Immuno-epidemiologic Correlates of Pandemic H1N1 Surveillance Observations: Higher Antibody and Lower Cell-Mediated Immune Responses with Advanced Age
Identifieur interne : 000628 ( Pmc/Curation ); précédent : 000627; suivant : 000629Immuno-epidemiologic Correlates of Pandemic H1N1 Surveillance Observations: Higher Antibody and Lower Cell-Mediated Immune Responses with Advanced Age
Auteurs : Danuta M. Skowronski ; Travis S. Hottes ; Janet E. Mcelhaney [Canada] ; Naveed Z. Janjua ; Suzana Sabaiduc ; Tracy Chan ; Beth Gentleman [Canada] ; Dale Purych ; Jennifer Gardy ; David M. Patrick ; Robert C. Brunham ; Gaston De Serres [Canada] ; Martin PetricSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2011.
Abstract
Url:
DOI: 10.1093/infdis/jiq039
PubMed: 21288814
PubMed Central: 3071066
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: Pour aller vers cette notice dans l'étape Curation :000628
Links to Exploration step
PMC:3071066Curation
No country items
Dale Purych<affiliation><nlm:aff id="aff7">BC Biomedical Laboratories Ltd, Surrey, British Columbia</nlm:aff><wicri:noCountry code="subfield">British Columbia</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff5">Department of Pathology and Laboratory Medicine, University of British Columbia</nlm:aff><wicri:noCountry code="subfield">University of British Columbia</wicri:noCountry></affiliation>Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Immuno-epidemiologic Correlates of Pandemic H1N1 Surveillance Observations: Higher Antibody and Lower Cell-Mediated Immune Responses with Advanced Age</title><author><name sortKey="Skowronski, Danuta M" sort="Skowronski, Danuta M" uniqKey="Skowronski D" first="Danuta M." last="Skowronski">Danuta M. Skowronski</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Population and Public Health</nlm:aff></affiliation></author><author><name sortKey="Hottes, Travis S" sort="Hottes, Travis S" uniqKey="Hottes T" first="Travis S." last="Hottes">Travis S. Hottes</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation></author><author><name sortKey="Mcelhaney, Janet E" sort="Mcelhaney, Janet E" uniqKey="Mcelhaney J" first="Janet E." last="Mcelhaney">Janet E. Mcelhaney</name><affiliation><nlm:aff id="aff3">Department of Medicine</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6">Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea></affiliation></author><author><name sortKey="Janjua, Naveed Z" sort="Janjua, Naveed Z" uniqKey="Janjua N" first="Naveed Z." last="Janjua">Naveed Z. Janjua</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Population and Public Health</nlm:aff></affiliation></author><author><name sortKey="Sabaiduc, Suzana" sort="Sabaiduc, Suzana" uniqKey="Sabaiduc S" first="Suzana" last="Sabaiduc">Suzana Sabaiduc</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation></author><author><name sortKey="Chan, Tracy" sort="Chan, Tracy" uniqKey="Chan T" first="Tracy" last="Chan">Tracy Chan</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation></author><author><name sortKey="Gentleman, Beth" sort="Gentleman, Beth" uniqKey="Gentleman B" first="Beth" last="Gentleman">Beth Gentleman</name><affiliation><nlm:aff id="aff3">Department of Medicine</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6">Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea></affiliation></author><author><name sortKey="Purych, Dale" sort="Purych, Dale" uniqKey="Purych D" first="Dale" last="Purych">Dale Purych</name><affiliation><nlm:aff id="aff7">BC Biomedical Laboratories Ltd, Surrey, British Columbia</nlm:aff><wicri:noCountry code="subfield">British Columbia</wicri:noCountry></affiliation></author><author><name sortKey="Gardy, Jennifer" sort="Gardy, Jennifer" uniqKey="Gardy J" first="Jennifer" last="Gardy">Jennifer Gardy</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Microbiology and Immunology</nlm:aff></affiliation></author><author><name sortKey="Patrick, David M" sort="Patrick, David M" uniqKey="Patrick D" first="David M." last="Patrick">David M. Patrick</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Population and Public Health</nlm:aff></affiliation></author><author><name sortKey="Brunham, Robert C" sort="Brunham, Robert C" uniqKey="Brunham R" first="Robert C." last="Brunham">Robert C. Brunham</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="De Serres, Gaston" sort="De Serres, Gaston" uniqKey="De Serres G" first="Gaston" last="De Serres">Gaston De Serres</name><affiliation><nlm:aff id="aff8">Institut national de santé publique du Québec</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9">Department of Social and Preventive Medicine, Université Laval, Québec, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Social and Preventive Medicine, Université Laval, Québec</wicri:regionArea></affiliation></author><author><name sortKey="Petric, Martin" sort="Petric, Martin" uniqKey="Petric M" first="Martin" last="Petric">Martin Petric</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Pathology and Laboratory Medicine, University of British Columbia</nlm:aff><wicri:noCountry code="subfield">University of British Columbia</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21288814</idno><idno type="pmc">3071066</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071066</idno><idno type="RBID">PMC:3071066</idno><idno type="doi">10.1093/infdis/jiq039</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000628</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000628</idno><idno type="wicri:Area/Pmc/Curation">000628</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000628</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Immuno-epidemiologic Correlates of Pandemic H1N1 Surveillance Observations: Higher Antibody and Lower Cell-Mediated Immune Responses with Advanced Age</title><author><name sortKey="Skowronski, Danuta M" sort="Skowronski, Danuta M" uniqKey="Skowronski D" first="Danuta M." last="Skowronski">Danuta M. Skowronski</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Population and Public Health</nlm:aff></affiliation></author><author><name sortKey="Hottes, Travis S" sort="Hottes, Travis S" uniqKey="Hottes T" first="Travis S." last="Hottes">Travis S. Hottes</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation></author><author><name sortKey="Mcelhaney, Janet E" sort="Mcelhaney, Janet E" uniqKey="Mcelhaney J" first="Janet E." last="Mcelhaney">Janet E. Mcelhaney</name><affiliation><nlm:aff id="aff3">Department of Medicine</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6">Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea></affiliation></author><author><name sortKey="Janjua, Naveed Z" sort="Janjua, Naveed Z" uniqKey="Janjua N" first="Naveed Z." last="Janjua">Naveed Z. Janjua</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Population and Public Health</nlm:aff></affiliation></author><author><name sortKey="Sabaiduc, Suzana" sort="Sabaiduc, Suzana" uniqKey="Sabaiduc S" first="Suzana" last="Sabaiduc">Suzana Sabaiduc</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation></author><author><name sortKey="Chan, Tracy" sort="Chan, Tracy" uniqKey="Chan T" first="Tracy" last="Chan">Tracy Chan</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation></author><author><name sortKey="Gentleman, Beth" sort="Gentleman, Beth" uniqKey="Gentleman B" first="Beth" last="Gentleman">Beth Gentleman</name><affiliation><nlm:aff id="aff3">Department of Medicine</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6">Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea></affiliation></author><author><name sortKey="Purych, Dale" sort="Purych, Dale" uniqKey="Purych D" first="Dale" last="Purych">Dale Purych</name><affiliation><nlm:aff id="aff7">BC Biomedical Laboratories Ltd, Surrey, British Columbia</nlm:aff><wicri:noCountry code="subfield">British Columbia</wicri:noCountry></affiliation></author><author><name sortKey="Gardy, Jennifer" sort="Gardy, Jennifer" uniqKey="Gardy J" first="Jennifer" last="Gardy">Jennifer Gardy</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Microbiology and Immunology</nlm:aff></affiliation></author><author><name sortKey="Patrick, David M" sort="Patrick, David M" uniqKey="Patrick D" first="David M." last="Patrick">David M. Patrick</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Population and Public Health</nlm:aff></affiliation></author><author><name sortKey="Brunham, Robert C" sort="Brunham, Robert C" uniqKey="Brunham R" first="Robert C." last="Brunham">Robert C. Brunham</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Medicine</nlm:aff></affiliation></author><author><name sortKey="De Serres, Gaston" sort="De Serres, Gaston" uniqKey="De Serres G" first="Gaston" last="De Serres">Gaston De Serres</name><affiliation><nlm:aff id="aff8">Institut national de santé publique du Québec</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9">Department of Social and Preventive Medicine, Université Laval, Québec, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Social and Preventive Medicine, Université Laval, Québec</wicri:regionArea></affiliation></author><author><name sortKey="Petric, Martin" sort="Petric, Martin" uniqKey="Petric M" first="Martin" last="Petric">Martin Petric</name><affiliation><nlm:aff id="aff1">British Columbia Centre for Disease Control</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Pathology and Laboratory Medicine, University of British Columbia</nlm:aff><wicri:noCountry code="subfield">University of British Columbia</wicri:noCountry></affiliation></author></analytic><series><title level="j">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><bold><italic>Background.</italic></bold> Pandemic H1N1 (pH1N1) surveillance data showed lower attack rates but higher risk of severe outcomes with advanced age. We explored immuno-epidemiologic correlates of surveillance findings including humoral and cell-mediated immunity (CMI).</p><p><bold><italic>Methods.</italic></bold> In an age-based design, ∼100 banked/residual sera per 10-year age stratum were assessed by hemagglutination inhibition (HI) and microneutralization (MN) assays for preexisting antibody to pH1N1 and recent seasonal H1N1 and H3N2 strains. In a separate birth cohort design defined by childhood influenza A/subtype priming (1919–1929: H1N1; 1945–1949: H1N1; 1958–1960: H2N2; 1969–1970: H3N2; 1978–1989: H3N2/H1N1), whole blood was collected from up to 50 volunteers per birth cohort. The ratio of Th1(IFN-γ):Th2(IL-10) cytokine responses was evaluated in vitro.</p><p><bold><italic>Results.</italic></bold> Antibody to seasonal viruses was highest in school-age children. Cross-reactive HI/MN antibody to pH1N1 was low among participants <70 years of age (yoa; 6%/4% ≥ 40), but seroprevalence increased at 70–79 yoa (27%/6%), increased even more at 80–89 yoa (65%/47%), and was highest at ≥90 yoa (88%/76%). CMI to pH1N1 was evident in all 5 birth cohorts but was lower compared with seasonal strains. There was little differentiation by subtype priming, but the Th1:Th2 ratio for all viruses dropped significantly in the 2 oldest cohorts.</p><p><bold><italic>Conclusions.</italic></bold> Preexisting antibody may have protected the very old from pH1N1 infection, while diminished CMI may have contributed to greater severity once infected. In the young, cross-reactive pH1N1 antibody was mostly absent, while more intact CMI may have protected against severe outcomes.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Infect Dis</journal-id><journal-id journal-id-type="hwp">jinfdis</journal-id><journal-id journal-id-type="publisher-id">jinfdis</journal-id><journal-title-group><journal-title>The Journal of Infectious Diseases</journal-title></journal-title-group><issn pub-type="ppub">0022-1899</issn><issn pub-type="epub">1537-6613</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21288814</article-id><article-id pub-id-type="pmc">3071066</article-id><article-id pub-id-type="doi">10.1093/infdis/jiq039</article-id><article-categories><subj-group subj-group-type="heading"><subject>Major Articles and Brief Reports</subject><subj-group><subject>Viruses</subject></subj-group></subj-group></article-categories><title-group><article-title>Immuno-epidemiologic Correlates of Pandemic H1N1 Surveillance Observations: Higher Antibody and Lower Cell-Mediated Immune Responses with Advanced Age</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Skowronski</surname><given-names>Danuta M.</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hottes</surname><given-names>Travis S.</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>McElhaney</surname><given-names>Janet E.</given-names></name><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Janjua</surname><given-names>Naveed Z.</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Sabaiduc</surname><given-names>Suzana</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chan</surname><given-names>Tracy</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gentleman</surname><given-names>Beth</given-names></name><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Purych</surname><given-names>Dale</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Gardy</surname><given-names>Jennifer</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Patrick</surname><given-names>David M.</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Brunham</surname><given-names>Robert C.</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>De Serres</surname><given-names>Gaston</given-names></name><xref ref-type="aff" rid="aff8">8</xref><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Petric</surname><given-names>Martin</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff5">5</xref></contrib></contrib-group><aff id="aff1"><label>1</label>British Columbia Centre for Disease Control</aff><aff id="aff2"><label>2</label>School of Population and Public Health</aff><aff id="aff3"><label>3</label>Department of Medicine</aff><aff id="aff4"><label>4</label>Department of Microbiology and Immunology</aff><aff id="aff5"><label>5</label>Department of Pathology and Laboratory Medicine, University of British Columbia</aff><aff id="aff6"><label>6</label>Vancouver Coastal Health Research Institute, Vancouver, Canada</aff><aff id="aff7"><label>7</label>BC Biomedical Laboratories Ltd, Surrey, British Columbia</aff><aff id="aff8"><label>8</label>Institut national de santé publique du Québec</aff><aff id="aff9"><label>9</label>Department of Social and Preventive Medicine, Université Laval, Québec, Canada</aff><author-notes><corresp>Reprints or correspondence: Dr Danuta M. Skowronski, BC Center for Disease Control, 655 West 12<sup>th</sup> Ave., Vancouver, BC, V5Z 4R4, Canada (<email>danuta.skowronski@bccdc.ca</email>).</corresp><fn><p>Potential conflicts of interest: J.E.M, has received research grant funding from GlaxoSmithKline and Merck Frosst for separate studies, has received honoraria for presentations from Merck Frosst and Sanofi and for advisory committee participation from GlaxoSmithKline, and has served as a consultant to data monitoring committees for Sanofi. D.M.S. and G.D.S. have previously received research grant support from Sanofi-Pasteur and GlaxoSmithKline for separate studies. No other authors have potential conflicts of interest to declare.</p></fn><fn><p>Presented in part: 13th Annual Conference on Vaccine Research in Bethesda, Maryland, 26–28 April 2010 (abstract S10); and the 2010 Options VII Conference, Hong Kong, China, 3–7 September 2010 (P-416).</p></fn></author-notes><pub-date pub-type="ppub"><day>15</day><month>1</month><year>2011</year></pub-date><volume>203</volume><issue>2</issue><fpage>158</fpage><lpage>167</lpage><permissions><copyright-statement>© The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com</copyright-statement><copyright-year>2010</copyright-year></permissions><abstract><p><bold><italic>Background.</italic></bold> Pandemic H1N1 (pH1N1) surveillance data showed lower attack rates but higher risk of severe outcomes with advanced age. We explored immuno-epidemiologic correlates of surveillance findings including humoral and cell-mediated immunity (CMI).</p><p><bold><italic>Methods.</italic></bold> In an age-based design, ∼100 banked/residual sera per 10-year age stratum were assessed by hemagglutination inhibition (HI) and microneutralization (MN) assays for preexisting antibody to pH1N1 and recent seasonal H1N1 and H3N2 strains. In a separate birth cohort design defined by childhood influenza A/subtype priming (1919–1929: H1N1; 1945–1949: H1N1; 1958–1960: H2N2; 1969–1970: H3N2; 1978–1989: H3N2/H1N1), whole blood was collected from up to 50 volunteers per birth cohort. The ratio of Th1(IFN-γ):Th2(IL-10) cytokine responses was evaluated in vitro.</p><p><bold><italic>Results.</italic></bold> Antibody to seasonal viruses was highest in school-age children. Cross-reactive HI/MN antibody to pH1N1 was low among participants <70 years of age (yoa; 6%/4% ≥ 40), but seroprevalence increased at 70–79 yoa (27%/6%), increased even more at 80–89 yoa (65%/47%), and was highest at ≥90 yoa (88%/76%). CMI to pH1N1 was evident in all 5 birth cohorts but was lower compared with seasonal strains. There was little differentiation by subtype priming, but the Th1:Th2 ratio for all viruses dropped significantly in the 2 oldest cohorts.</p><p><bold><italic>Conclusions.</italic></bold> Preexisting antibody may have protected the very old from pH1N1 infection, while diminished CMI may have contributed to greater severity once infected. In the young, cross-reactive pH1N1 antibody was mostly absent, while more intact CMI may have protected against severe outcomes.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/H2N2V1/Data/Pmc/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000628 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd -nk 000628 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= H2N2V1
|flux= Pmc
|étape= Curation
|type= RBID
|clé= PMC:3071066
|texte= Immuno-epidemiologic Correlates of Pandemic H1N1 Surveillance Observations: Higher Antibody and Lower Cell-Mediated Immune Responses with Advanced Age
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Curation/RBID.i -Sk "pubmed:21288814" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd \
| NlmPubMed2Wicri -a H2N2V1
| This area was generated with Dilib version V0.6.33. |  |