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Early liver transplantation for acute alcoholic hepatitis: We can’t say no

  • Philippe Mathurin
    Correspondence
    Corresponding author. Address: Service Maladies de l’Appareil digestif, Hôpital Huriez, Rue Polonovski F- 59037, Lille cedex, France; Tel.: 33 3 20 44 55 97.
    Affiliations
    Service des maladies de l’appareil digestif, CHU Lille and Inserm U995, Lille, France

    Université Lille 2, CHU Lille and Inserm U995, Lille, France
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      Summary

      In patients with severe alcoholic hepatitis who are not responding to medical therapy, it is detrimental to postpone the decision to list a patient as there are no therapeutic alternatives. Early transplantation of patients with severe alcoholic hepatitis, using a restrictive selection process, has increasingly been used in the last decade with acceptable relapse rates. Indeed, early transplantation has gained the support of a growing number of experts from different countries, as shown by the European, American and Latin American recommendations. However, there is still great heterogeneity in its application between countries and even between centres within the same country.

      Keywords

      Early liver transplantation: How can we say no?

      In most countries transplant procedures performed for patients with alcohol-related liver disease are on the rise. This is largely related to advances in antiviral treatments for hepatitis C, which have led to a sharp decline in liver-related morbidity and mortality in infected patients. Accordingly, in the next decade, the proportion of patients listed with a primary diagnosis of hepatitis C will decrease while, at a same time, the proportion listed for alcohol-related liver disease or non-alcoholic fatty liver disease will steadily increase – trends which have already been observed.
      • Belli L.S.
      • Perricone G.
      • Adam R.
      • Cortesi P.A.
      • Strazzabosco M.
      • Facchetti R.
      • et al.
      Impact of DAAs on liver transplantation: major effects on the evolution of indications and results. An ELITA study based on the ELTR registry.
      Due to the prerequisite for abstinence, patients with alcoholic hepatitis have long been excluded from liver transplantation programmes.
      • Bathgate A.
      J. and Units U. K. Liver Transplant. Recommendations for alcohol-related liver disease.
      However progress in the early identification of non-responders to medical therapy who are unlikely to survive
      • Dunn W.
      • Jamil L.H.
      • Brown L.S.
      • Wiesner R.H.
      • Kim W.R.
      • Menon K.V.
      • et al.
      MELD accurately predicts mortality in patients with alcoholic hepatitis.
      • Louvet A.
      • Naveau S.
      • Abdelnour M.
      • Ramond M.J.
      • Diaz E.
      • Fartoux L.
      • et al.
      The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
      • Louvet A.
      • Thursz M.R.
      • Kim D.J.
      • Labreuche J.
      • Atkinson S.R.
      • Sidhu S.S.
      • et al.
      Corticosteroids reduce risk of death within 28 Days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo-a meta-analysis of individual data from controlled trials.
      • Mathurin P.
      • O'Grady J.
      • Carithers R.L.
      • Phillips M.
      • Louvet A.
      • Mendenhall C.L.
      • et al.
      Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.
      • Mathurin P.
      • Abdelnour M.
      • Ramond M.J.
      • Carbonnell N.
      • Fartoux L.
      • Serfaty L.
      • et al.
      Early change in bilirubin levels (ECBL) is an important prognostic factor in severe biopsy-proven alcoholic hepatitis (AH) treated by prednisolone.
      led to a consensus among French experts, who strongly recommend innovative approaches to liver transplantation, including consideration of liver transplantation in patients with severe alcoholic hepatitis who are not responding to medical therapy.
      Consensus conference: indications for liver transplantation, January 19 and 20, 2005, lyon-palais des congrès: text of recommendations (long version).
      This statement was mainly based on 3 ethical dilemmas: i) unlike other presentations of alcohol-related liver disease, abstinence does not allow patients with severe alcoholic hepatitis who are not responding to medical therapy to recover from their liver disease (these patients would still need a transplant); ii) the use of the length of abstinence and of the 6-month rule as decision-making tools to predict alcohol relapse are associated with methodological shortcomings; iii) postponing a decision to list a patient (e.g. by requesting a period of abstinence) is detrimental in the context of a therapeutic dead end.
      The use of prognostic scores such as the Lille model,
      • Louvet A.
      • Naveau S.
      • Abdelnour M.
      • Ramond M.J.
      • Diaz E.
      • Fartoux L.
      • et al.
      The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
      early worsening of liver function,
      • Dunn W.
      • Jamil L.H.
      • Brown L.S.
      • Wiesner R.H.
      • Kim W.R.
      • Menon K.V.
      • et al.
      MELD accurately predicts mortality in patients with alcoholic hepatitis.
      or a combination of the model for end-stage liver disease (MELD) and Lille models
      • Louvet A.
      • Labreuche J.
      • Artru F.
      • Boursier J.
      • Kim D.J.
      • O'Grady J.
      • et al.
      Combining data from liver disease scoring systems better predicts outcomes of patients with alcoholic hepatitis.
      enables rigorous identification of patients with severe alcoholic hepatitis who are not responding to medical therapy; these patients have a 6-month mortality rate of approximately 70–80%.
      • Lucey M.R.
      • Mathurin P.
      • Morgan T.R.
      Alcoholic hepatitis.
      Before referring a patient to a transplant centre for early liver transplantation, clinicians should stop corticosteroid therapy as soon as a poor response to treatment is identified (i.e. a Lille score greater than 0.45 on day 7 of treatment). In addition, the detection and early treatment of fungal or bacterial infection is an important component of therapeutic management. Use of the 6-month rule excludes patients at low risk of alcohol relapse from prompt listing for liver transplantation, while the length of abstinence prior to listing appears to be a relatively poor indicator.
      • Beresford T.P.
      • Everson G.T.
      Liver transplantation for alcoholic liver disease: bias, beliefs, 6-month rule, and relapse- but where are the data.
      The United Network for Organ Sharing (UNOS)
      • Beresford T.P.
      • Everson G.T.
      Liver transplantation for alcoholic liver disease: bias, beliefs, 6-month rule, and relapse- but where are the data.
      and the French Conference Consensus on Liver Transplantation
      Consensus conference: indications for liver transplantation, January 19 and 20, 2005, lyon-palais des congrès: text of recommendations (long version).
      do not strictly recommend the use of the 6-month rule because of its deficiencies.
      The first study evaluating the impact of early transplantation in patients with severe alcoholic hepatitis not responding to medical therapy was performed using very strict selection criteria (Table 1): a process of meetings with members of the medical and surgical teams and nursing staff, absence of co-morbidities or psychiatric disorders, no history of a decompensating event, patient ignorance of underlying cirrhosis, supportive family members, patient's commitment to stay sober after transplantation, approval of the liver transplant selection committee.
      • Mathurin P.
      • Moreno C.
      • Samuel D.
      • Dumortier J.
      • Salleron J.
      • Durand F.
      • et al.
      Early liver transplantation for severe alcoholic hepatitis.
      Mortality was reduced by 3 times in early transplanted patients in comparison to non-transplanted patients and the alcohol relapse rate was low during follow-up. Once listed, if a transplant is not obtained within a period of less than 30 days, the probability of death on the waiting list is close to 80%. Early liver transplantation transformed the fate of these non-responders, initially at a therapeutic impasse, into an evolution similar to those responding to medical treatment. The percentage of patients resuming alcohol consumption was less than 15% during the follow-up period.
      • Mathurin P.
      • Moreno C.
      • Samuel D.
      • Dumortier J.
      • Salleron J.
      • Durand F.
      • et al.
      Early liver transplantation for severe alcoholic hepatitis.
      The first replicative study with an almost identical selection protocol confirmed the higher survival of early transplanted patients compared to non-transplanted matched controls (89% vs. 11%) with an acceptable risk of relapse (25%) compared to that usually observed in the setting of transplantation for patients selected according to the 6-month rule.
      • Im G.Y.
      • Kim-Schluger L.
      • Shenoy A.
      • Schubert E.
      • Goel A.
      • Friedman S.L.
      • et al.
      Early liver transplantation for severe alcoholic hepatitis in the United States--A single-center experience.
      An overview of practice of early transplantation for severe alcoholic hepatitis in the US was carried out by means of a retrospective analysis of the activity of 12 liver transplant programmes in 8 UNOS regions.
      • Lee B.P.
      • Mehta N.
      • Platt L.
      • Gurakar A.
      • Rice J.P.
      • Lucey M.R.
      • et al.
      A. Outcomes of early liver transplantation for patients with severe alcoholic hepatitis.
      One and 3-year survival rates were excellent (94% and 84%, respectively) and comparable to survival rates for other transplant indications. There were significant differences in patient selection between the American and European experiences. The American experts did not require a histological diagnosis of alcoholic hepatitis. Such an approach is associated with a 30–50% risk of including patients without disease, which explains why only 59% of the American patients had alcoholic hepatitis on explant. French and Belgian patients were selected during hospitalisation while American patients were selected after a median period of abstinence of 2 months. It is therefore likely that the American patients were less severe because only those surviving a short period of abstinence could be selected. After liver transplantation, relapse in alcohol consumption and sustained alcohol use occurred in around 30% and 20% of cases, respectively, and alcohol consumption was the leading cause of post-transplant death.
      • Lee B.P.
      • Mehta N.
      • Platt L.
      • Gurakar A.
      • Rice J.P.
      • Lucey M.R.
      • et al.
      A. Outcomes of early liver transplantation for patients with severe alcoholic hepatitis.
      Younger age was an independent risk factor for relapse in alcohol use. In fact, although convincing, these data were not enough to persuade sceptical experts who are waiting for additional data. They suggested that this procedure could be analysed as a question of utility, justice and respect for persons, the tripod of principles established by the UNOS,
      • Solga S.F.
      • Serper M.
      • Young R.A.
      • Forde K.A.
      Transplantation for alcoholic hepatitis: are we achieving justice and utility?.
      although the authors should have recognised that these principles had been considered by several ethics committees and scientific societies.
      EASL Clinical Practice Guidelines
      Management of alcohol-related liver disease.
      • Arab J.P.
      • Roblero J.P.
      • Altamirano J.
      • Bessone F.
      • Chaves Araujo R.
      • Higuera-De la Tijera F.
      • et al.
      Alcohol-related liver disease: clinical practice guidelines by the Latin American association for the study of the liver (ALEH).
      • Crabb D.W.
      • Im G.Y.
      • Szabo G.
      • Mellinger J.L.
      • Lucey M.R.
      Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American association for the study of liver diseases.
      • Donckier V.
      • Lucidi V.
      • Gustot T.
      • Moreno C.
      Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy.
      • Mitchell M.C.
      • Friedman L.S.
      • McClain C.J.
      Medical management of severe alcoholic hepatitis: expert review from the clinical practice updates committee of the AGA institute.
      Table 1Selection criteria for early transplantation in patients with severe alcoholic hepatitis (i.e Maddrey ≥32) not responding to medical therapy.
      Assessment of lack of response to medical therapy
       Lille Score>0.45
       Join-Effect Model (Lille + MELD)≥1.45 for high risk of mortality or ≥2.82 for very high risk of mortality
      First liver-decompensating event
      Patient ignorance of underlying cirrhosis
      Absence of medical comorbidities
      Decision-making parties
       Nurse
       Resident, Fellow
       Specialist in Addiction
       Senior Hepatologist
       Surgeon, Anesthetist
      Evaluation of the addictological profile of the patient
       Absence of severe coexisting or psychiatric disorders
       Supportive family members who do not have alcohol use disorders
       Patient’s commitment to adhere to lifelong total abstinence
       No episode of violence upon alcohol use
       Aware of the need to build a new life
       Fully involved in the selection process of early liver transplantation
      MELD, model for end-stage liver disease.
      The selection process required 4 decision-making parties to reach a consensus about the suitability of the candidate for transplantation.
      Some experts fear that any modification in the selection process of candidates with alcohol-related liver disease could exacerbate the organ shortage. However, the imbalance between number of organs and patients on the waiting list is not in itself an argument for prohibiting the adaptation of practices based on scientific data and the need to improve the prognosis of patients with severe forms of liver injury regardless of the cause. This organ allocation dilemma cannot be resolved without taking into account several ethical issues. In the context of scarce life-sustaining resources, framework models have been proposed to assist medical decision making. For patients in life-threatening medical situations, a couple of ethical principles appear to be essential based on expert consensus.
      • Daugherty Biddison E.L.
      • Gwon H.
      • Schoch-Spana M.
      • Cavalier R.
      • White D.B.
      • et al.
      The community speaks: understanding ethical values in allocation of scarce lifesaving resources during disasters.
      The first is whether the patient can undergo the medical procedure without a significant risk of periprocedural death. The second is the long-term survival prospect after discharge from the hospital.
      • Lee B.P.
      • Mehta N.
      • Platt L.
      • Gurakar A.
      • Rice J.P.
      • Lucey M.R.
      • et al.
      A. Outcomes of early liver transplantation for patients with severe alcoholic hepatitis.
      In the setting of severe alcoholic hepatitis, all studies evaluating early transplantation have found a low risk of transplantation-related death similar to that previously reported after this procedure. In terms of long-term survival, a mathematical model showed that early liver transplantation is associated with approximately a 4.5-fold increase in comparison to delayed transplantation.
      • Lee B.P.
      • Samur S.
      • Dalgic O.O.
      • Bethea E.D.
      • Lucey M.R.
      • Weinberg E.
      • et al.
      Model to calculate harms and benefits of early vs delayed liver transplantation for patients with alcohol-associated hepatitis.
      The long-term survival benefit has recently been confirmed by a French study presented at the 2020 EASL Congress. However, those ethical principles are sufficient only for catastrophic public health emergencies requiring a rapid decision-making process for the allocation of scarce mechanical ventilation.
      In a context unrelated to a health disaster, it is obvious that many additional criteria, both ethical and medical, need to be considered to reach expert consensus.
      • Donckier V.
      • Lucidi V.
      • Gustot T.
      • Moreno C.
      Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy.
      Among other things, public opinion is very attached to a deliberative democracy which can only be achieved through the existence of committee selection. To avoid heterogeneity of access to transplantation, the notion of procedural justice could be integrated with a standardised approach. It can be noted that the selection as proposed in early liver transplantation already uses a standardised approach integrating the identification of non-response and of candidates at low risk of relapse.
      Other ethical concerns have been raised such as the fear that uncontrolled access to transplantation could increase the graft shortage for other aetiologies because each graft taken for early liver transplantation is one removed from the pool.
      • Solga S.F.
      • Serper M.
      • Young R.A.
      • Forde K.A.
      Transplantation for alcoholic hepatitis: are we achieving justice and utility?.
      This fear is not appropriate because early liver transplantation accounts for less than 5–10% of grafts. The unethical prioritisation of other aetiologies ahead of severe alcoholic hepatitis in the MELD allocation system, as recently proposed by some experts, cannot be considered because it amounts to a stigmatisation of patients with alcohol-related liver disease.
      • Solga S.F.
      • Serper M.
      • Young R.A.
      • Forde K.A.
      Transplantation for alcoholic hepatitis: are we achieving justice and utility?.
      The authors do not come up with similar proposals for obese patients with diabetes who did not consider recommendations on weight control and glycaemic balance, nor comply with hygiene and dietary rules.
      • Solga S.F.
      • Serper M.
      • Young R.A.
      • Forde K.A.
      Transplantation for alcoholic hepatitis: are we achieving justice and utility?.
      In addition, the authors’ proposal was based in part on a potential risk of misconduct by transplant centres, who they claimed may increase their own activity in the context of competition while neglecting the common good of organ sharing. It is surprising that such a fear is targeted at patients with severe alcoholic hepatitis when the risks of abusively listing candidates can be observed regardless of the aetiology.
      • Tacke F.
      • Kroy D.C.
      • Barreiros A.P.
      • Neumann U.P.
      Liver transplantation in Germany.
      The authors should acknowledge that ethical committees have already ruled on the fact patients with self-inflicted diseases should have the same access to medical resources.
      • Donckier V.
      • Lucidi V.
      • Gustot T.
      • Moreno C.
      Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy.
      ,
      • Mathurin P.
      • Lucey M.R.
      Liver transplantation in patients with alcohol-related liver disease: current status and future directions.
      Even in the situation of transplantation for fulminant failure, it has never been proposed to penalise patients who intentionally overdose on acetaminophen or active drug abusers who contract acute hepatitis B virus.
      There is a great heterogeneity between countries and even between centres regarding whether or not to list a patient with severe alcoholic hepatitis. In Germany, the early liver transplant procedure is framed as unsuitable for a rapid decision-making process as the authorisation to list can only be obtained by a centre after having questioned the office of the Federal Medical Association.
      • Tacke F.
      • Kroy D.C.
      • Barreiros A.P.
      • Neumann U.P.
      Liver transplantation in Germany.
      In Canada, all transplant centres still require the 6-month rule of abstinence before listing patients with alcohol-related liver disease and none had performed early liver transplantation.
      • Chandok N.
      • Aljawad M.
      • White A.
      • Hernandez-Alejandro R.
      • Marotta P.
      • Yoshida E.M.
      Liver transplantation for alcoholic liver disease among Canadian transplant centres: a national study.
      However, the directors of the Canadian transplant centres recognised the value of a discussion about a possible change in Canadian policy towards patients with alcoholic hepatitis.
      • Chandok N.
      • Aljawad M.
      • White A.
      • Hernandez-Alejandro R.
      • Marotta P.
      • Yoshida E.M.
      Liver transplantation for alcoholic liver disease among Canadian transplant centres: a national study.
      Conversely in other countries whose experts have endorsed early transplantation,
      • Mathurin P.
      • Lucey M.R.
      Liver transplantation in patients with alcohol-related liver disease: current status and future directions.
      ,
      • Burra P.
      • Bizzaro D.
      • Forza G.
      • Feltrin A.
      • Volpe B.
      • Ronzan A.
      • et al.
      Severe acute alcoholic hepatitis: can we offer early liver transplantation?.
      ,
      • Lee B.P.
      • Im G.Y.
      • Rice J.P.
      • Weinberg E.
      • Hsu C.
      • Fix O.K.
      • et al.
      Underestimation of liver transplantation for alcoholic hepatitis in the national transplant database.
      a growing number of centres list patients with severe alcoholic hepatitis through a very strict selection process, explaining why the burden of this indication remains low. The selection process developed by the French investigators leads to less than 5% of patients with severe alcoholic hepatitis being placed on the waiting list. The percentage of transplant centres performing this procedure has increased from 31% to 100% in France
      • Antonini T.M.
      • Guillaud O.
      • Dumortier J.
      • Dharancy S.
      • Saliba F.
      • Mathurin P.
      • et al.
      Impact of a first study of early transplantation in acute alcoholic hepatitis: results of a nationwide survey in French liver transplantation programs.
      and from 0% to 50% in the US.
      • Bangaru S.
      • Pedersen M.R.
      • MacConmara M.P.
      • Singal A.G.
      • Mufti A.R.
      Survey of liver transplantation practices for severe acute alcoholic hepatitis.
      In the US, the 3 main reasons raised by centres not performing the procedure were the belief that the 6-month rule was beneficial in terms of improving liver function and reducing the risk of alcohol relapse and the fear of a negative impact on public opinion.
      • Bangaru S.
      • Pedersen M.R.
      • MacConmara M.P.
      • Singal A.G.
      • Mufti A.R.
      Survey of liver transplantation practices for severe acute alcoholic hepatitis.
      One of the obstacles that seems the most difficult to grasp is the possible impact of the programme on the public's willingness to donate organs. In order to obtain quantitative data on this issue, an online survey was carried out using a representative sample of the donor public.
      • Stroh G.
      • Rosell T.
      • Dong F.
      • Forster J.
      Early liver transplantation for patients with acute alcoholic hepatitis: public views and the effects on organ donation.
      Among the 503 respondents, two-thirds were considering donating their organs, 21% were unsure and 11% were unwilling. Respondents who were completely abstinent were less likely to donate than the others. Almost 86% of the respondents found that early transplantation was consistent with a rational use of grafts while the remaining 14% did not share this opinion. Middle-age, good social support and financial stability were the patient characteristics considered as the most relevant by respondents for selecting candidates for early transplantation.
      • Stroh G.
      • Rosell T.
      • Dong F.
      • Forster J.
      Early liver transplantation for patients with acute alcoholic hepatitis: public views and the effects on organ donation.
      Consequently, public opinion seems to approve early transplantation in patients with severe alcoholic hepatitis, even if this entity is partly self-inflicted. Moreover, it is important to stress that organ donation has not weakened in France, a country where early liver transplantation has been integrated into routine practice.
      • Donckier V.
      • Lucidi V.
      • Gustot T.
      • Moreno C.
      Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy.
      The concept of early transplantation raises several issues that remain unsettled.
      • Mathurin P.
      • Lucey M.R.
      Liver transplantation in patients with alcohol-related liver disease: current status and future directions.
      Among others, exclusion of patients with a history of liver decompensations is based on the concept that such patients chose to ignore a warning.
      • Donckier V.
      • Lucidi V.
      • Gustot T.
      • Moreno C.
      Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy.
      This criterion is questionable as it introduces a judgmental aspect to therapeutic decision making.
      • Donckier V.
      • Lucidi V.
      • Gustot T.
      • Moreno C.
      Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy.
      Such a criterion should be re-evaluated in more rational terms such as utility, impact on waiting list mortality and risk of alcohol relapse compared to those currently selected. It is likely that, for example, a patient who had a single relapse after 10 years of follow-up after a first decompensation probably does not have the same risk of relapse as another patient without prolonged periods of abstinence during similar follow-up. Some experts suggest shortening the period of abstinence from 6 months to 1 to 3 months. In terms of gain in life expectancy, a modelling approach showed that delayed transplantation at 1 and 3 months led to higher life expectancy than transplantation performed using the 6-month rule.
      • Lee B.P.
      • Samur S.
      • Dalgic O.O.
      • Bethea E.D.
      • Lucey M.R.
      • Weinberg E.
      • et al.
      Model to calculate harms and benefits of early vs delayed liver transplantation for patients with alcohol-associated hepatitis.
      However, shortening the period of abstinence was still an inferior strategy in terms of survival benefit compared to early transplantation.
      • Lee B.P.
      • Samur S.
      • Dalgic O.O.
      • Bethea E.D.
      • Lucey M.R.
      • Weinberg E.
      • et al.
      Model to calculate harms and benefits of early vs delayed liver transplantation for patients with alcohol-associated hepatitis.
      In summary, in the last decade, early transplantation, using a restrictive selection process, has found its place in the therapeutic arsenal for patients with severe alcoholic hepatitis. Early transplantation has gained the support of a growing number of experts from different countries, as shown by the European, American and Latin American recommendations.
      EASL Clinical Practice Guidelines
      Management of alcohol-related liver disease.
      ,
      • Arab J.P.
      • Roblero J.P.
      • Altamirano J.
      • Bessone F.
      • Chaves Araujo R.
      • Higuera-De la Tijera F.
      • et al.
      Alcohol-related liver disease: clinical practice guidelines by the Latin American association for the study of the liver (ALEH).
      ,
      • Mitchell M.C.
      • Friedman L.S.
      • McClain C.J.
      Medical management of severe alcoholic hepatitis: expert review from the clinical practice updates committee of the AGA institute.
      A selection approach based on the use of a dedicated score based on social and addiction parameters could be interesting and is currently undergoing investigation in a prospective controlled trial (NCT01756794), which is being conducted by the Lille Team.

      Abbreviation

      MELD, model for end-stage liver disease; UNOS, United Network for Organ Sharing.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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