trial

EClinicalMedicine (2022)

Thaís Tittanegro Louise China Ewan Forrest Yiannis Kallis Stephen Ryder

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.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.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.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.Wellcome Trust and Department of Health and Social Care.

Spontaneous bacterial peritonitis

Procalcitonin

10.1016/j.eclinm.2022.101716

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Citations (7)

O089 : Increased neuronal expression of K-type glutaminase potentiates brain edema in acute liver failure mice through a TLR4 dependent pathway

Journal of Hepatology (2015)

Yalda Sharifi Gavin Wright M. Jover Naina Shah Francesco Scaravilli

Brain Edema

Glutaminase

10.1016/s0168-8278(15)30108-2

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OP08 Evidence for early astrocyte activation, cellular stress and compensatory microglial related transforming growth factor-α responses in bile-duct ligated rats

Gut (2010)

Gavin Wright Tracey A. Newman Yalda Sharifi Neil Davis R Jalan

Introduction Inflammation and ammonia are important mediators in the pathogenesis of hepatic encephalopathy and though the mechanisms are unclear astrocytes are thought to have a central role. Recently Microglia, which also mediate brain inflammation, were implicated in the brain effects of acute liver failure; however their influence in chronic liver disease is unknown. Aim The aim of this longitudinal study was to characterise the early brain responses in bile-duct ligated (BDL) rats in the 4-weeks following ligation. Method Twenty-four male Sprague-Dawley rats were studied after sham-operation or BDL and sacrificed at either 1-day or, 1-, 2- or 4 weeks post-surgery (n=4/group). Consciousness, brain water content, arterial ammonia, plasma biochemistry and proinflammatory (IL-6, TNF-α and γ-IFN) and antiinflammatory (IL-4 and IL-10) cytokines, were analysed. Immunohistochemical markers of activated microglia (ED1, OX6 and Iba-1), astrocytes (GFAP), inflammatory responses (IL-1s and iNOS), cellular stress (HSP-25) and the predominant antiinflammatory and alternative microglial activation marker TGF-s (using RT-PCR), were also analysed. Results Compared to Shams, arterial and brain ammonia (p Conclusion Regional astrocyte activation and cellular stress (indicated by increased HSP-25 expression), are early features of BDL. These events are associated with increased brain proinflammatory cytokine production and iNOS expression. This proinflammatory response is not due to obvious microglia activation, but consequent upon activation of astrocytes, possibly related to hyperammonemia and/or associated cell swelling. However, an observed TGF-s response may reflect compensatory antiinflammatory microglial responses, designed to limit the effect of astrocyte activation; with interventions targeting its brain expression potential novel therapies for hepatic encephalopathy.

Proinflammatory cytokine

Neuroglia

10.1136/gut.2010.223362.8

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