2007 Amendments to the National Academies’ Guidelines for Human Embryonic Stem Cell Research

INTRODUCTION

The National Academies’ report Guidelines for Human Embryonic Stem Cell Research was developed by the Committee on Guidelines for Human Embryonic Stem Cell Research and released in April 2005. The body of the report provided the background and rationale for the choices involved in formulating the guidelines, which were compiled in its final chapter. Because human embryonic stem (hES) cell research touches on many ethical, legal, scientific, and policy issues that are of concern to some people, the Guidelines are intended to make explicit how research with hES cells can be pursued most responsibly. While the Guidelines are primarily intended to address researchers in the United States, they may have applicability internationally as well.

The 2005 publication of the Guidelines offered a common set of ethical standards for a field that, due to the absence of comprehensive federal funding, was lacking national standards for research. Many have found the guidelines useful, but several constituencies identified sections of the Guidelines that they believe should be clarified. In addition, numerous scientific organizations and individuals encouraged the National Academies to establish an advisory committee to keep the Guidelines up to date, given the rapid pace of scientific developments in the field of stem cell research. Further,



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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research 2007 Amendments to the National Academies’ Guidelines for Human Embryonic Stem Cell Research INTRODUCTION The National Academies’ report Guidelines for Human Embryonic Stem Cell Research was developed by the Committee on Guidelines for Human Embryonic Stem Cell Research and released in April 2005. The body of the report provided the background and rationale for the choices involved in formulating the guidelines, which were compiled in its final chapter. Because human embryonic stem (hES) cell research touches on many ethical, legal, scientific, and policy issues that are of concern to some people, the Guidelines are intended to make explicit how research with hES cells can be pursued most responsibly. While the Guidelines are primarily intended to address researchers in the United States, they may have applicability internationally as well. The 2005 publication of the Guidelines offered a common set of ethical standards for a field that, due to the absence of comprehensive federal funding, was lacking national standards for research. Many have found the guidelines useful, but several constituencies identified sections of the Guidelines that they believe should be clarified. In addition, numerous scientific organizations and individuals encouraged the National Academies to establish an advisory committee to keep the Guidelines up to date, given the rapid pace of scientific developments in the field of stem cell research. Further,

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research Statement of Task of the Human Embryonic Stem Cell Research Advisory Committee The Advisory Committee will meet two to three times per year over a period of 36 months to (1) monitor and review scientific developments and changing ethical, legal, and policy issues related to human embryonic stem cell research, (2) discuss the need for revisions to the Guidelines for Human Embryonic Stem Cell Research, and (3) prepare periodic reports to update the Guidelines as needed. Minimal but necessary changes may be issued as letter reports, but more extensive modifications may necessitate the preparation of traditional reports to fully provide the rationale for the changes. Sources of information that will be considered by the Advisory Committee will include public symposia organized by the Committee to review developments in stem cell science and how these impact the ethical and policy issues surrounding hES cell research. they urged the National Academies to consider correcting or clarifying aspects of the Guidelines in the light of experience. Responding to these requests for revision and ongoing monitoring, the Human Embryonic Stem Cell Research Advisory Committee was established in 2006 with support from The Ellison Medical Foundation, The Greenwall Foundation, and the Howard Hughes Medical Institute. The Human Embryonic Stem Cell Research Advisory Committee has engaged in a number of efforts to gather information about the need, if any, for revision of the Guidelines. The Committee met for the first time in July 2006 and heard from a number of invited guests representing organizations and academic institutions that are actively involved in stem cell research. In addition, in early November 2006, the Committee organized a symposium at which invited speakers reviewed the latest scientific developments, described how these developments might affect the analysis of associated ethical issues, and identified possible effects on the workability or justifiability of the current Guidelines. The Committee also hosted a panel discussion at the symposium for representatives of seven Embryonic Stem Cell Research Oversight (ESCRO) committees.1 This panel shared their experiences in working with the content and procedures of the Guidelines. 1 The 2005 Guidelines called for institutions involved in hES cell research to establish ESCRO committees to provide institutional oversight on all issues related to derivation and use of hES cell lines and to facilitate education of investigators involved in hES cell research.

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research As an ongoing effort, the Committee is also monitoring discussions of the Guidelines held by others, such as the April 2006 Association of American Medical Colleges (AAMC) meeting for medical school administrators to discuss the conduct and management of stem cell research at their institutions, a discussion which encompassed a review and critique of the Guidelines, and which was summarized for the Committee at its July meeting.2 The Committee has also established a listserv for ESCRO committee members and staff to communicate and share questions and answers, and will be hosting a series of regional meetings in the spring of 2007 to bring together ESCRO committee members and staff, receive input from ESCRO committees, and clarify the Guidelines. In addition, members of the Committee have been actively soliciting input from their colleagues and receiving comments via a Web site3 established for this purpose. The Committee identified issues that appeared to merit consideration of revisions of the Guidelines. This report addresses issues that are both in need of amendment and amenable to prompt solution. The Committee is issuing this first set of amendments primarily to clarify or re-emphasize earlier recommendations and conclusions. Because the changes being made are minor and affect only Sections 1 and 2 of the Guidelines, this brief letter report is the best method of communicating these changes. Future deliberations of the Committee will deal with items for which additional information gathering and more extensive debate and discussion will probably be necessary. For example, the Committee has received numerous comments both praising and disputing the current policy on no compensation for oocyte donors. Similarly, some commenters have expressed dissatisfaction with the current restrictions on research using chimeras or have asked for further guidance on how to evaluate such research. More time will be required for the Committee to give adequate consideration to these and other issues and it will report on its findings in the future. Four changes to the Guidelines are discussed herein: clarifying the phrase “provenance of the cell lines” (changes to Section 1.2); use of the hES cells approved for use in federally-funded research (addition of Section 1.4); 2 A summary of the AAMC meeting was subsequently published as “Human Embryonic Stem Cell Research: Regulatory and Administrative Challenges.” This AAMC monograph is available at <http://www.aamc.org/publications>. 3 <http://www.nationalacademies.org/stemcells>.

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research importation of hES cell lines into an institution or jurisdiction (addition of Section 1.5); and allowing ESCRO committees to serve multiple institutions (changes to Section 2.0 and addition of Section 2.1). These amended Guidelines supersede those issued in 2005 by the Committee on Guidelines for Human Embryonic Stem Cell Research. It is important that these clarifications be interpreted in context with the complete set of amended Guidelines, which is included at the end of this report. It is also worth noting that these Guidelines continue to use the word “blastocyst” to refer to the stage of embryonic development from which hES cells are obtained. Both the public and the scientific community are engaged in conversation about the best terminology by which to describe this field of research, and the Committee will be attentive to those discussions as they develop. This report also discusses two additional issues that do not result in formal changes to the Guidelines: (a) the lack of informed consent from sperm donors for some frozen in vitro fertilization (IVF) blastocysts and (b) advice for ESCRO committees in establishing criteria for considering the science in hES cell research proposals. CLARIFYING THE PHRASE “PROVENANCE OF THE CELL LINES” The National Academies’ Human Embryonic Stem Cell Research Advisory Committee has received many comments from the scientific community questioning the meaning of the phrase “provenance of the cell lines,” which occurs in Sections 1.2(a) and 6.1, to describe documentation of the derivation of stem cell lines. The wording of Section 1.2(a) is confusing due to unintended redundancy. It asks for documentation of the provenance of cell lines, documentation of appropriate informed consent in their derivation, and evidence of compliance with required review by an Institutional Review Board (IRB) and other committees, all of which address approximately the same issue. This makes it appear that “documenting the provenance of the cell lines” is something other than documenting informed consent and IRB approval. In order to resolve this confusion, the text of Section 1.2(a) is rewritten (see underlined wording) to read:

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research 1.2(a) hES Cell Research Permissible After Currently Mandated Reviews Purely in vitro hES cell research that uses previously derived hES cell lines is permissible provided that the ESCRO committee or equivalent body designated by the investigator’s institution (see Section 2.0) receives documentation of the provenance of the cell lines including: (i) documentation of the use of an acceptable informed consent process that was approved by an Institutional Review Board (IRB) or foreign equivalent for their derivation (consistent with Section 3.6); and (ii) documentation of compliance with any additional required review by an Institutional Animal Care and Use Committee (IACUC), Institutional Biosafety Committee (IBC), or other institutionally mandated review. USE OF NIH-APPROVED hES CELL LINES The National Academies’ Guidelines were issued a few years after a limited number of cell lines were deemed as useable in federally funded research in the United States.4 As of the publication of this report in early 2007, these “NIH-approved cell lines” are the only hES cell lines that may be used in federally funded research. NIH-approved cell lines were derived before August 2001 under protocols that predated the issuance of the National Academies’ Guidelines in 2005. Nonetheless, NIH’s agreement to fund research using these lines was premised on confirmation that all the cell lines in question were derived from blastocysts that were donated without payment, with voluntary, informed consent, and pursuant to an IRB-approved protocol. The precise details of the consent process for the NIH-approved cell lines may not have included each element called for in the National Academies’ Guidelines. In particular, the Guidelines require informed consent from all embryo, gamete, and somatic cell donors, even anonymous gamete donors. For the 4 “President Discusses Stem Cell Research,” August 9, 2001. <http://www.whitehouse.gov/news/releases/2001/08/20010809-2.html>.

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research NIH-approved cell lines, the presence or absence of anonymously donated gametes cannot be confirmed, thus rendering impossible a determination of whether consent was obtained from all gamete donors. The NIH-approved cell lines were, however, derived from embryos that were donated under protocols that were substantially similar to those contemplated by the Guidelines. Norms and procedures evolve, but it would be unnecessarily rigid to discourage institutions that follow the National Academies’ Guidelines from working on the cell lines that are eligible for federal funding. The protocols under which the NIH-approved cell lines were derived were consistent with ethical norms then in place, were substantially similar to those now adopted in these Guidelines, and were adequately documented. The Committee considers the NIH-approved cell lines to be a special category because they are governed by a unique set of federal pronouncements (presidential statement and NIH rules). The intention of “grandfathering” the NIH-approved cell lines is to avoid precluding hES cell research that would otherwise be rendered difficult or impossible for investigators using NIH funding who wish to follow the National Academies’ Guidelines. The clarification is not intended to “encourage” the use of these cell lines, either inside or outside the United States. For these reasons, retroactive application of the Guidelines is not warranted in this circumstance. Therefore, the Guidelines are amended by adding a new Section 1.4: 1.4 Use of NIH-Approved hES Cell Lines (a) It is acceptable to use hES cell lines that were approved in August 2001 for use in U.S. federally funded research. (b) ESCRO committees should include on their registry a list of NIH-approved cell lines that have been used at their institution in accord with the requirement in Section 2.0 of the Guidelines. (c) Presence on the list of NIH-approved cell lines constitutes adequate documentation of provenance, as per Section 6.1 of the Guidelines.

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research IMPORTATION OF hES CELL LINES INTO AN INSTITUTION OR JURISDICTION Institutions following the National Academies’ Guidelines may find themselves considering proposals for the importation of cell lines derived according to different rules, such as those from the United Kingdom, Canada, and the California Institute for Regenerative Medicine. These cell lines, while meeting all legal requirements of the respective jurisdictions for cell line derivation, may not have been derived in a manner that accords in every detail with the National Academies’ Guidelines. For example, hES cell line derivations in the United Kingdom are managed through a licensing procedure that differs from the IRB and ESCRO committee review processes recommended in the Guidelines. Within the United States, state laws may vary from the Guidelines. California’s laws, regulations, and guidelines, for example, though consistent with the Guidelines, apply some additional requirements concerning the details of the consent form, conflict-of-interest disclosures, and management of adverse medical events that may result from the donation of oocytes. As other states regulate such research, some state laws may differ from the Guidelines in some details but be sufficiently similar to be substantially equivalent. Section 7.0 of the National Academies’ Guidelines anticipates this problem in the international context. Section 7.0 specifically contemplates acceptance of cell lines derived under the extant legal and ethical regimes of another country provided that those regimes are substantially equivalent to the regime laid out in the Guidelines. This deference facilitates collaboration among institutions and shows proper respect for the diversity of authority in this area. This is analogous to the technique by which the U.S. federal government determines whether to accept the ethical and procedural norms of foreign research ethics review bodies as acceptable proxies for domestic IRB review. Section 7.0 of the current National Academies’ Guidelines reads: “If a U.S.-based investigator collaborates with an investigator in another country, the ESCRO committee may determine that the procedures prescribed by the foreign institution afford protections consistent with these guidelines, and the ESCRO committee may approve the substitution of some of or all of the foreign procedures for its own.” Therefore, without in any way suggesting that the addition of a new section should be construed by ESCRO committees to revoke any of the requirements of these Guidelines with respect to new donations or cell line derivations undertaken at their own institutions, the Guidelines are amended

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research by adding a new Section 1.5. This section applies to cell lines derived both before and after release of the Guidelines. ESCRO committees can review pre-2005 derivations and determine whether or not they are acceptable, following the guidance in new Section 1.5. 1.5 Acceptability of Research Using hES Cell Lines Imported from Other Institutions or Jurisdictions (a) Before approving use of hES cell lines imported from other institutions or jurisdictions, ESCRO committees should consider whether such cell lines have been “acceptably derived.” (b) “Acceptably derived” means that the cell lines were derived from gametes or embryos for which the donation protocol was reviewed and approved by an IRB or, in the case of donations taking place outside the United States, a substantially equivalent oversight body; consent to donate was voluntary and informed; donation was made with reimbursement policies consistent with these Guidelines; and donation and derivation complied with the extant legal requirements of the relevant jurisdiction. (c) ESCRO committees should include on their registry a list of cell lines that have been imported from other institutions or jurisdictions and information on the specific guidelines, regulations, or statutes under which the derivation of the imported cell lines was conducted. This is in accord with the requirement in Section 2.0 of the Guidelines that calls for ESCRO committees to maintain registries listing the cell lines in use at their institutions. ESCRO COMMITTEES SERVING MULTIPLE INSTITUTIONS The report Guidelines for Human Embryonic Stem Cell Research laid out a series of recommendations pertaining to the composition and role of ESCRO committees. Based on feedback from the community, it appears that

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research some of these recommendations need clarification. Although the text of Chapter 3 contains the statement that “In some cases, smaller institutions may wish to avail themselves of the services of larger facilities that have ESCRO committees,” the idea that it is acceptable for institutions to use a nonlocal (external) ESCRO committee was unintentionally omitted from the wording of Section 2.0 of the Guidelines. Furthermore, since the Guidelines were issued in April 2005, it has become clear that there are other models for establishing ESCRO committees consistent with the principles of the Guidelines. New alternatives for the organization of IRB reviews are currently emerging that can serve as models for ESCRO review. For example, the National Cancer Institute (NCI) has established a “Central IRB Initiative”5 that is “designed to help reduce the administrative burden on local IRBs and investigators while continuing a high level of protection for human research participants.” The NCI states that a local IRB’s use of the Central IRB would facilitate the review of clinical trial protocols. The initiative is sponsored by NCI in consultation with the Department of Health and Human Services’ Office for Human Research Protections (OHRP). OHRP’s current guidance in the form of “Frequently Asked Questions” on its Web site6 addresses institutions that do not have internal IRBs and provides options that include negotiating agreements with other institutions to have research reviewed as well as the use of commercial or independent IRBs. Finally, a November 2005 workshop summary report on “Alternative Models of IRB Review”7 sponsored by the National Institutes of Health, OHRP, AAMC, and the American Society for Clinical Oncology explored the use of up to 10 alternative models, such as sharing materials among local IRBs, institutions relying on review by the IRB of another institution, and sites forming consortia to use a single IRB in a collaborative process. Although acceptance of the use of such alternative models for IRBs has not yet been indicated in updated guidance from OHRP or the Food and Drug Administration, the trend toward collaborative efforts is a topic that is actively under discussion and offers the possibility of more efficient and timely IRB (and, by analogy, ESCRO committee) review. The Tri-Institutional ESCRO Committee established by Rockefeller University, Memorial-Sloan Kettering Cancer Center, and Weill Medical College of Cornell University is an example of a single committee serving three research 5 See <http://www.ncicirb.org/> for more information about the initiative. 6 <http://www.hhs.gov/ohrp/faq.html>. 7 <http://www.hhs.gov/ohrp/sachrp/documents/AltModIRB.pdf>.

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research institutions. Although the Committee on Guidelines for Human Embryonic Stem Cell Research quite clearly intended to allow for the use of shared or central ESCRO committees, it failed to state that explicitly. Therefore, Section 2.0 of the Guidelines is amended. (New wording is underlined.) For projects involving more than one institution, there have also been concerns about the difficulty of multiple ESCRO committee reviews. Section 2.1 is added to explicitly allow—but not require—that multi-institution collaborations can be reviewed by a single ESCRO committee. 2.0 ESTABLISHMENT OF AN INSTITUTIONAL EMBRYONIC STEM CELL RESEARCH OVERSIGHT COMMITTEE To provide oversight of all issues related to derivation and use of hES cell lines and to facilitate education of investigators involved in hES cell research, each institution should have activities involving hES cells overseen by an Embryonic Stem Cell Research Oversight (ESCRO) committee. This committee could be internal to a single institution or established jointly with one or more other institutions. Alternatively, an institution may have its proposals reviewed by an ESCRO committee of another institution, or by an independent ESCRO committee. An ESCRO committee should include independent representatives of the lay public as well as persons with expertise in developmental biology, stem cell research, molecular biology, assisted reproduction, and ethical and legal issues in hES cell research. It must have suitable scientific, medical, and ethical expertise to conduct its own review and should have the resources needed to coordinate the management of the various other reviews required for a particular protocol. A preexisting committee could serve the functions of the ESCRO committee provided that it has the recommended expertise and representation to perform the various roles described in this report. For example, an institution might elect to constitute an ESCRO committee from among some members of an IRB. But the ESCRO committee should not be a subcommittee of the IRB, as its responsibilities extend beyond human subject protections. Furthermore, much hES cell research does not require IRB review. The ESCRO committee should

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research provide oversight over all issues related to derivation and use of hES cell lines, review and approve the scientific merit of research protocols, review compliance of all in-house hES cell research with all relevant regulations and these guidelines, maintain registries of hES cell research conducted at the institution and hES cell lines derived or imported by institutional investigators, and facilitate education of investigators involved in hES cell research. An institution that uses an external ESCRO committee should nevertheless ensure that the registry and educational functions of an internal ESCRO committee are carried out by the external ESCRO committee on its behalf or internally by other administrative units. 2.1 For projects that involve more than one institution, review of the scientific merit, justification, and compliance status of the research may be carried out by a single ESCRO committee if all participating institutions agree to accept the results of the review. FROZEN IVF BLASTOCYSTS DERIVED FROM ANONYMOUS SPERM DONORS: ABSENCE OF INFORMED CONSENT Members of the scientific community raised concerns that the National Academies’ Guidelines require that donors of all embryos, gametes, and somatic cells give informed consent for the use of their tissues for the derivation of human embryonic stem cell lines. Specifically, Section 3.3 of the Guidelines states that “When donor gametes have been used in the IVF process, resulting blastocysts may not be used for research without consent of all gamete donors.” This requirement might preclude the use of frozen blastocysts from IVF clinics, which do not customarily request informed consent from sperm donors. The Committee, therefore, was asked to consider the effects this requirement might have on the available supply of

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research blastocysts for hES cell research and whether the population of frozen blastocysts now residing at IVF clinics needs to be “grandfathered” or exempt from the requirement for sperm donor consent. To evaluate these effects, the Committee contacted the Society for Assisted Reproductive Technology (SART), which is actively involved in the collection of data on outcomes from its member IVF clinics. SART works closely with the Centers for Disease Control and Prevention in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Wyden Act) to reflect accurately outcomes of the procedures commonly used in IVF practices.8 The information returned in response to the Committee’s request indicated that the number of blastocysts created with anonymous donor sperm in SART member practices is only about 3.5 percent.9 Given this small number, it is the Committee’s view that maintaining the requirement for sperm donor consent in cases where human embryonic stem cell lines are to be derived from excess IVF clinic blastocysts should not significantly affect the availability of blastocysts for donation to research. The Committee, therefore, has concluded that it is not necessary to modify the Guidelines by “grandfathering” the frozen embryo population in IVF clinics and exempting them from the informed consent requirement for sperm donors. In light of the inability to determine whether any of these donors would have foregone sperm donation had they known of possible nonreproductive uses of the resulting blastocysts, the existing Guidelines reasonably balance respect for the gamete donors’ expectations with the needs of the research community. CONSIDERING THE SCIENCE IN hES CELL RESEARCH PROPOSALS: ADVICE FOR ESCRO COMMITTEES It has been brought to the Committee’s attention that some ESCRO committees would appreciate additional guidance on how to evaluate research proposals that are submitted for ESCRO committee review. In several places, the Guidelines emphasize the need to consider the scientific rationale for an experiment as part of the ethical analysis of the experiment. Although this section of this report does not amend the Guidelines, the 8 See <http://www.sart.org/WhatIsSART.html> for more information about this data collection effort. 9 2004 SART CORS© database.

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2007 Amendments The National Academies’ Guidelines for Human Embryonic Stem Cell Research Committee has compiled a list of questions that ESCRO committees may wish to consider when evaluating the scientific aspects of proposals for research involving hES cells. Many of these questions are contained in the 2005 report Guidelines for Human Embryonic Stem Cell Research but are distributed throughout the report. Not all of these questions will be applicable to every situation. Neither will answers to these questions necessarily be definitive with respect to the acceptability of the proposed research. Their goal is to ensure that the relevant scientific and ethical issues are considered. Sample Questions for Reviewing hES Cell Research What is the scientific question being asked by the proposed research involving hES cells? Does the underlying hypothesis address an important scientific question? Could the question reasonably be addressed in any other way? Does the research team have the appropriate expertise and training in deriving or culturing either human or nonhuman stem cells? If training is the primary purpose of the proposal, is the training being conducted under the supervision of appropriate experts? Has the investigator articulated a compelling rationale for using human stem cells instead of nonhuman stem cells? Has the investigator articulated a compelling rationale for using hES cells instead of other types of stem cells? Has the investigator justified the selection of the stem cell line(s) to be used? Has the investigator articulated a rationale for creating a new stem cell line or could the proposed research be conducted with existing cell lines? If more than one cell line is to be derived, has the investigator justified the number he/she proposes to make? Additional questions arise in considering protocols involving introduction of hES cells or cellular derivatives thereof into an animal host to form a chimera. Some of those questions were addressed in the 2005 Guidelines for Human Embryonic Stem Cell Research, and the committee intends to revisit these issues in future discussions.

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