[12] Ryan CK, Johnson LA, Germin BI, Marcos A. Onehundred consecutive hepatic biopsies in the workup of livingdonors for right lobe liver transplantation. Liver Transpl2002;8:1114.

[13] Tan HP, Patel-Tom K, Marcos A. Adult living donor livertransplantation: who is the ideal donor and recipient?. J Hepatol2005;43:13.

[14] Clavien PA. Third forum on liver transplantation. Living donorliver transplantation. Who needs it? How to do it? Who should doit?. J Hepatol 2005;43:11.

[15] Portmann B, Wight DGD. Pathology of liver transplantation(excluding rejection). In: Calne R, editor. Liver Transplantation:The Cambridge and King’ s College Hospital Experience. Cam-bridge: Grune & Stratton; 1987. p. 437.

[16] Ploeg RJ, D’Alessandro AM, Knechtle SJ, Stegall MD, Pirsch JD,Hoffmann RM, et al. Risk factors for primary dysfunction afterliver transplantation – a multivariate analysis. Transplantation1993;55:807.

[17] Strasberg SM, Howard TK, Molmenti EP, Hertl M. Selecting thedonor liver: risk factors for poor function after orthotopic livertransplantation. Hepatology 1994;20:829.

[18] Fishbein TM, Fiel MI, Emre S, Cubukcu O, Guy SR, SchwartzME, et al. Use of livers with microvesicular fat safely expands thedonor pool. Transplantation 1997;64:248.

[19] Hayashi M, Fujii K, Kiuchi T, Uryuhara K, Kasahara M,Takatsuki M, et al. Effects of fatty infiltration of the graft on theoutcome of living-related liver transplantation. Transplant Proc1999;31:403.

[20] Briceno J, Padillo J, Rufian S, Solorzano G, Pera C. Assignmentof steatotic livers by the Mayo model for end-stage liver disease.Transpl Int 2005;18:577.

[21] Selzner N, Selzner M, Jochum W, Amann-Vesti B, Graf R,Clavien PA. Mouse livers with macrosteatosis are more suscep-tible to normothermic ischemic injury than those with microstea-tosis. J Hepatol 2006;44:694.

[22] Urena MA, Ruiz-Delgado FC, Gonzalez EM, Segurola CL,Romero CJ, Garcia IG, et al. Assessing risk of the use of liverswith macro and microsteatosis in a liver transplant program.Transplant Proc 1998;30:3288.

[23] Yoong KF, Gunson BK, Neil DA, Mirza DF, Mayer AD,Buckels JA, et al. Impact of donor liver microvesicular steatosison the outcome of liver retransplantation. Transplant Proc1999;31:550.

[24] Cho JY, Suh KS, Kwon CH, Yi NJ, Cho SY, Jang JJ, et al. Thehepatic regeneration power of mild steatotic grafts is notimpaired in living-donor liver transplantation. Liver Transpl2005;11:210.

[25] Fan ST, Lo CM, Liu CL, Yong BH, Chan JK, Ng IO. Safety ofdonors in live donor liver transplantation using right lobe grafts.Arch Surg 2000;135:336.

[26] McCormack L, Clavien PA. Understanding the meaning of fat inthe liver. Liver Transpl 2005;11:137.

[27] Hwang S, Lee SG, Jang SJ, Cho SH, Kim KH, Ahn CS, et al. Theeffect of donor weight reduction on hepatic steatosis for livingdonor liver transplantation. Liver Transpl 2004;10:721.

[28] Selzner N, Rudiger H, Graf R, Clavien PA. Protective strategiesagainst ischemic injury of the liver. Gastroenterology2003;125:917.

[29] Clavien PA, Selzner M, Rudiger HA, Graf R, Kadry Z, RoussonV, et al. A prospective randomized study in 100 consecutivepatients undergoing major liver resection with versus withoutischemic preconditioning. Ann Surg 2003;238:843.

[30] Azoulay D, Del Gaudio M, Andreani P, Ichai P, Sebag M, AdamR, et al. Effects of 10 minutes of ischemic preconditioning of thecadaveric liver on the graft’s preservation and function: the yingand the yang. Ann Surg 2005;242:133.

[31] Kurihara T, Adachi Y, Yamagata M, Abe K, Akimoto M,Hashimoto H, et al. Role of eicosapentaenoic acid in lipidmetabolism in the liver, with special reference to experimentalfatty liver. Clin Ther 1994;16:830.

[32] Alwayn IP, Andersson C, Zauscher B, Gura K, Nose V, Puder M.Omega-3 fatty acids improve hepatic steatosis in a murine model:potential implications for the marginal steatotic liver donor.Transplantation 2005;79:606.

[33] Chui AK, Haghighi K, Painter D, Jayasundera M, Hall G, RaoAR, et al. Donor fatty (steatotic) liver allografts in orthotopicliver transplantation. Transplant Proc 1998;30:3286.

[34] Canelo R, Braun F, Sattler B, Klinge B, Lorf T, Ramadori G,et al. Is a fatty liver dangerous for transplantation?. TransplantProc 1999;31:414.

[35] VerranD,KusykT, PainterD,Fisher J,KooreyD, Strasser S, et al.Clinical experience gained from the use of 120 steatotic donor liversfor orthotopic liver transplantation. Liver Transpl 2003;9:500.

Can non-heart-beating donors replace cadaveric heart-beatingliver donors?

Rahul Deshpande, Nigel Heaton*

Kings College London School of Medicine at Kings College Hospital, Institute of Liver Studies, Denmark Hill, Camberwell, London SE5 9RS, UK

1. Introduction

Recently non-heart-beating donation (or also calleddonation after cardiac death) has re-emerged as a majorpotential way of increasing the supply of organs fortransplantation. The success of renal transplantationfrom non-heart-beating donors (NHBD) [1] has led to

* Corresponding author. Tel.: +44 20 73463762; fax: +44 20

73463575.

E-mail address: nigel.heaton@kingsch.nhs.uk (N. Heaton).

Abbreviations: NHBD, non-heart-beating donor; ICU, intensivecare unit

doi:10.1016/j.jhep.2006.07.017

Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513 499

a renewed and wide interest in liver, pancreas and lungretrieval [2,3].

In the early years of transplantation, before the defi-nition and legal acceptance of brain death, NHBD wasthe principal source of grafts. Following introductionof the concept of irreversible coma [4] and brain death,cadaveric donation gradually replaced NHBD due tothe superior results obtained. However, with subsequentimprovements in immunosuppression, organ preserva-tion and the standardisation of surgical techniques, livergrafts from NHBD appear to be a valuable new sourceof organs with significant potential for expansion of thedonor pool.

2. Non-heart-beating donation

Non-heart-beating donors have been classified intofour categories according to the Maastricht criteria(Table 1). The division into controlled and uncon-trolled NHBD is helpful as it underlines differences inethics, clinical practice, graft outcome and futurepotential between the two groups [5]. Controlled dona-tion occurs in a hospital intensive care unit (ICU) set-ting in a controlled environment usually with a policydriven planned withdrawal of treatment. In uncon-trolled donation, donor death occurs either outsidethe hospital or in the emergency room following unsuc-cessful attempts at resuscitation. Most of the currentpublished literature relates to controlled NHBD. Theethics of controlled NHB donation are readily under-stood and accepted by doctors and the public. Thereis more time to assess the donors for co-morbidity;they tend to be haemodynamically stable, with normalliver and renal function. The donors are extubatedafter planned treatment withdrawal either in the ICUor in the operating room. These patients usually havebrain injury incompatible with life with rapid cessationof cardiopulmonary function. Warm ischaemia can beaccurately assessed and cold ischaemia minimised byprior preparation of a suitable recipient. There is ade-quate opportunity to counsel both the donor familyand the recipient. In comparison to uncontrolledNHBD they tend to be older, have greater co-morbid-ity and have had organ support on the ICU. It hasbeen estimated that controlled NHBD in its currentform has the potential to increase the donor liver poolby at least 20% [6].

Uncontrolled NHBD are more likely to be youngerand fitter without significant co-morbidity. However,death occurs in an uncontrolled setting, often after pro-longed periods of resuscitation, which makes assessmentof warm ischaemic time problematic. The legal, ethicaland logistic issues that have to be overcome are consid-erable. However, an approximately twofold net increasein the donor pool has been successfully achieved by aSpanish group [7] and it has been speculated that thereis the potential to increase the donor pool by up to300%. The resources to be invested in such a programmeare significant.

3. Reported outcomes after liver transplantation fromcontrolled NHBD (Table 2)

All techniques used to procure organs from con-trolled NHBD aim to keep warm ischaemia to a mini-mum. A variety of techniques have been utilisedincluding cardiopulmonary bypass with or without cool-ing, extracorporeal membrane oxygenation and super-rapid retrieval as a modification of the en bloc multior-gan harvest technique [3]. Our own technique involvesrapid aortic and caval cannulation, topical cooling, aor-tic clamping and perfusion of the aorta with heparinisedMarshall’s solution followed by cannulation of the supe-rior mesenteric vein to perfuse the liver with Universityof Wisconsin solution [6]. The best outcome from con-trolled NHBD livers has been associated with less than30 min of warm ischaemia, cold ischaemic times of lessthan 8 h and donor age of less than 50 years [6,8,9]. Avariety of techniques, including pulsatile and non-pulsa-tile machine perfusion, have been utilised experimentallyto try to prolong organ preservations to allow moredetailed assessment of the graft. To date there are littleclinical data in liver transplantation to identify, whichtechniques will prevail in the longer term [10].

Early experience of NHBD was associated with infe-rior patient and graft survival, particularly for theuncontrolled group [3]. Casavilla et al. reported the early

Table 1

First International Workshop on non-heart-beating donation, Maas-

tricht, 1994

Categories of non-heart-beating donation(categories 1 and 2, Uncontrolled; 3 and 4, Controlled)1. Dead on arrival2. Unsuccessful resuscitation3. Awaiting cardiac arrest-ventilator switch off4. Cardiac arrest while brain-dead

Table 2

Outcome after liver transplantation from NHBD

Author Year N Pat.survivala

Graftsurvivala

Controlled NHBD

Muiesan et al. [6] 2005 32 87% 84%Abt et al. [12] 2004 144 79.7% 70.2%Foley et al. [13] 2005 36 80% 67%Manzarbeitiaet al. [14]

2004 19 89.5%

Uncontrolled NHBD

Otero et al. [19] 2004 20 80% (2 yr) 55% (2 yr)Quintela et al. [20] 2005 10 90% (57m) 80% (57m)

N, number of patients.a One-year survival, unless otherwise stated.

500 Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513

experience of Pittsburgh with poor graft survival sec-ondary to vascular complications and primary non-function. D’Alessandro et al. reported a significantlyhigher incidence of primary non-function (PNF) andworse graft and patient survival in recipients of con-trolled NHBD [11]. More recently, Abt et al. reporteda higher incidence of PNF and retransplantation whencompared to HBD [12]. A publication from our owncentre reported a single case of PNF in a series of 32consecutive liver transplants from controlled NHBD[6]. Current experience suggests that the results of con-trolled NHBD are now approaching those of heart-beat-ing donation (HBD) [6]. Graft and patient survival atone year is 90% and 94%, respectively, in our own insti-tution after 54 liver transplants from controlled NHBD.

There are continuing concerns regarding reports ofvascular and biliary complications in recipients of con-trolled NHBD livers. Foley et al. reported a 16.6% inci-dence of hepatic artery stenosis, 13.8% incidence ofbiliary stricture and 16.7% incidence of biloma andabscess [13]. There was a high rate of graft loss second-ary to these complications. The majority of centres withsignificant experience of NHBD livers have reported ahigher incidence of non-anastomotic biliary strictures.Abt et al. proposed that the increased susceptibilitytowards ischaemic cholangiopathy was a consequenceof longer warm or cold ischaemia times and microcircu-latory injury [8]. Manzarbeitia et al. have also reported ahigher incidence of vascular complications when com-pared to brain dead heart-beating donors [14].

Attempts have been made to identify donor and reci-pient characteristics associated with poor outcome [11].Prolonged cold ischaemia is associated with graft func-tion and biliary complications. Beyond 12 h graft failureapproaching 60% has been reported. Keeping the coldischaemic time to less than 8 h reduces the graft failureto 10% [11]. Warm ischaemic periods of greater than30 min have a high risk of graft non-function. Donorage greater than 40 years also appears to increase therisk of graft failure. The choice of recipient may alsohave a bearing on graft outcome with those on organsupport pre-transplant doing less well [11]. It appearsthat NHBD livers have lower functioning hepatocytemass and hepatocyte viability in experimental and clini-cal studies [6]. The development of clinical programmesand the recognition of ‘good’ controlled NHBD livershas led to the use of liver reduction techniques for suc-cessful transplantation of 10 children at our centre[15]. These results suggest that these ‘good’ donorsshould not be considered to be marginal.

4. Outcomes after liver transplantation from uncontrolled

NHBDs

Early results of uncontrolled NHBD were notencouraging. There was a high incidence of PNF and

graft loss due to vascular complications [3]. However,studies reported excellent graft and patient survival inkidney recipients [16] and long-term renal function wasreported to be better in Maastricht types 1 and 2 ascompared to types 3 and 4 [17]. Alvarez et al. usingwell-defined criteria for accepting uncontrolled NHBDreported good graft function in both transplanted kid-neys and livers [18]. Otero et al. reported significantlyhigher rates of PNF, biliary complications and initialorgan dysfunction in 20 liver recipients from uncon-trolled NHBD [19]. More recently there have been sev-eral case reports of successful uncontrolled NHBDmaintained on mechanical chest and abdominal com-pression, cardio-pulmonary bypass or on ECMO [20].Wider application and evaluation of these techniquesand subsequent graft function are required.

5. The use of NHBD to expand the donor pool

What is the potential for NHBD to expand the donorpool and how do we realise them? The results of con-trolled NHBD are now approaching those obtainedwith HBD provided that donor age is less than 50 years,warm ischaemia does not extend beyond 30 min andcold ischaemia is kept to a minimum with a cut off of10 h being accepted as reasonable by the majority ofcentres. This may increase the donor pool by 20%, betterthan living donation (which may help 10%), but fallingshort of what is required.

How can graft quality and early function be improved?Warm ischaemia cannot be avoided, but has to be mini-mised by excellent surgical technique, the use of low vis-cosity perfusion fluids possibly under pressure(50 mmHg) to clear the microcirculation and thoroughflushing of the biliary tree. The use of heparin pre-dona-tion (if allowed) and thrombolytic agents to maintainthe microcirculation is considered to improve functionand reduce vascular and possibly biliary complications.The need for cold preservation and the subsequent effectsof ischaemia/reperfusion injury on the graft are impor-tant determinants of graft survival [21]. Experimentalstudies suggest that pre-treatment of NHBD prior towithdrawal of care may improve outcome by ameliorat-ing ischaemia/reperfusion injuries [22]. A number ofagents are being evaluated in experimental studies. Theavoidance of cold ischaemia using techniques such as nor-mothermic continuous organ perfusion could expand thesafe use of more marginal donors and such models arebeing developed. Other techniques such as short termhypothermic oxygenated perfusion prior to implantationmay also rescue NHBD grafts [23].

The choice of recipient should be restricted to avoidlong difficult dissections and possibly those with severeportal hypertension or those on organ support. Tech-niques of implantation have not been formally evaluatedin clinical trials, but clinical experience from small for

Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513 501

size grafts and experimental studies suggest that allevia-tion of severe portal hypertension, blood flush and arte-rial reperfusion may be of value and may extend donorcriteria for NHBD. With extended criteria for controlledNHBD it may be possible to expand the potential poolby 30–40% over the next 10 years.

To successfully exploit uncontrolled NHBD a num-ber of important obstacles need to be overcome (Table3). The most pressing is to establish a legal frameworkthat is acceptable to the public. At present uncontrolledNHBD is contentious and considered illegal in manycountries. The point when resuscitation becomes futileand organ donation should be considered is not alwaysclear and there are no internationally agreed guidelines.Public acceptance and changes to the law, which allowthe use of continuous mechanical chest and abdominalcompression, cardiopulmonary bypass techniques orextracorporeal membrane oxygenation whilst familymembers are consulted, are required. Presumed consent(opt out) helps to provide the appropriate legal frame-work for this type of donation.

The logistics of establishing a programme of uncon-trolled donation are also significant. To obtain organsfrom patients who have collapsed on the street or failresuscitation in the emergency room requires a dedicat-ed resuscitation ambulance team available 24 h a dayable to reach the scene within a very short time [18].Alvarez et al. reported their experience of 111 potentialcategory–1 uncontrolled NHBD [17]. Of these, 53 wereaccepted as donors and resulted in the retrieval of 72kidneys and 12 livers. Of the 12 livers retrieved eightwere transplanted with good function. Of note, themedian time from cardiac arrest to arrival in hospitalwas 68 min and to being placed on cardio-pulmonarybypass was 111 min. The assessment of the warm ischae-mic time, the effectiveness of resuscitation and the suit-ability of the donor under these conditions is muchmore difficult. The initial investment in the training

and provision of emergency services is high and the earlyreturn relatively low. Effective resuscitation will buytime for assessment of the donor and the potential graft.Reliable tests predicting graft function are needed. Liverbiopsy is of limited value and other markers that havebeen used, which include Glutathione S-transferaseand xanthine oxidase, are not reliable indicators of sub-sequent function.

Could NHBD replace HBD? It has been suggestedthat the absence of brain stem death in NHBD catego-ries 1–3 may be associated with less inflammatory infil-trate in the donor organs and that long-term graftsurvival may be better. The data are not yet available,but the incidence of acute rejection is currently about25% (personal observation), certainly no higher thanobserved for HBD. Data are lacking for long-term out-come in liver recipients, but long-term graft survival inNHBD kidneys is excellent [1]. The early results of livertransplantation from controlled NHBD are approach-ing those obtained with HBD provided that conserva-tive selection criteria are used. This will supplementthe donor pool by 20%, but cannot replace HBD andshould be viewed as complementary. Of concern, theremay be a trend towards NHDB away from HBD toreduce donor hospital stay and to satisfy the wishes ofdonor family for cardio-pulmonary death, which maylimit the overall increase in organ donation (i.e., a switchfrom HBD to NHBD as a mode of death). The greatestpotential lies with uncontrolled NHBD, but changes areneeded from Governments to provide a clear legalframework, funding and training for the infrastructureand acceptance by the public. The development of treat-ments to preserve, resuscitate and maintain these graftsin the medium term and tests which can accuratelyassess potential graft function will begin to tap thispotential. If successful, NHBD could rival or surpassHBD and living donation as a source of organs fortransplantation.

Table 3

Prerequisites for establishing a NHBD liver transplant program

Controlled NHBD

(1) Ensure appropriate legal framework(2) Establish protocols for NHBD retrieval and train donor coordinators and other teams(3) Identify Intensive Care Units and agree protocols for withdrawal of treatment(4) Develop a successful NHBD kidney program followed by liver program, concentrating experience initially within a small team(5) Address consent and allocation issues for NHBD liver transplantation(6) Concentrate on busiest units first with extensive experience of use of marginal grafts and then expand the program

Uncontrolled NHBD

(1) Establish legal and ethical framework acceptable to the public(2) Carry out public and political consultation with consideration towards ‘presumed consent’ (opt out) policy for organ donation(3) Develop a regional strategy and funding for 24-h availability of dedicated resuscitation ambulances deployed within defined territories to identifyand resuscitate potential donors(4) Establish a robust protocol for cessation of resuscitation, consent issues, donor maintenance and subsequent retrieval(5) Twenty-four-hour availability of a dedicated retrieval team of surgeons, nurses and donor coordinators trained for uncontrolled NHBD(6) Develop cooperation and involvement of the hospital emergence department to establish the program (if possible, develop uncontrolled NHBDafter a successful controlled NHBD program)

502 Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513

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[2] D’ Alessandro AM, Hoffmann RM, Knechtle SJ, et al. Successfulextra-renal transplantation from non-heart-beating donors.Transplantation 1995;59:977–982.

[3] Casavilla A, Ramirez C, Shapiro R, et al. Experience with liverand kidney allografts from non-heart-beating donors. Transplan-tation 1995;59:197–203.

[4] A definition of irreversible coma. Report of the Ad HocCommittee of the Harvard Medical School to Examine theDefinition of Brain Death. JAMA 1968;205:337–340.

[5] Kootstra G, Daemen JH, Oomen AP. Categories of non-heart-beating donors. Transplant Proc 1995;27:2893–2894.

[6] Muiesan P, Girlanda R, Jassem W, et al. Single-centre experiencewith liver transplantation from controlled non-heartbeatingdonors: a viable source of grafts. Ann Surg 2005;242:732–738.

[7] Alvarez J, del Barrio MR, Arias J, et al. Five years of experiencewith non-heart-beating donors coming from the streets. Trans-plant Proc 2002;34:2589–2590.

[8] Abt PL, Crawford MD, Desai NM, et al. Liver transplantationfrom controlled non-heart-beating donors: an increased incidenceof biliary complications. Transplantation 2003;75:1659–1663.

[9] Monbaliu D, Crabbe T, Roskams T, et al. Livers from non-heart-beating donors tolerate short periods of warm ischemia. Trans-plantation 2005;79:1226–1230.

[10] Uchiyama M, Matsuno K, Hama H, et al. Comparison betweennonpulsatile and pulsatile machine perfusion preservation in livertransplantation from non-heart-beating donors. Transplant Proc2001;33:936–938.

[11] D’Alessandro AM, Fernandez LA, Chin LT, et al. Donationafter cardiac death: the University of Wisconsin experience. AnnTransplant 2004;9:68–71.

[12] Abt PL, Desai NM, Crawford MD, et al. Survival following livertransplantation from non-heart-beating donors. Ann Surg2004;239:87–92.

[13] Foley DP, Fernandez LA, Leverson G, et al. Donation aftercardiac death: the University of Wisconsin experience with livertransplantation. Ann Surg 2005;242:724–731.

[14] Manzarbeitia CY, Ortiz JA, Jeon H, et al. Long-term outcome ofcontrolled, non-heart-beating donor liver transplantation. Trans-plantation 2004;78:211–215.

[15] Muiesan P, Jassem W, Girlanda R, et al. Segmental livertransplantation from non-heart beating donors–an early experi-ence with implications for the future. Am J Transplant2006;6:1012–1016.

[16] NicholsonML,MetcalfeMS,White SA, et al. A comparison of theresults of renal transplantation from non-heart-beating, conven-tional cadaveric, and living donors. Kidney Int 2000;58:2585–2591.

[17] Sanchez-Fructuoso AI, de Miguel Marques, Prats D, et al. Non-heart-beating donors: experience from the Hospital Clinico ofMadrid. J Nephrol 2003;16:387–392.

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[20] Quintela J, Gala B, Baamonde I, et al. Long-term results for livertransplantation from non-heart-beating donors maintained withchest and abdominal compression-decompression. TransplantProc 2005;37:3857–3858.

[21] Reddy S, Greenwood J, Maniakin N, et al. Non-heart-beatingdonor porcine livers: the adverse effect of cooling. Liver Transpl2005;11:35–38.

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[23] Dutkowski P, Graf R, Clavien PA. Rescue of the cold preservedrat liver by hypothermic oxygenated machine perfusion. Am JTransplant 2006;6:903–912.

How can donors with a previous malignancy be evaluated?

Joseph F. Buell*, Rita R. Alloway, E. Steve Woodle

The University of Cincinnati, Division of Transplantation, Cincinnati, OH, USA

1. Introduction

Solid organ transplantation has flourished over thelast three decades with improvements in surgical tech-nique and modern immunosuppression resulting in

improved patient outcomes. Traditionally, solid organtransplantation has been limited by organ availability.The principal source of these organs has been cadavericdonation. A steady increase in organ donation wasobserved in the early 1990s realized through publicawareness and education programs [1]. Concurrentlyseveral surgical innovations in live donor kidney, pancre-as, liver and intestinal transplantation have also contrib-uted to an increase in transplants. However, both effortshave appeared to have achieved a plateau in the last fewyears.

* Corresponding author. Tel.: +1 513 558 6010; fax: +1 513 558

3580.

E-mail address: Joseph.buell@uc.edu (J.F. Buell).

Abbreviations: OPTN, Organ Procurement and TransplantationNetwork; UNOS, united network for organ sharing; DCIS, ductalcarcinoma in situ.

doi:10.1016/j.jhep.2006.07.018

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