domenica 6 gennaio 2013


January 2013

Vittorio Agnoletto is a physician, the co-founder of LILA (Lega Italiana per la Lotta contro l’AIDS) and its national chairman from 1992 to 2001, former European Parliament member, a Professor of Health and Human Rights at the University of Milan. Carlo Gnetti is a journalist. Last November, they published a book together – AIDS: lo scandalo del vaccino italiano – which tells the nearly fifteen-year history of the anti-Tat vaccine tested by Dr. Barbara Ensoli at the Istituto Superiore di Sanità (ISS), Rome.

In this book the authors gather the doubts, the criticisms, the precise and detailed objections and the countless unanswered questions that this story has roused since its inception. And they do so through the many articles published in the general press, the few scientific papers closely related to the trial published in specialized journals, the declarations, the missed declarations and the real reticence of some of the protagonists, building what magistrate and President of the Surveillance Court of Bologna Francesco Maisto called “a strongly marked circumstantial trail”. (For the definition given by judge Maisto, see the interview that Emiliano Silvestri made with Vittorio Agnoletto for Radio Radicale, min. 13:55).

The authors’ ultimate aim is to establish the truth of a story that dominated the Italian scientific and media scene in the last 15 years. The main theme of the book, indeed, is an urgent request for clarification; its hope is that those who know will speak, because if the doubts about the conduct of the trial were consistent and demonstrated real, then people involved in the clinical trials – in Italy and especially in South Africa – could be running serious risks.

The book is introduced by a foreword by Robert Gallo, co-discoverer of HIV along with Montagnier and Barré-Sinoussi. Here he summarizes the scientific concerns about a vaccine based on the Tat protein, which was discovered by his own working group. According to Professor Gallo, by the early 1990s and well before the start of the trials of Barbara Ensoli in 1998 it was already known that Tat could give at most a modest therapeutic contribution, but it alone certainly could never be the basis of a preventive vaccine. “An illogical idea for a preventive vaccine” – writes Gallo. Indeed, “after 15 years there are no confirmed results that support this approach, nor is it of use today as a therapeutic vaccine”.

And with combination antiretroviral therapy available since 1995, also the therapeutic contribution of Tat seems to Gallo now essentially useless.

The issues addressed by Agnoletto and Gnetti range from lack of transparency to ethical concerns, from the costs of the project to the extremely swollen times of all stages of the trial, to familism, to media overexposure: all those issues are intertwined. In summary:

·         The lack of transparency of the whole experimentation is highlighted especially in relation to changes of the protocol while the trials were in progress and without notification to the other researchers involved; to the partial publication of data and therefore their lack of validation, with the consequent passage from one phase of the experimentation to another without justifying and explaining the results of the previous phases; to the confusion between trials of a preventive vaccine, then a therapeutic one, then again a preventive one, but completely different from the previous, coming back from a phase II trial to a phase I new trial - with no one of the project Principal Investigators taking the burden of saying “it was a wrong path for these and these reasons, we changed our minds”.

·         The ethical concerns are about the way in which the monkeys were treated during the preclinical phase (which might have distorted the data from the animal model which provided the basis for moving to human trials), and about the fact that the volunteers enrolled in the trials in South Africa might not obtain the same protection enjoyed by the participants to the European trials, because the control mechanisms there, such as ethics committees, might not always provide the same guarantees we enjoy here.

·         The issue of the project’s funding is complicated, because it is interwoven with the political and not only scientific decision to allocate almost half of the total public funding for the fight against AIDS over the past decade to research widely criticized by leading scientists around the world and almost completely absent from the major international scientific conferences. Further perplexity arises from the fact that more than 20 million euros have been added by the Ministry of Foreign Affairs to the funds allocated by the Ministry of Health, which is the ministry that normally deals institutionally with this kind of research and finances it through a peer reviewed mechanism of evaluation and control, in which scientists not involved in the project judge the potential of the research program. The Ministry of Foreign Affairs has taken these 20 million euros away from the funds for international cooperation and allocated them to the construction of a laboratory in South Africa for on-site analysis of the results of the trial. But funds for cooperation are not allocated on the basis of a peer review mechanism. To this must be added the consideration that no pharmaceutical company seems interested in producing this vaccine.

·         The familism might seem like a minor problem, a “simple” scientific malpractice. But it is not, because having the brother of the leader of the research project as the director of the laboratory where data collected from the trial are analyzed poses a serious threat to the interpretation of these data. And this is just one of several cases in which controller and controlled are the same entity and a conflict of interest arises.

A few days before the book arrived in bookstores, Barbara Ensoli sent to a mailing list some Considerations useful to clarity, a summary of which was published in the 27 November issue of La Repubblica and which is, to date, the only (semi)official reaction by the Istituto Superiore di Sanità.
It is a sort of “memorandum” in which Ensoli repeats the official version of the history of the anti-Tat vaccine, that can be read in the dedicated website, but is careful not to respond to the criticisms moved in the book, rather accusing the authors of having falsified and distorted “everything”, adopting the “defamatory obstinacy” of Robert Gallo and Fernando Aiuti, whom Ensoli “knows very well, and she is aware of what they are able to do to gain visibility”.
Agnoletto and Gnetti are also accused of an “obvious” intent to defame “the vaccine, the Istituto Superiore di Sanità (‘ISS’) and its President, Prof. Garaci, but also public institutions: the Ministry of Health and the various ministries who have taken place over the years, the Ministry of Foreign Affairs, the Undersecretary Letta of Prime Minister Berlusconi, the National AIDS Commission, scientists and Italian public research and, ultimately, the Italian system as a whole, which is represented as unreliable” (p. 1).
According to Ensoli, the “book is so defamatory that is natural to ask for what purpose it was written, and if there are economic/political/international interests that could benefit from the mud the authors throw on the Italian system” (ibid.). This induces Barbara Ensoli to conclude her “Considerations” – which were supposed to be “useful to clarity”, but which do not clarify anything but a certain anxiety of their author – wondering who “really” is behind all of this: “Which lobbies are at work? Where do they want to get?” (p. 8). 

Where do they want to get, is a question I thought I could ask directly to Vittorio Agnoletto. But I didn’t ask which lobbies are behind him and if he is an AIDS denialist (according to Ensoli, the book “contains many denialist cues”): I would be ashamed to take seriously the rhetoric of the plots, of the lobbies and “cui prodest?”, as well as the generic and unsubstantiated accusations (which are all classic dialectic tricks of the denialist argumentation) that Dr. Ensoli adopted as a defense strategy.

The following is the result of our conversation.

• I would like some brief clarification on controversial points of the transition from preclinical phase in the testing of the anti-Tat vaccine to phase I and from phase I to II. Let’s start with the problems related to animal experiments.
Each trial, before arriving at clinical stages, passes from a preclinical phase on animals that, in this case, was carried out on monkeys. Among other things, it was an item on a television program that talked about the treatment of monkeys in October 2004 that was the first public and media opportunity to have a look at how this vaccine was progressing, and even then there were some controversies.
The things to say about the monkeys are quite simple. First, there are the testimonies of two people who worked on this project (immunologist Antonio Scardino and veterinarian Antonella Comini), who have been able to verify directly how the trial proceeded within the animal enclosure and have called into question the way in which the monkeys were treated, because the animals must be kept in good health and under certain conditions, so that their reaction to the experimentation could be free from any risk of misinterpretation due to the conditions of life and the state of monkeys’ organism.
The most problematic aspect is that none of the people we tried to contact was willing to talk about two protocols  – called Npt and Id – which used the Tat protein in various formulations. Of these protocols very little is known. It may be that we missed an article, but we did not find a publication that describes from A to Z the development of these protocols. But since they are presented as crucial to the transition to phase I, there is no certainty as to how they were performed. If we had been able to meet Dr. Ensoli, we would have asked her to reassure us on some information that we have no chance to verify: we want to be sure that the monkeys on which the vaccine was tested had the same response, namely that they were not infected, while all the monkeys that were not vaccinated became infected. Indeed, if it should turn out that some monkeys that should not become infected got infected, or vice versa, many question marks would weigh on these two protocols and this would call into question all the rest of the research on humans.
How is it that, at the mention of these protocols, we obtain total silence, everyone is afraid and no one answers? This is a very relevant question, because we have not found any publication describing the whole testing of these protocols. It therefore remains a mystery that could affect the transition to the clinic, especially since the first paper on monkeys in 1999 involved a very limited number of animals, so that other analyses were mandatory.
Another issue that has never been clarified regards the protocol of vaccine administration to the animals, which had been planned in certain doses and at certain times: some researchers reported that their impression was that the doses and the administrations to stimulate the immunization were modified according to the reactions of individual monkeys.
A research project cannot be performed that way. Two associations were denied access to the ISS documentation to make a comparison between the presented protocol and that actually realized.
If we add that some of the researchers – veterinarians and doctors – who have worked with monkeys left the ISS and went to work somewhere else, and if we add the scandal that followed the program Report on monkeys, then the question marks are really many.
Therefore, already with regard to the preclinical phase emerges a recurring question in this whole affaire: why none of the project leaders agreed to answer? If everything has been done properly, why not speak? Why not be proud of such an important research? 

• In this somewhat mysterious way, experimentation moved to a clinical phase I divided into two arms: a preventive vaccine and a therapeutic one. From then on, the preventive vaccine is lost in the mists.
The phase I studies, both of the preventive, both of the therapeutic vaccines, ended in 2005, and both the ISS and the Ministry in various public events claimed that everything went well and that it was necessary to raise funds to proceed to phase II.
There are some publications on phase I, but remains a mystery, after all the optimistic claims and a few data published in articles – that we report in the book – that nobody speaks anymore of the preventive vaccine, until in 2011 we find that a phase I of a completely different preventive vaccine starts.
The key point of confusion in public opinion is the fact that the ISS and the Ministry still say that phase I was successful and they moved on to phase II, but in their communication to media they do not specify that the vaccine in phase II is the therapeutic one (which is not a vaccine, but an immunotherapy). This is confusing to those who play a sensitive role in communication. To recall just a recent example, when our book was published, La Repubblica published a short interview with Dr. Ensoli. The headline of the interview says that they are already in phase II (Completata la fase II, funziona). Anyone who reads this, thinks that they are talking about the preventive vaccine. I consider unethical that the communication of an institution like the ISS is so ambiguous.
Phase I ends, the preventive vaccine in fact stops, and from the clinical point of view the question is this: if we were told that phase I went well, why didn’t they move to phase II and why did a new phase I start many years later with a different preventive vaccine?
From a clinical standpoint is relevant to know on what the expected results of phase I got stranded, because it allows us to understand also the limitations of the research.
This was the fundamental question we wanted to ask the project supervisors. Professor Adriano Lazzarin, responsible for the trial here in Milan, I wished to ask why a phase II for the preventive vaccine never started, and what are the results that have imposed a stop. It cannot be said that this has been due to lack of funds, because money to start a phase II of the therapeutic vaccine has been found.
There are also some clinical concerns about phase II of the therapeutic vaccine: Tat is always administered to patients on antiretroviral therapy and it is at best an adjuvant, a booster of the immune system, always in the hope that it lacks side effects and toxicities, as Professor Gallo is concerned about in the Preface to our book. Even assuming that all goes well, in no event will Tat replace antiretrovirals. 

• What does it mean that data (always partial, ad interim) of this trial have not been validated? Indeed, to publish in PLoS ONE, as Ensoli did, is not the same as publishing in Nature, Immunology or AIDS. It is true that PLoS ONE is peer reviewed (although submissions are not excluded on the basis of lack of perceived importance or adherence to a scientific field), but this journal publishes primary research and its purpose is to create an open access archive of news and open issues, available for scientific community feedbacks and discussions. It is a sort of a book of dreams and hopes of the medical research (PLoS ONE offers to its readers the opportunity to discuss papers online, but Ensoli’s 2010 article - Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART  - received no comments). In order to be accepted by the scientific community, the studies must be validated through the publication on far different journals, with far different impact factors and greater specialization. And also the fact that there were no reactions from the scientific community, written replies or comments during international conferences, says – beyond the lack of interest that this research raises in the rest of the world – that data have not been validated, doesn’t it? I remember that Gallo in the foreword to the book says that there are no confirmed results that support this approach.
With regard to the modality of data communication, this story does not work from the start. We live in a media society and everything becomes entertainment, but in the world of medical science it is not so: there are practices established at an international level.
The announcement of this project comes in October 1998, and it’s hyped at a congress on AIDS and cancer in the presence of press and television. But nothing had been published yet in scientific journals.
The practice is that communication to public opinion takes place after the work has been completed, at least the step you are talking about, and the article has been sent to a scientific journal, which has approved and published, or is going to publish, it. Here, on the contrary, more than 8 months passed before the publication of data relating to very few monkeys (5 of 7 monkeys that, after being vaccinated and controlled 7 months later, would prove capable of blocking viral replication). In this way the public announcement takes on the appearance of a sensational ad and is, in fact, intended to try to build the image of the people involved, and of course to facilitate the fundraising, rather than being directed to strictly scientific aspects.

This procedure is also found in what you say about PLoS ONE, which is, in my opinion, an absolutely respectable journal for its function and for its social value, also because it is open access. But if you are doing research on a vaccine you must publish these data on specialized journals, with high impact factors.
Beyond the public announcement and publication of data, there is a third aspect in which the international scientific community verifies a trial: the large conferences, the moment of encounter and discussion with other scientists. Here, too, there is a minimal participation at international conferences.
All this involves two collateral aspects: first, there should be attention from the mass media before making high-sounding headlines on this kind of news, because the articles are written always by the same specialized journalists, who know that an announcement on major impact topics must be verified. Second, the authorities funding this project know that scientific projects must match certain criteria, for example the impact factor of the supporting publications. Here, however, even in the absence of these elements, they went on providing financing. 

Immunologist Professor Aiuti, one of the head physicians participating in the clinical phase I, addressed three methodological criticisms to the conduct of the trial: 1) he asked why the first phase of the trial was stopped prematurely, involving far fewer volunteers than was established by the protocol and then exposing the project to the risk that data collected are not verifiable; 2) he has objected that the remarks made by the inspectors of the Agenzia Italiana del Farmaco (AIFA) on “critical deviations” from the original protocol have not been taken into account; 3) he was critical that phase I data might be transmitted to the press before the researchers involved could see them, thereby exposing the project to the risk of the failure of the double-blind. In May 2007 Dr. Ensoli sued Professor Aiuti for libel and a few months ago she lost the case. Now, I would like to understand the significance of this lawsuit and the meaning of a judgment unfavorable to Ensoli: if the court ruled against her, this implies that the scientific criticisms of the trial by Aiuti do not constitute defamation. If it is true that the trial was conducted and communicated improperly, what could (or should) this lead to in practice?
The judgment does not enter into the merits of the criticisms, but simply states that those criticisms are part of a scientific debate and that they were not aimed at creating disrepute. 

But have these criticisms ever been answered?
In response to the heavy remarks by AIFA, Dr. Ensoli sent to AIFA itself a document, which we could not have access to, but which is among the papers of the legal action, not known to Aiuti when he moved his criticisms. AIFA has accepted some of Ensoli’s replies, while on others it said it is still awaiting a clarification.
What is certain is that it is very odd that in the face of a document such as that of AIFA which makes very serious objections to the conduct of the trial the ISS and the Ministry – the sponsors – not only have not demanded public explanations from the director of the project, but the ISS even joined Ensoli in the suit against Aiuti.
So the criticisms of Aiuti are still waiting for a reply. You said that the number of the volunteers in the trial has been reduced compared to that under the protocol. But Aiuti adds that this decision has not even been discussed with those in charge of the trial. Who decided this variation in the protocol?
I wrote it in the book, but it is worth underlining here: I had heavy clashes with Professor Aiuti. In the ‘90s we also had a court case, and our political and cultural approaches are very different. If, starting from such different cultural standpoints, we get to ask the same questions, this strengthens our criticism. 

• It is unusual to sue someone because he makes a scientific criticism of you, isn’t it?
It hardly ever happens in science. But to frighten people with the threat of a civil action or with a lawsuit may be an intimidating method, that is generally used to silence people.
I wrote it in the book: I was given documents from a colleague who communicated to others involved in the research the concerns of Professor Aiuti and immediately received a letter from lawyers, threatening a defamation case. She sent me that letter, but asked not to be named. 

• Dr. Glenda Gray too, who heads a unit at Chris Hani Baragwuanath Hospital in Soweto, spoke of this to journalist Jon Cohen (see "Feud Over AIDS Vaccine Trials Leads Prominent Italian Researchers to Court”, Science, August 10, 2007). So these methods of intimidation have not been used only against Professor Aiuti.
I think the easiest thing would have been that Ensoli had organized a press conference or written an article saying “I was presented those criticisms … I say on the subject …”.
In the book we tell the story that arose around the July 1, 2005 Gala, where it was announced the success of phase I. Aiuti rose up saying that the trial was double-blind, not even those in charge of the trial knew the data, and it was unacceptable to communicate data to the public even before they were known to researchers involved in the project. A press release from the ISS specified that there had been a misunderstanding and data would be presented to the public at a later event. But we were able to demonstrate that a newscast on November 7, 2004 – seven months earlier, then – had already announced that the vaccine was safe as it had no side effects and that this result was the outcome of phase I. Who passed this information? Or if it was an invention of the reporter then the ISS had the duty to retract it because it is a public institution and the announcement given had an impact on public and social behavior. Or this information was passed to the journalist. But in that case the problem is serious and the project director should have been the first to rise up. The impression is therefore that the media management prevailed over everything else.
Since we published the book, many people ask me the reason for this ugly story. My impression is that three different things mixed together: the desire of a group of researchers to emerge at any cost not only on the scientific scene, but also on the public stage; the need of Italian governments to claim a leading role of Italy in scientific research, as an instrument of affirmation of the “grandeur” of Italy, in crisis in other areas – hence the choice of a topic that had the biggest media impact; a political proximity of some researchers to decision-making roles that matter.
My guess is that these mechanisms, once started, became unstoppable. 

• We have seen that the transition from the animal model to the first phase on humans is at the least questionable and that the progression from phase I to II also does not seem to have been justified on the basis of validated data. What, then, are the risks that could affect volunteers enrolled in the trials, both in Italy and in South Africa? From what you have said, this is precisely the reason for the urgency in publishing your book.
We have no documentation stating that this experimentation in itself may be harmful to humans. The point is that if people involved in the trials are told that the putative vaccine has undergone a series of phases, it is obvious that somehow it is taken for granted the hypothetical, possible safety of this product. On the other end, testing of a vaccine is verified because you see that, in real life, the vaccinated do not become infected when they come into contact with the pathogen. That is why phase III must enroll several thousands of people and must be performed in countries with a high prevalence of HIV.
But if this hypothetical protective efficacy was not actually proved and if you were to question some of the previous phases, then you would face here potential risk behaviors of those vaccinated, which would not protect themselves because they are convinced of being immunized. When this preventive vaccine starts again from phase I, starts again with a different design and, what is more, it is started also in South Africa, where the health care system works differently than in  Europe, we have this concern for volunteers.
On the other hand, the agreement with South Africa would provide also an assignment of over 20 million euros for the construction of laboratories. Then, of course, South Africa is interested in having this research, because it receives such funding. So our fears that health surveillance needed in this type of trials is not guaranteed increase even more.
We are worried about the level of “safety” that is or is not guaranteed. If you do not shed light on the early stages of the trial, this question mark continues to weigh on. Hence the need for the book to be published in haste, before the trial steps to the next stages and before they are possibly wasted other public funds to finance a project that you must be sure that is going in the right direction.
Finally, there remain questions about the possible toxicity of Tat used in a therapeutic vaccine for HIV positive people, because Gallo, who has worked a lot on this protein, does not exclude that there might be toxicity.

• What is involved in the diversion of the few available public funds from other research that, perhaps, if properly supported, would have been more productive?
Italy has cut funds for research. For three years it hasn’t paid the money pledged to the Global Fund to fight AIDS, tuberculosis and malaria. There is no serious investment in prevention. We have 160 – 180.000 people living with HIV who are living longer fortunately, but this also increases the risks of transmission.
What results could be achieved by funding other research, I do not know. But, potentially, we could have lost a lot. It can be argued that the huge funding for this vaccine has diverted funds from other projects, thus indirectly bringing damage to Italian research. 

• So we can assume that the funding for this vaccine, presented as a source of pride, has actually impaired Italian research and community.
Yes, and I also speculate that the issue of funds may have something to do with the unwillingness of the vast majority of researchers to talk about this project because obviously those involved do not want to talk - but also those who are not involved fear cuts to the little funding they do receive. 

• I would like to explore the question of the effects, both on general population and on people with HIV, of the communication strategy adopted by ISS in speaking about the vaccine to the media. In particular, I would like to understand the effects that the mistrust generated by unfulfilled promises may have on the emotional balance of people living with a serious chronic illness and on their adherence to treatment. And I would also like to know if a generalized distrust towards research, formed as a result of the succession of deceptive news, might affect the willingness of people to volunteer in clinical trials.
This communication strategy can have the effect of making general population believe that the vaccine is already here, and then of lowering the guard on prevention. See the recent survey by Anlaids  of Roman students, in which we discover that more than 20% of respondents believe that the vaccine exists and is available.
The big scandal in ISS communication is also related to the preventive vaccine. You may ask why HIV positive people should care for a preventive vaccine; but this is actually a very relevant question, because if  there were a preventive vaccine the social stigmatization and every form of discrimination against people with HIV would collapse. This would completely change the daily lives of HIV positive people, because they no longer would be perceived, and perceive themselves, as a threat to others.
The second point is what you say: on a psychological level, expecially now that drugs which greatly extend lifespan are available, it is vital to think that the extended time of your life will be used to make new discoveries, which in turn will further lengthen your time, improving also the quality of your life. Confidence in research and in those who conduct it is essential, and there is no other disease like HIV/AIDS, where HIV positive people are self-organized and sometimes even become “scientific community” in the exchange of information about research. Often this isn’t just a unidirectional relationship, but a mutual exchange with the scientific community. The discovery that such an important research is conducted in such a controversial way may certainly have an emotional impact on people living with HIV, and this also leads to a drop of hope and, of course, to an unwillingness to volunteer in clinical trials.
There are also many studies that show how a situation of prolonged depression impacts on the immune system, either directly, from the organic point of view, or indirectly, due to a worse adherence to antiretroviral therapy.
So those who make public announcements that are regularly proved wrong by facts bear a huge responsibility. 

• Do you have any comments about the “Considerations” sent by Dr. Ensoli to HIV positive people, activists and associations? Don’t you think it’s paradoxical being accused of having written a book that “contains many denialist cues”, and this right by someone who makes a wide use of the rhetoric of conspiracies and occult lobbies, who addresses to you generic and unsubstantiated accusations, who avoids responding to your criticisms preferring to shift the discussion towards the “chief systems” (the “sistema Italia”, even!), posing as a victim of an international plot and even backbiting, someone who, in the past, preferred to sue rather than responding to scientific allegations – all, these, typical denialist rhetorical strategies?
From this document it is clear that she has no remarks to disprove what we have written. What struck me most is that there is not one refutation. There is a personal controversy with Gallo and Aiuti, and it’s very serious that she accuses us of being AIDS denialists, very serious. Clearly, that accusation was made to disqualify our work and, since she says that the book is libelous, what is defamatory for me is the accusation of denialism.

This just shows that Dr. Ensoli had nothing to cling to. There is no reply on the topics we talked about today – those more strictly scientific, which are the most important – but there is not even a reply on issues like the conflicts of interest, the familism, the role of her brother …
To me it seemed, for those who read the book, a serious own goal. 

• The aim of the book, repeatedly stated, is a call for clarity. From who?
For example, I expected, and I still expect, to hear a word from Professor Stefano Vella, who was the president of the International AIDS Society, who was the one who brought to South Africa the World Conference on AIDS, and therefore has a not just Italian perspective. He has all the means to know how a scientific research must be performed and what is the international framework of the research. Moreover, he is totally within the ISS, but not involved in the anti-Tat vaccine trials, so he has all the elements to evaluate this project. 

From the feedback received so far, do you think that something is happening? For example, could the interview with Radio Radicale lead to an involvement of the Radical Party and eventually to a new parliamentary question after the elections?
I am optimistic on three issues: I think some member of the next Parliament will be willing to resubmit an interpellation. Some colleagues contacted me and it seems they are discussing with their own conscience on how to intervene and provide additional information. Finally, I hope that a magistrate will take the lead on the matter. I am aware that it is not easy for a judge to address the scientific aspects; it is certainly easier to deal with this matter starting from the financial aspects and then, from there, address the experimentation. But if a judge opened an investigation, this would facilitate a political intervention in the Parliament and it would also give an incentive to those colleagues who know how things turned out to resolve their crisis of conscience and decide to speak.

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