Oseltamivir Is Effective against 1918 Influenza Virus Infection of Macaques but Vulnerable to Escape
Identifieur interne : 000052 ( Pmc/Checkpoint ); précédent : 000051; suivant : 000053Oseltamivir Is Effective against 1918 Influenza Virus Infection of Macaques but Vulnerable to Escape
Auteurs : Friederike Feldmann [Canada, États-Unis] ; Darwyn Kobasa [Canada] ; Carissa Embury-Hyatt [Canada] ; Allen Grolla [Canada] ; Tracy Taylor [Canada] ; Maki Kiso [Japon] ; Satoshi Kakugawa [Japon] ; Jason Gren [Canada] ; Steven M. Jones [Canada] ; Yoshihiro Kawaoka [Japon, États-Unis] ; Heinz Feldmann [Canada, États-Unis]Source :
- mBio [ 2150-7511 ] ; 2019.
Abstract
Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.
Url:
DOI: 10.1128/mBio.02059-19
PubMed: 31641086
PubMed Central: 6805992
Affiliations:
- Canada, Japon, États-Unis
- Manitoba, Montana, Région de Kantō, Wisconsin
- Madison (Wisconsin), Tokyo, Winnipeg
- Université de Tokyo, Université du Manitoba, Université du Wisconsin à Madison
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id="aff1"><addr-line>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba</wicri:regionArea><wicri:noRegion>Manitoba</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2"><addr-line>Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Kobasa, Darwyn" sort="Kobasa, Darwyn" uniqKey="Kobasa D" first="Darwyn" last="Kobasa">Darwyn Kobasa</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba</wicri:regionArea><wicri:noRegion>Manitoba</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea><orgName type="university">Université du Manitoba</orgName><placeName><settlement type="city">Winnipeg</settlement><region type="state">Manitoba</region></placeName></affiliation></author><author><name sortKey="Embury Hyatt, Carissa" sort="Embury Hyatt, Carissa" uniqKey="Embury Hyatt C" first="Carissa" last="Embury-Hyatt">Carissa Embury-Hyatt</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba</wicri:regionArea><wicri:noRegion>Manitoba</wicri:noRegion></affiliation></author><author><name sortKey="Grolla, Allen" sort="Grolla, Allen" uniqKey="Grolla A" first="Allen" last="Grolla">Allen Grolla</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba</wicri:regionArea><wicri:noRegion>Manitoba</wicri:noRegion></affiliation></author><author><name sortKey="Taylor, Tracy" sort="Taylor, Tracy" uniqKey="Taylor T" first="Tracy" last="Taylor">Tracy Taylor</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba</wicri:regionArea><wicri:noRegion>Manitoba</wicri:noRegion></affiliation></author><author><name sortKey="Kiso, Maki" sort="Kiso, Maki" uniqKey="Kiso M" first="Maki" last="Kiso">Maki Kiso</name><affiliation wicri:level="4"><nlm:aff id="aff5"><addr-line>Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Kakugawa, Satoshi" sort="Kakugawa, Satoshi" uniqKey="Kakugawa S" first="Satoshi" last="Kakugawa">Satoshi Kakugawa</name><affiliation wicri:level="4"><nlm:aff id="aff5"><addr-line>Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Gren, Jason" sort="Gren, Jason" uniqKey="Gren J" first="Jason" last="Gren">Jason Gren</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba</wicri:regionArea><wicri:noRegion>Manitoba</wicri:noRegion></affiliation></author><author><name sortKey="Jones, Steven M" sort="Jones, Steven M" uniqKey="Jones S" first="Steven M." last="Jones">Steven M. Jones</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba</wicri:regionArea><wicri:noRegion>Manitoba</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan</wicri:regionArea><wicri:noRegion>Saskatchewan</wicri:noRegion></affiliation></author><author><name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name><affiliation wicri:level="4"><nlm:aff id="aff5"><addr-line>Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName><orgName type="university">Université de Tokyo</orgName><placeName><settlement type="city">Madison (Wisconsin)</settlement><region type="state">Wisconsin</region></placeName><orgName type="university" n="3">Université du Wisconsin à Madison</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="aff7"><addr-line>Department of Pathobiological Sciences, University of Wisconsin—Madison, Madison, Wisconsin, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathobiological Sciences, University of Wisconsin—Madison, Madison, Wisconsin</wicri:regionArea><placeName><region type="state">Wisconsin</region><settlement type="city">Madison (Wisconsin)</settlement></placeName><orgName type="university">Université du Wisconsin à Madison</orgName><placeName><settlement type="city">Madison (Wisconsin)</settlement><region type="state">Wisconsin</region></placeName><orgName type="university" n="3">Université du Wisconsin à Madison</orgName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama</wicri:regionArea><wicri:noRegion>Saitama</wicri:noRegion><placeName><settlement type="city">Tokyo</settlement><region type="province">Région de Kantō</region></placeName><orgName type="university" n="3">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Feldmann, Heinz" sort="Feldmann, Heinz" uniqKey="Feldmann H" first="Heinz" last="Feldmann">Heinz Feldmann</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba</wicri:regionArea><wicri:noRegion>Manitoba</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2"><addr-line>Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation><affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba</wicri:regionArea><orgName type="university">Université du Manitoba</orgName><placeName><settlement type="city">Winnipeg</settlement><region type="state">Manitoba</region></placeName></affiliation></author></analytic><series><title level="j">mBio</title><idno type="eISSN">2150-7511</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Taubenberger, Jk" uniqKey="Taubenberger J">JK Taubenberger</name></author><author><name sortKey="Reid, Ah" uniqKey="Reid A">AH Reid</name></author><author><name sortKey="Lourens, Rm" uniqKey="Lourens R">RM Lourens</name></author><author><name sortKey="Wang, R" uniqKey="Wang R">R Wang</name></author><author><name sortKey="Jin, G" uniqKey="Jin G">G Jin</name></author><author><name sortKey="Fanning, Tg" uniqKey="Fanning T">TG Fanning</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Taubenberger, Jk" uniqKey="Taubenberger J">JK Taubenberger</name></author><author><name sortKey="Hultin, Jv" uniqKey="Hultin J">JV Hultin</name></author><author><name sortKey="Morens, Dm" uniqKey="Morens D">DM 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<front><journal-meta><journal-id journal-id-type="nlm-ta">mBio</journal-id><journal-id journal-id-type="iso-abbrev">mBio</journal-id><journal-id journal-id-type="hwp">mbio</journal-id><journal-id journal-id-type="pmc">mbio</journal-id><journal-id journal-id-type="publisher-id">mBio</journal-id><journal-title-group><journal-title>mBio</journal-title></journal-title-group><issn pub-type="epub">2150-7511</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31641086</article-id><article-id pub-id-type="pmc">6805992</article-id><article-id pub-id-type="publisher-id">mBio02059-19</article-id><article-id pub-id-type="doi">10.1128/mBio.02059-19</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="overline"><subject>Therapeutics and Prevention</subject></subj-group></article-categories><title-group><article-title>Oseltamivir Is Effective against 1918 Influenza Virus Infection of Macaques but Vulnerable to Escape</article-title><alt-title alt-title-type="running-head">Oseltamivir Efficacy against 1918 Influenza Virus</alt-title><alt-title alt-title-type="short-authors">Feldmann et al.</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Feldmann</surname><given-names>Friederike</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-6371-7493</contrib-id><name><surname>Kobasa</surname><given-names>Darwyn</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Embury-Hyatt</surname><given-names>Carissa</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Grolla</surname><given-names>Allen</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Taylor</surname><given-names>Tracy</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Kiso</surname><given-names>Maki</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Kakugawa</surname><given-names>Satoshi</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Gren</surname><given-names>Jason</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Jones</surname><given-names>Steven M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author" corresp="yes" equal-contrib="no"><name><surname>Kawaoka</surname><given-names>Yoshihiro</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref><xref ref-type="aff" rid="aff7"><sup>g</sup></xref><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author" corresp="yes" equal-contrib="no"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-9448-8227</contrib-id><name><surname>Feldmann</surname><given-names>Heinz</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><aff id="aff1"><label>a</label><addr-line>National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada</addr-line></aff><aff id="aff2"><label>b</label><addr-line>Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA</addr-line></aff><aff id="aff3"><label>c</label><addr-line>Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada</addr-line></aff><aff id="aff4"><label>d</label><addr-line>National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada</addr-line></aff><aff id="aff5"><label>e</label><addr-line>Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line></aff><aff id="aff6"><label>f</label><addr-line>School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</addr-line></aff><aff id="aff7"><label>g</label><addr-line>Department of Pathobiological Sciences, University of Wisconsin—Madison, Madison, Wisconsin, USA</addr-line></aff><aff id="aff8"><label>h</label><addr-line>ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan</addr-line></aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Griffin</surname><given-names>Diane E.</given-names></name><role>Editor</role><aff>Johns Hopkins Bloomberg School of Public Health</aff></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Yoshihiro Kawaoka, <email>kawaokay@svm.vetmed.wisc.edu</email>, or Heinz Feldmann, <email>feldmannh@niaid.nih.gov</email>.</corresp><fn fn-type="equal"><p>F.F. and D.K. contributed equally to this article.</p></fn></author-notes><pub-date pub-type="epub"><day>22</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><season>Sep-Oct</season><year>2019</year></pub-date><volume>10</volume><issue>5</issue><elocation-id>e02059-19</elocation-id><history><date date-type="received"><day>5</day><month>8</month><year>2019</year></date><date date-type="accepted"><day>20</day><month>8</month><year>2019</year></date></history><permissions><license license-type="open-access" xlink:href="https://doi.org/10.1128/AuthorWarrantyLicense.v1"><license-p>This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="mBio.02059-19.pdf"></self-uri><abstract abstract-type="precis"><p>Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.</p></abstract><abstract><title>ABSTRACT</title><p>The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. <italic>In vitro</italic> studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug.</p></abstract><kwd-group><title>KEYWORDS</title><kwd>1918 influenza virus</kwd><kwd>treatment</kwd><kwd>oseltamivir</kwd><kwd>drug resistance</kwd></kwd-group><counts><count count="2" count-type="supplementary-material"></count><fig-count count="2"></fig-count><table-count count="2"></table-count><equation-count count="0"></equation-count><ref-count count="29"></ref-count><page-count count="9"></page-count><word-count count="6550"></word-count></counts><custom-meta-group><custom-meta><meta-name>cover-date</meta-name><meta-value>September/October 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>Canada</li><li>Japon</li><li>États-Unis</li></country><region><li>Manitoba</li><li>Montana</li><li>Région de Kantō</li><li>Wisconsin</li></region><settlement><li>Madison (Wisconsin)</li><li>Tokyo</li><li>Winnipeg</li></settlement><orgName><li>Université de Tokyo</li><li>Université du Manitoba</li><li>Université du Wisconsin à Madison</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Feldmann, Friederike" sort="Feldmann, Friederike" uniqKey="Feldmann F" first="Friederike" last="Feldmann">Friederike Feldmann</name></noRegion><name sortKey="Embury Hyatt, Carissa" sort="Embury Hyatt, Carissa" uniqKey="Embury Hyatt C" first="Carissa" last="Embury-Hyatt">Carissa Embury-Hyatt</name><name sortKey="Feldmann, Heinz" sort="Feldmann, Heinz" uniqKey="Feldmann H" first="Heinz" last="Feldmann">Heinz Feldmann</name><name sortKey="Feldmann, Heinz" sort="Feldmann, Heinz" uniqKey="Feldmann H" first="Heinz" last="Feldmann">Heinz Feldmann</name><name sortKey="Gren, Jason" sort="Gren, Jason" uniqKey="Gren J" first="Jason" last="Gren">Jason Gren</name><name sortKey="Grolla, Allen" sort="Grolla, Allen" uniqKey="Grolla A" first="Allen" last="Grolla">Allen Grolla</name><name sortKey="Jones, Steven M" sort="Jones, Steven M" uniqKey="Jones S" first="Steven M." last="Jones">Steven M. Jones</name><name sortKey="Jones, Steven M" sort="Jones, Steven M" uniqKey="Jones S" first="Steven M." last="Jones">Steven M. Jones</name><name sortKey="Kobasa, Darwyn" sort="Kobasa, Darwyn" uniqKey="Kobasa D" first="Darwyn" last="Kobasa">Darwyn Kobasa</name><name sortKey="Kobasa, Darwyn" sort="Kobasa, Darwyn" uniqKey="Kobasa D" first="Darwyn" last="Kobasa">Darwyn Kobasa</name><name sortKey="Taylor, Tracy" sort="Taylor, Tracy" uniqKey="Taylor T" first="Tracy" last="Taylor">Tracy Taylor</name></country><country name="États-Unis"><region name="Montana"><name sortKey="Feldmann, Friederike" sort="Feldmann, Friederike" uniqKey="Feldmann F" first="Friederike" last="Feldmann">Friederike Feldmann</name></region><name sortKey="Feldmann, Heinz" sort="Feldmann, Heinz" uniqKey="Feldmann H" first="Heinz" last="Feldmann">Heinz Feldmann</name><name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name></country><country name="Japon"><region name="Région de Kantō"><name sortKey="Kiso, Maki" sort="Kiso, Maki" uniqKey="Kiso M" first="Maki" last="Kiso">Maki Kiso</name></region><name sortKey="Kakugawa, Satoshi" sort="Kakugawa, Satoshi" uniqKey="Kakugawa S" first="Satoshi" last="Kakugawa">Satoshi Kakugawa</name><name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name><name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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