B-Lymphocyte Depletion With Rituximab and β-Cell Function: Two-Year Results
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Auteurs : Mark D. Pescovitz [États-Unis] ; Carla J. Greenbaum [États-Unis] ; Brian Bundy [États-Unis] ; Dorothy J. Becker [États-Unis] ; Stephen E. Gitelman [États-Unis] ; Robin Goland [États-Unis] ; Peter A. Gottlieb [États-Unis] ; Jennifer B. Marks [États-Unis] ; Antoinette Moran [États-Unis] ; Philip Raskin [États-Unis] ; Henry Rodriguez [États-Unis] ; Desmond A. Schatz [États-Unis] ; Diane K. Wherrett [Canada] ; Darrell M. Wilson [États-Unis] ; Jeffrey P. Krischer [États-Unis] ; Jay S. Skyler [États-Unis]Source :
- Diabetes Care [ 0149-5992 ] ; 2014.
Abstract
We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type 1 diabetes mellitus (T1DM) at 1 year. Subjects were followed further to determine whether there was persistence of effect.
Eighty-seven subjects (aged 8–40 years) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome—baseline-adjusted mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 1 year—showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months.
The rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects. Over 30 months, AUC, insulin dose, and HbA1c were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times with the placebo group means using a global test (
Like several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide but does not appear to fundamentally alter the underlying pathophysiology of the disease.
Url:
DOI: 10.2337/dc13-0626
PubMed: 24026563
PubMed Central: 3898764
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Schatz</name><affiliation wicri:level="2"><nlm:aff id="aff11">University of Florida, Gainesville, FL</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>University of Florida, Gainesville</wicri:cityArea></affiliation></author><author><name sortKey="Wherrett, Diane K" sort="Wherrett, Diane K" uniqKey="Wherrett D" first="Diane K." last="Wherrett">Diane K. Wherrett</name><affiliation wicri:level="1"><nlm:aff id="aff12">Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Hospital for Sick Children, University of Toronto, Toronto, Ontario</wicri:regionArea></affiliation></author><author><name sortKey="Wilson, Darrell M" sort="Wilson, Darrell M" uniqKey="Wilson D" first="Darrell M." last="Wilson">Darrell M. 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Skyler</name><affiliation wicri:level="2"><nlm:aff id="aff8">University of Miami Diabetes Research Institute, Miami, FL</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>University of Miami Diabetes Research Institute, Miami</wicri:cityArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24026563</idno><idno type="pmc">3898764</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898764</idno><idno type="RBID">PMC:3898764</idno><idno type="doi">10.2337/dc13-0626</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001A87</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001A87</idno><idno type="wicri:Area/Pmc/Curation">001A62</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001A62</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">B-Lymphocyte Depletion With Rituximab and β-Cell Function: Two-Year Results</title><author><name sortKey="Pescovitz, Mark D" sort="Pescovitz, Mark D" uniqKey="Pescovitz M" first="Mark D." last="Pescovitz">Mark D. Pescovitz</name><affiliation wicri:level="2"><nlm:aff id="aff1">Indiana University School of Medicine, Indianapolis, IN</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Indiana University School of Medicine, Indianapolis</wicri:cityArea></affiliation></author><author><name sortKey="Greenbaum, Carla J" sort="Greenbaum, Carla J" uniqKey="Greenbaum C" first="Carla J." last="Greenbaum">Carla J. Greenbaum</name><affiliation wicri:level="2"><nlm:aff id="aff2">Benaroya Research Institute, Seattle, WA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Washington (État)</region></placeName><wicri:cityArea>Benaroya Research Institute, Seattle</wicri:cityArea></affiliation></author><author><name sortKey="Bundy, Brian" sort="Bundy, Brian" uniqKey="Bundy B" first="Brian" last="Bundy">Brian Bundy</name><affiliation wicri:level="2"><nlm:aff id="aff3">University of South Florida, Tampa, FL</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>University of South Florida, Tampa</wicri:cityArea></affiliation></author><author><name sortKey="Becker, Dorothy J" sort="Becker, Dorothy J" uniqKey="Becker D" first="Dorothy J." last="Becker">Dorothy J. Becker</name><affiliation wicri:level="2"><nlm:aff id="aff4">University of Pittsburgh, Pittsburgh, PA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Gitelman, Stephen E" sort="Gitelman, Stephen E" uniqKey="Gitelman S" first="Stephen E." last="Gitelman">Stephen E. Gitelman</name><affiliation wicri:level="2"><nlm:aff id="aff5">University of California, San Francisco, San Francisco, CA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>University of California, San Francisco, San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Goland, Robin" sort="Goland, Robin" uniqKey="Goland R" first="Robin" last="Goland">Robin Goland</name><affiliation wicri:level="2"><nlm:aff id="aff6">Columbia University, New York, NY</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Columbia University, New York</wicri:cityArea></affiliation></author><author><name sortKey="Gottlieb, Peter A" sort="Gottlieb, Peter A" uniqKey="Gottlieb P" first="Peter A." last="Gottlieb">Peter A. Gottlieb</name><affiliation wicri:level="2"><nlm:aff id="aff7">University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Marks, Jennifer B" sort="Marks, Jennifer B" uniqKey="Marks J" first="Jennifer B." last="Marks">Jennifer B. Marks</name><affiliation wicri:level="2"><nlm:aff id="aff8">University of Miami Diabetes Research Institute, Miami, FL</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>University of Miami Diabetes Research Institute, Miami</wicri:cityArea></affiliation></author><author><name sortKey="Moran, Antoinette" sort="Moran, Antoinette" uniqKey="Moran A" first="Antoinette" last="Moran">Antoinette Moran</name><affiliation wicri:level="2"><nlm:aff id="aff9">University of Minnesota, Minneapolis, MN</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>University of Minnesota, Minneapolis</wicri:cityArea></affiliation></author><author><name sortKey="Raskin, Philip" sort="Raskin, Philip" uniqKey="Raskin P" first="Philip" last="Raskin">Philip Raskin</name><affiliation wicri:level="2"><nlm:aff id="aff10">University of Texas Southwestern Medical School, Dallas, TX</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>University of Texas Southwestern Medical School, Dallas</wicri:cityArea></affiliation></author><author><name sortKey="Rodriguez, Henry" sort="Rodriguez, Henry" uniqKey="Rodriguez H" first="Henry" last="Rodriguez">Henry Rodriguez</name><affiliation wicri:level="2"><nlm:aff id="aff1">Indiana University School of Medicine, Indianapolis, IN</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Indiana University School of Medicine, Indianapolis</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="aff3">University of South Florida, Tampa, FL</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>University of South Florida, Tampa</wicri:cityArea></affiliation></author><author><name sortKey="Schatz, Desmond A" sort="Schatz, Desmond A" uniqKey="Schatz D" first="Desmond A." last="Schatz">Desmond A. Schatz</name><affiliation wicri:level="2"><nlm:aff id="aff11">University of Florida, Gainesville, FL</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>University of Florida, Gainesville</wicri:cityArea></affiliation></author><author><name sortKey="Wherrett, Diane K" sort="Wherrett, Diane K" uniqKey="Wherrett D" first="Diane K." last="Wherrett">Diane K. Wherrett</name><affiliation wicri:level="1"><nlm:aff id="aff12">Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Hospital for Sick Children, University of Toronto, Toronto, Ontario</wicri:regionArea></affiliation></author><author><name sortKey="Wilson, Darrell M" sort="Wilson, Darrell M" uniqKey="Wilson D" first="Darrell M." last="Wilson">Darrell M. Wilson</name><affiliation wicri:level="2"><nlm:aff id="aff13">Stanford University, Stanford, CA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Stanford University, Stanford</wicri:cityArea></affiliation></author><author><name sortKey="Krischer, Jeffrey P" sort="Krischer, Jeffrey P" uniqKey="Krischer J" first="Jeffrey P." last="Krischer">Jeffrey P. Krischer</name><affiliation wicri:level="2"><nlm:aff id="aff3">University of South Florida, Tampa, FL</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>University of South Florida, Tampa</wicri:cityArea></affiliation></author><author><name sortKey="Skyler, Jay S" sort="Skyler, Jay S" uniqKey="Skyler J" first="Jay S." last="Skyler">Jay S. Skyler</name><affiliation wicri:level="2"><nlm:aff id="aff8">University of Miami Diabetes Research Institute, Miami, FL</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>University of Miami Diabetes Research Institute, Miami</wicri:cityArea></affiliation></author></analytic><series><title level="j">Diabetes Care</title><idno type="ISSN">0149-5992</idno><idno type="eISSN">1935-5548</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>OBJECTIVE</title><p>We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type 1 diabetes mellitus (T1DM) at 1 year. Subjects were followed further to determine whether there was persistence of effect.</p></sec><sec><title>RESEARCH DESIGN AND METHODS</title><p>Eighty-seven subjects (aged 8–40 years) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome—baseline-adjusted mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 1 year—showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months.</p></sec><sec><title>RESULTS</title><p>The rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects. Over 30 months, AUC, insulin dose, and HbA<sub>1c</sub> were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times with the placebo group means using a global test (<italic>P</italic> = 0.03). Odds ratio for loss of C-peptide to <0.2 nmol/L following rituximab was 0.565 (<italic>P</italic> = 0.064). B-lymphocytes recovered to baseline values by 18 months. Serum IgG levels were maintained in the normal range but IgM levels were depressed.</p></sec><sec><title>CONCLUSIONS</title><p>Like several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide but does not appear to fundamentally alter the underlying pathophysiology of the disease.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Steffes, Mw" uniqKey="Steffes M">MW Steffes</name></author><author><name sortKey="Sibley, S" uniqKey="Sibley S">S Sibley</name></author><author><name sortKey="Jackson, M" uniqKey="Jackson M">M Jackson</name></author><author><name sortKey="Thomas, W" uniqKey="Thomas W">W Thomas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Herold, Kc" uniqKey="Herold K">KC Herold</name></author><author><name sortKey="Hagopian, W" uniqKey="Hagopian W">W Hagopian</name></author><author><name sortKey="Auger, 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uniqKey="Peter H">HH Peter</name></author><author><name sortKey="Warnatz, K" uniqKey="Warnatz K">K Warnatz</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Diabetes Care</journal-id><journal-id journal-id-type="iso-abbrev">Diabetes Care</journal-id><journal-id journal-id-type="hwp">diacare</journal-id><journal-id journal-id-type="pmc">dcare</journal-id><journal-id journal-id-type="publisher-id">Diabetes Care</journal-id><journal-title-group><journal-title>Diabetes Care</journal-title></journal-title-group><issn pub-type="ppub">0149-5992</issn><issn pub-type="epub">1935-5548</issn><publisher><publisher-name>American Diabetes Association</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24026563</article-id><article-id pub-id-type="pmc">3898764</article-id><article-id pub-id-type="publisher-id">0626</article-id><article-id pub-id-type="doi">10.2337/dc13-0626</article-id><article-categories><subj-group subj-group-type="heading"><subject>Emerging Technologies and Therapeutics</subject></subj-group></article-categories><title-group><article-title>B-Lymphocyte Depletion With Rituximab and β-Cell Function: Two-Year Results</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Pescovitz</surname><given-names>Mark D.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="fn" rid="fn3">†</xref></contrib><contrib contrib-type="author"><name><surname>Greenbaum</surname><given-names>Carla J.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bundy</surname><given-names>Brian</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Becker</surname><given-names>Dorothy J.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gitelman</surname><given-names>Stephen E.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Goland</surname><given-names>Robin</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gottlieb</surname><given-names>Peter A.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Marks</surname><given-names>Jennifer B.</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Moran</surname><given-names>Antoinette</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Raskin</surname><given-names>Philip</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rodriguez</surname><given-names>Henry</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schatz</surname><given-names>Desmond A.</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wherrett</surname><given-names>Diane K.</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wilson</surname><given-names>Darrell M.</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Krischer</surname><given-names>Jeffrey P.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Skyler</surname><given-names>Jay S.</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref><xref ref-type="corresp" rid="cor1"></xref></contrib><contrib contrib-type="author"><collab>the Type 1 Diabetes TrialNet Anti-CD20 Study Group</collab><xref ref-type="fn" rid="fn4">*</xref></contrib><aff id="aff1"><sup>1</sup>Indiana University School of Medicine, Indianapolis, IN</aff><aff id="aff2"><sup>2</sup>Benaroya Research Institute, Seattle, WA</aff><aff id="aff3"><sup>3</sup>University of South Florida, Tampa, FL</aff><aff id="aff4"><sup>4</sup>University of Pittsburgh, Pittsburgh, PA</aff><aff id="aff5"><sup>5</sup>University of California, San Francisco, San Francisco, CA</aff><aff id="aff6"><sup>6</sup>Columbia University, New York, NY</aff><aff id="aff7"><sup>7</sup>University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO</aff><aff id="aff8"><sup>8</sup>University of Miami Diabetes Research Institute, Miami, FL</aff><aff id="aff9"><sup>9</sup>University of Minnesota, Minneapolis, MN</aff><aff id="aff10"><sup>10</sup>University of Texas Southwestern Medical School, Dallas, TX</aff><aff id="aff11"><sup>11</sup>University of Florida, Gainesville, FL</aff><aff id="aff12"><sup>12</sup>Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada</aff><aff id="aff13"><sup>13</sup>Stanford University, Stanford, CA</aff></contrib-group><author-notes><corresp id="cor1">Corresponding author: Jay S. Skyler, <email>jskyler@miami.edu</email>.</corresp></author-notes><pub-date pub-type="ppub"><month>2</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>11</day><month>1</month><year>2014</year></pub-date><volume>37</volume><issue>2</issue><fpage>453</fpage><lpage>459</lpage><history><date date-type="received"><day>13</day><month>3</month><year>2013</year></date><date date-type="accepted"><day>6</day><month>9</month><year>2013</year></date></history><permissions><copyright-statement>© 2014 by the American Diabetes Association.</copyright-statement><copyright-year>2014</copyright-year><license license-type="creative-commons"><license-p>Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/3.0/">http://creativecommons.org/licenses/by-nc-nd/3.0/</ext-link> for details.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="453.pdf"></self-uri><abstract><sec><title>OBJECTIVE</title><p>We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type 1 diabetes mellitus (T1DM) at 1 year. Subjects were followed further to determine whether there was persistence of effect.</p></sec><sec><title>RESEARCH DESIGN AND METHODS</title><p>Eighty-seven subjects (aged 8–40 years) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome—baseline-adjusted mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 1 year—showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months.</p></sec><sec><title>RESULTS</title><p>The rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects. Over 30 months, AUC, insulin dose, and HbA<sub>1c</sub> were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times with the placebo group means using a global test (<italic>P</italic> = 0.03). Odds ratio for loss of C-peptide to <0.2 nmol/L following rituximab was 0.565 (<italic>P</italic> = 0.064). B-lymphocytes recovered to baseline values by 18 months. Serum IgG levels were maintained in the normal range but IgM levels were depressed.</p></sec><sec><title>CONCLUSIONS</title><p>Like several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide but does not appear to fundamentally alter the underlying pathophysiology of the disease.</p></sec></abstract><counts><page-count count="7"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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