Semin Liver Dis 2008; 28(1): 096-109
DOI: 10.1055/s-2008-1040324
© Thieme Medical Publishers

Artificial Liver Support Systems in the Management of Complications of Cirrhosis

Vanessa Stadlbauer1 , Nathan A. Davies1 , Sambit Sen1 , Rajiv Jalan1
  • 1Liver Failure Group, Institute of Hepatology, Division of Medicine, University College London, London, United Kingdom
Further Information

Publication History

Publication Date:
22 February 2008 (online)

ABSTRACT

Acute-on-chronic liver failure (ACLF) is associated with multiorgan dysfunction requiring intensive care support and carries an exceptionally high risk of mortality. Decompensation of liver cirrhosis is triggered by different precipitating events but the final common pathway is hypothesized to be unregulated systemic inflammation. The concept of an artificial liver that may impact favorably upon the inflammatory response and provide liver function to prevent complications seems to be promising. This article aims to describe the currently available artificial and bioartificial systems and reviews their effect on different complications of cirrhosis, such as liver function and hepatic hemodynamics, renal function and systemic hemodynamics, hepatic encephalopathy, inflammation/infection, and coagulation. Due to the difficulties in studying large patient numbers with ACLF and the heterogeneity of this patient group, only limited data on survival are available. The currently available studies indicate that there is a survival benefit for artificial and bioartificial liver support in certain subgroups of patients; however, further studies are warranted. At present several studies in this field are under way. In this review several of the companies interested in the manufacture of the respective devices provide an up-to-date report of ongoing trials. In summary, artificial and bioartificial liver support are already playing important roles in the treatment of complications of ACLF. Better understanding of the pathophysiology of ACLF, further development of the current systems, and their evaluation in appropriately controlled clinical studies are necessary to translate their application to improvement in outcome of patients with ACLF.

REFERENCES

  • 1 World Health Organization .Projections of mortality and burden of disease to 2030. Available at: http://www.who.int/healthinfo/statistics/bodprojections2030/en/index.html
  • 2 Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options.  Blood Purif. 2002;  20 252-261
  • 3 Jalan R, Stadlbauer V, Sen S et al.. Natural history of acute decompensation of cirrhosis: the basis of the definition, prognosis and pathophysiology of acute on chronic liver failure.  Hepatology. 2006;  44 371A
  • 4 Stockmann H B, Ijzermans J N. Prospects for the temporary treatment of acute liver failure.  Eur J Gastroenterol Hepatol. 2002;  14 195-203
  • 5 Shawcross D L, Davies N A, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.  J Hepatol. 2004;  40 247-254
  • 6 Shawcross D L, Wright G, Olde Damink S W, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy.  Metab Brain Dis. 2007;  22 125-138
  • 7 Wright G, Davies N A, Shawcross D L et al.. Endotoxemia produces coma and brain swelling in bile duct-ligated rats.  Hepatology. 2007;  45 1517-1526
  • 8 Mookerjee R P, Sen S, Davies N A, Hodges S J, Williams R, Jalan R. Tumour necrosis factor-alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis.  Gut. 2003;  52 1182-1187
  • 9 Mookerjee R P, Malaki M, Davies N A et al.. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis.  Hepatology. 2007;  45 62-71
  • 10 Mookerjee R P, Dalton R N, Davies N A et al.. Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure.  Liver Transpl. 2007;  13 400-405
  • 11 Moreau R, Lebrec D. The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond.  Hepatology. 2006;  43 385-394
  • 12 Genesca J, Gonzalez A, Segura R et al.. Interleukin-6, nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis.  Am J Gastroenterol. 1999;  94 169-177
  • 13 Kurtovic J, Boyle M, Bihari D, Riordan S M. Nitric-oxide-lowering effect of terlipressin in decompensated cirrhosis: comparison to the molecular adsorbent recirculating system and correlation with clinical status.  Eur J Gastroenterol Hepatol. 2004;  16 1335-1338
  • 14 Sen S, Davies N A, Mookerjee R P et al.. Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study.  Liver Transpl. 2004;  10 1109-1119
  • 15 Mookerjee R P, Stadlbauer V, Lidder S et al.. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts outcome.  Hepatology. 2007;  46 831-840
  • 16 Allen J W, Hassanein T, Bhatia S N. Advances in bioartificial liver devices.  Hepatology. 2001;  34 447-455
  • 17 Strain A J, Neuberger J M. A bioartificial liver: state of the art.  Science. 2002;  295 1005-1009
  • 18 Chamuleau R A, Deurholt T, Hoekstra R. Which are the right cells to be used in a bioartificial liver?.  Metab Brain Dis. 2005;  20 327-335
  • 19 Di Nicuolo G, van de Kerkhove M P, Hoekstra R et al.. No evidence of in vitro and in vivo porcine endogenous retrovirus infection after plasmapheresis through the AMC-bioartificial liver.  Xenotransplantation. 2005;  12 286-292
  • 20 Busse B, Gerlach J C. Bioreactors for hybrid liver support: historical aspects and novel designs.  Ann NY Acad Sci. 1999;  875 326-339
  • 21 Ash S R, Steczko J, Knab W R et al.. Push-pull sorbent-based pheresis and hemodiabsorption in the treatment of hepatic failure: preliminary results of a clinical trial with the BioLogic-DTPF System.  Ther Apher. 2000;  4 218-228
  • 22 Rozga J. Liver support technology: an update.  Xenotransplantation. 2006;  13 380-389
  • 23 Jalan R, Kapoor D. Reversal of diuretic-induced hepatic encephalopathy with infusion of albumin but not colloid.  Clin Sci (Lond). 2004;  106 467-474
  • 24 Ortega R, Ginès P, Uriz J et al.. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.  Hepatology. 2002;  36 941-948
  • 25 Sort P, Navasa M, Arroyo V et al.. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.  N Engl J Med. 1999;  341 403-409
  • 26 Quinlan G J, Martin G S, Evans T W. Albumin: biochemical properties and therapeutic potential.  Hepatology. 2005;  41 1211-1219
  • 27 Davies N A, Schnurr K, Sen S, Hodges S J, Matthes G, Jalan R. Serum albumin shows conformational, structural and functional abnormalities in cirrhotic patients, which worsens with severity of liver disease and are unaffected by albumin dialysis.  Hepatology. 2005;  42 A66
  • 28 Oettl K, Greilberger J, Stadlbauer V et al.. Redox state of serum albumin and carbonyl content of plasma proteins in advanced liver disease.  Free Radic Res. 2006;  40 S151
  • 29 Stange J, Ramlow W, Mitzner S, Schmidt R, Klinkmann H. Dialysis against a recycled albumin solution enables the removal of albumin-bound toxins.  Artif Organs. 1993;  17 809-813
  • 30 Mitzner S R, Stange J, Klammt S et al.. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial.  Liver Transpl. 2000;  6 277-286
  • 31 Heemann U, Treichel U, Loock J et al.. Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study.  Hepatology. 2002;  36 949-958
  • 32 Falkenhagen D, Strobl W, Vogt G et al.. Fractionated plasma separation and adsorption system: a novel system for blood purification to remove albumin bound substances.  Artif Organs. 1999;  23 81-86
  • 33 Rifai K, Ernst T, Kretschmer U et al.. Prometheus: a new extracorporeal system for the treatment of liver failure.  J Hepatol. 2003;  39 984-990
  • 34 Peszynski P, Klammt S, Peters E, Mitzner S, Stange J, Schmidt R. Albumin dialysis: single pass vs. recirculation (MARS).  Liver. 2002;  22(suppl 2) 40-42
  • 35 Sauer I M, Goetz M, Steffen I et al.. In vitro comparison of the molecular adsorbent recirculation system (MARS) and single-pass albumin dialysis (SPAD).  Hepatology. 2004;  39 1408-1414
  • 36 Sauer I M, Zeilinger K, Obermayer N et al.. Primary human liver cells as source for modular extracorporeal liver support: a preliminary report.  Int J Artif Organs. 2002;  25 1001-1005
  • 37 Mazariegos G V, Patzer II J F, Lopez R C et al.. First clinical use of a novel bioartificial liver support system (BLSS).  Am J Transplant. 2002;  2 260-266
  • 38 Dorrell C, Grompe M. Liver repair by intra- and extrahepatic progenitors.  Stem Cell Rev. 2005;  1 61-64
  • 39 Oh S H, Hatch H M, Petersen B E. Hepatic oval “stem” cell in liver regeneration.  Semin Cell Dev Biol. 2002;  13 405-409
  • 40 Hughes R D, Cochrane A M, Thomson A D, Murray-Lyon I M, Williams R. The cytotoxicity of plasma from patients with acute hepatic failure to isolated rabbit hepatocytes.  Br J Exp Pathol. 1976;  57 348-353
  • 41 Miwa Y, Ellis A J, Hughes R D, Langley P G, Wendon J A, Williams R. Effect of ELAD liver support on plasma HGF and TGF-beta 1 in acute liver failure.  Int J Artif Organs. 1996;  19 240-244
  • 42 Hughes R D, Nicolaou N, Langley P G, Ellis A J, Wendon J A, Williams R. Plasma cytokine levels and coagulation and complement activation during use of the extracorporeal liver assist device in acute liver failure.  Artif Organs. 1998;  22 854-858
  • 43 Hurley J C, Tosolini F A, Louis W J. Quantitative Limulus lysate assay for endotoxin and the effect of plasma.  J Clin Pathol. 1991;  44 849-854
  • 44 Abdala E, Baia C ES, Mies S et al.. Bacterial translocation during liver transplantation: a randomized trial comparing conventional with venovenous bypass vs. piggyback methods.  Liver Transpl. 2007;  13 488-496
  • 45 Liu Q, Duan Z P, Huang C, Zhao C H. Evaluation of effect of hybrid bioartificial liver using end-stage liver disease model.  World J Gastroenterol. 2004;  10 1379-1381
  • 46 Mitzner S, Loock J, Peszynski P et al.. Improvement in central nervous system functions during treatment of liver failure with albumin dialysis MARS: a review of clinical, biochemical, and electrophysiological data.  Metab Brain Dis. 2002;  17 463-475
  • 47 Jalan R, Sen S. Extracorporeal albumin dialysis for intoxication from protein-bound agents.  Crit Care Med. 2004;  32 1436-1437 , author reply 1437
  • 48 Sen S, Ytrebo L M, Rose C et al.. Albumin dialysis: a new therapeutic strategy for intoxication from protein-bound drugs.  Intensive Care Med. 2004;  30 496-501
  • 49 Stange J, Mitzner S, Ramlow W, Gliesche T, Hickstein H, Schmidt R. A new procedure for the removal of protein-bound drugs and toxins.  ASAIO J. 1993;  39 M621-M625
  • 50 Stange J, Mitzner S. A carrier-mediated transport of toxins in a hybrid membrane: safety barrier between a patient's blood and a bioartificial liver.  Int J Artif Organs. 1996;  19 677-691
  • 51 Laleman W, Wilmer A, Evenepoel P et al.. Effect of the Molecular Adsorbent Recirculating System and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure.  Crit Care. 2006;  10 R108
  • 52 Stadlbauer V, Krisper P, Aigner R et al.. Effect of extracorporeal liver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure.  Crit Care. 2006;  10 R169
  • 53 Sen S, Ratnaraj N, Davies N A et al.. Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS).  Epilepsia. 2003;  44 265-267
  • 54 Stadlbauer V, Krisper P, Beuers U et al.. Removal of bile acids by two different extracorporeal liver support systems in acute-on-chronic liver failure.  ASAIO J. 2007;  53 187-193
  • 55 Krisper P, Haditsch B, Stauber R et al.. In vivo quantification of liver dialysis: comparison of albumin dialysis and fractionated plasma separation.  J Hepatol. 2005;  43 451-457
  • 56 Catalina M V, Barrio J, Anaya F et al.. Hepatic and systemic haemodynamic changes after MARS in patients with acute-on-chronic liver failure.  Liver Int. 2003;  23(suppl 3) 39-43
  • 57 Sen S, Mookerjee R P, Cheshire L M, Davies N A, Williams R, Jalan R. Albumin dialysis reduces portal pressure acutely in patients with severe alcoholic hepatitis.  J Hepatol. 2005;  43 142-148
  • 58 Stange J, Mitzner S R, Risler T et al.. Molecular adsorbent recycling system (MARS): clinical results of a new membrane-based blood purification system for bioartificial liver support.  Artif Organs. 1999;  23 319-330
  • 59 Sorkine P, Ben Abraham R, Szold O et al.. Role of the molecular adsorbent recycling system (MARS) in the treatment of patients with acute exacerbation of chronic liver failure.  Crit Care Med. 2001;  29 1332-1336
  • 60 Rifai K, Ernst T, Kretschmer U et al.. The Prometheus device for extracorporeal support of combined liver and renal failure.  Blood Purif. 2005;  23 298-302
  • 61 Henriksen J H, Moller S, Schifter S, Bendtsen F. Increased arterial compliance in decompensated cirrhosis.  J Hepatol. 1999;  31 712-718
  • 62 Schrier R W, Arroyo V, Bernardi M, Epstein M, Henriksen J H, Rodés J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.  Hepatology. 1988;  8 1151-1157
  • 63 Mitzner S R, Klammt S, Peszynski P et al.. Improvement of multiple organ functions in hepatorenal syndrome during albumin dialysis with the molecular adsorbent recirculating system.  Ther Apher. 2001;  5 417-422
  • 64 Schmidt L E, Wang L P, Hansen B A, Larsen F S. Systemic hemodynamic effects of treatment with the molecular adsorbents recirculating system in patients with hyperacute liver failure: a prospective controlled trial.  Liver Transpl. 2003;  9 290-297
  • 65 Schmidt L E, Sorensen V R, Svendsen L B, Hansen B A, Larsen F S. Hemodynamic changes during a single treatment with the molecular adsorbents recirculating system in patients with acute-on-chronic liver failure.  Liver Transpl. 2001;  7 1034-1039
  • 66 Fernández J, Navasa M, Garcia-Pagan J C et al.. Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis.  J Hepatol. 2004;  41 384-390
  • 67 Stadlbauer V, Wright G AK, Banaji M et al.. Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis.  Gastroenterology. 2007;  , October 29 (Epub ahead of print)
  • 68 Jalan R, Mookerjee R P, Sen S, Redhead D N, Hayes P C, Williams R. Effect of TIPSS, terlipression, anti-TNF and paracentesis on renal blood flow autoregulation: new insights into the pathophysiological basis of renal dysfunction in cirrhosis.  Hepatology. 2004;  40 A1091
  • 69 Hassanein T I, Tofteng F, Brown Jr R S et al.. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.  Hepatology. 2007;  46 1853-1862
  • 70 Sen S, Rose C, Ytrebo L M et al.. Effect of albumin dialysis on intracranial pressure increase in pigs with acute liver failure: a randomized study.  Crit Care Med. 2006;  34 158-164
  • 71 Hiroma T, Nakamura T, Tamura M, Kaneko T, Komiyama A. Continuous venovenous hemodiafiltration in neonatal onset hyperammonemia.  Am J Perinatol. 2002;  19 221-224
  • 72 Cordoba J, Blei A T, Mujais S. Determinants of ammonia clearance by hemodialysis.  Artif Organs. 1996;  20 800-803
  • 73 Opolon P, Rapin J R, Huguet C et al.. Hepatic failure coma (HFC) treated by polyacrylonitrile membrane (PAN) hemodialysis (HD).  Trans Am Soc Artif Intern Organs. 1976;  22 701-710
  • 74 Kiley J E, Welch H F, Pender J C, Welch C S. Removal of blood ammonia by hemodialysis.  Proc Soc Exp Biol Med. 1956;  91 489-490
  • 75 Schmidt L E, Svendsen L B, Sorensen V R, Hansen B A, Larsen F S. Cerebral blood flow velocity increases during a single treatment with the Molecular Adsorbents Recirculating System in patients with acute on chronic liver failure.  Liver Transpl. 2001;  7 709-712
  • 76 Liu J, Kjaergard L L, Als-Nielsen B, Gluud C. Artificial and bioartificial support systems for liver failure: a Cochrane Hepato-Biliary Group Protocol.  Liver. 2002;  22 433-438
  • 77 Samuel D, Ichai P, Feray C et al.. Neurological improvement during bioartificial liver sessions in patients with acute liver failure awaiting transplantation.  Transplantation. 2002;  73 257-264
  • 78 Demetriou A A, Brown Jr R S, Busuttil R W et al.. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.  Ann Surg. 2004;  239 660-667 discussion 667-70
  • 79 Sen S, Williams R, Jalan R. The pathophysiological basis of acute-on-chronic liver failure.  Liver. 2002;  22(suppl 2) 5-13
  • 80 Rifai K, Ernst T, Kretschmer U, Haller H, Manns M P, Fliser D. Removal selectivity of Prometheus: a new extracorporeal liver support device.  World J Gastroenterol. 2006;  12 940-944
  • 81 Doria C, Marino I R. Bacteremia using the molecular adsorbent recirculating system in patients bridged to liver transplantation.  Exp Clin Transplant. 2005;  3 289-292
  • 82 Rifai K, Manns M P. Review article: clinical experience with Prometheus.  Ther Apher Dial. 2006;  10 132-137
  • 83 Doria C, Mandala L, Smith J D et al.. Thromboelastography used to assess coagulation during treatment with molecular adsorbent recirculating system.  Clin Transplant. 2004;  18 365-371
  • 84 Bachli E B, Schuepbach R A, Maggiorini M, Stocker R, Mullhaupt B, Renner E L. Artificial liver support with the Molecular Adsorbent Recirculating System: activation of coagulation and bleeding complications.  Liver Int. 2007;  27 475-484
  • 85 Faybik P, Bacher A, Kozek-Langenecker S A et al.. Molecular adsorbent recirculating system and hemostasis in patients at high risk of bleeding: an observational study.  Crit Care. 2006;  10 R24
  • 86 Pedersen R A, Kim W R, Sen S et al.. Is there really no life on MARS?.  Hepatology. 2004;  40 LB13
  • 87 Chen S C, Hewitt W R, Watanabe F D et al.. Clinical experience with a porcine hepatocyte-based liver support system.  Int J Artif Organs. 1996;  19 664-669
  • 88 Watanabe F D, Mullon C J, Hewitt W R et al.. Clinical experience with a bioartificial liver in the treatment of severe liver failure: a phase I clinical trial.  Ann Surg. 1997;  225 484-491 discussion 491-494
  • 89 van de Kerkhove M P, Di Florio E, Scuderi V et al.. Phase I clinical trial with the AMC-bioartificial liver.  Int J Artif Organs. 2002;  25 950-959
  • 90 Neuzil D F, Rozga J, Moscioni A D et al.. Use of a novel bioartificial liver in a patient with acute liver insufficiency.  Surgery. 1993;  113 340-343
  • 91 Ellis A J, Hughes R D, Nicholl D et al.. Temporary extracorporeal liver support for severe acute alcoholic hepatitis using the BioLogic-DT.  Int J Artif Organs. 1999;  22 27-34
  • 92 Sauer I M, Kardassis D, Zeillinger K et al.. Clinical extracorporeal hybrid liver support: phase I study with primary porcine liver cells.  Xenotransplantation. 2003;  10 460-469
  • 93 Khuroo M S, Farahat K L. Molecular adsorbent recirculating system for acute and acute-on-chronic liver failure: a meta-analysis.  Liver Transpl. 2004;  10 1099-1106
  • 94 El Banayosy A, Kizner L, Schueler V, Bergmeier S, Cobaugh D, Koerfer R. First use of the Molecular Adsorbent Recirculating System technique on patients with hypoxic liver failure after cardiogenic shock.  ASAIO J. 2004;  50 332-337
  • 95 Chen S, Zhang L, Shi Y, Yang X, Wang M. Molecular Adsorbent Recirculating System: clinical experience in patients with liver failure based on hepatitis B in China.  Liver. 2002;  22(suppl 2) 48-51
  • 96 Hessel F P, Mitzner S R, Rief J, Guellstorff B, Steiner S, Wasem J. Economic evaluation and 1-year survival analysis of MARS in patients with alcoholic liver disease.  Liver Int. 2003;  23(suppl 3) 66-72
  • 97 Stange J. Meta-analysis in albumin dialysis: are we really ready for it?.  Liver Transpl. 2004;  10 1107-1108
  • 98 Camus C, Lavoue S, Gacouin A et al.. Molecular adsorbent recirculating system dialysis in patients with acute liver failure who are assessed for liver transplantation.  Intensive Care Med. 2006;  32 1817-1825
  • 99 Stange J, Hassanein T, Lynch P et al.. Short-term survival of patients with severe intractable hepatic encephalopathy: the role of albumin dialysis.  Hepatology. 2005;  42 285A
  • 100 Evenepoel P, Laleman W, Wilmer A et al.. Detoxifying capacity and kinetics of Prometheus: a new extracorporeal system for the treatment of liver failure.  Blood Purif. 2005;  23 349-358
  • 101 Liu J P, Gluud L L, Als-Nielsen B, Gluud C. Artificial and bioartificial support systems for liver failure.  Cochrane Database Syst Rev. 2004;  CD003628
  • 102 Mareels G, Poyck P P, Eloot S, Chamuleau R A, Verdonck P R. Three-dimensional numerical modeling and computational fluid dynamics simulations to analyze and improve oxygen availability in the AMC bioartificial liver.  Ann Biomed Eng. 2006;  34 1729-1744
  • 103 Poyck P P, Hoekstra R, Chhatta A et al.. Time-related analysis of metabolic liver functions, cellular morphology, and gene expression of hepatocytes cultured in the bioartificial liver of the Academic Medical Center in Amsterdam (AMC-BAL).  Tissue Eng. 2007;  13 1235-1246
  • 104 Dhawan A, Mitry R R, Hughes R D. Hepatocyte transplantation for metabolic disorders: experience at King's College hospital and review of literature.  Acta Gastroenterol Belg. 2005;  68 457-460
  • 105 Aleem Khan A, Parveen N, Habeeb M A, Habibullah C M. Journey from hepatocyte transplantation to hepatic stem cells: a novel treatment strategy for liver diseases.  Indian J Med Res. 2006;  123 601-614
  • 106 Jalan R, Sen S, Williams R. Prospects for extracorporeal liver support.  Gut. 2004;  53 890-898
  • 107 Sugio S, Kashima A, Mochizuki S, Noda M, Kobayashi K. Crystal structure of human serum albumin at 2.5 A resolution.  Protein Eng. 1999;  12 439-446
  • 108 Curry S, Brick P, Franks N P. Fatty acid binding to human serum albumin: new insights from crystallographic studies.  Biochim Biophys Acta. 1999;  1441 131-140

Rajiv JalanM.D. 

The Institute of Hepatology, Division of Medicine, University College London

69-75 Chenies Mews, London WC1E 6HX, United Kingdom

Email: r.jalan@ucl.ac.uk

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