Neuraminidase Inhibitor Resistance in Influenza: Assessing the Danger of Its Generation and Spread
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{"title"=>"Neuraminidase inhibitor resistance in influenza: Assessing the danger of its generation and spread", "type"=>"journal", "authors"=>[{"first_name"=>"Andreas", "last_name"=>"Handel", "scopus_author_id"=>"15047983400"}, {"first_name"=>"Ira M.", "last_name"=>"Longini", "scopus_author_id"=>"26643585800"}, {"first_name"=>"Rustom", "last_name"=>"Antia", "scopus_author_id"=>"7004173216"}], "year"=>2007, "source"=>"PLoS Computational Biology", "identifiers"=>{"scopus"=>"2-s2.0-37849032458", "sgr"=>"37849032458", "issn"=>"1553734X", "doi"=>"10.1371/journal.pcbi.0030240", "pmid"=>"18069885", "isbn"=>"1553-7358", "pui"=>"351041300"}, "id"=>"41287bf6-1fc6-3a43-9f54-e8ae8167d2aa", "abstract"=>"Neuraminidase Inhibitors (NI) are currently the most effective drugs against influenza. Recent cases of NI resistance are a cause for concern. To assess the danger of NI resistance, a number of studies have reported the fraction of treated patients from which resistant strains could be isolated. Unfortunately, those results strongly depend on the details of the experimental protocol. Additionally, knowing the fraction of patients harboring resistance is not too useful by itself. Instead, we want to know how likely it is that an infected patient can generate a resistant infection in a secondary host, and how likely it is that the resistant strain subsequently spreads. While estimates for these parameters can often be obtained from epidemiological data, such data is lacking for NI resistance in influenza. Here, we use an approach that does not rely on epidemiological data. Instead, we combine data from influenza infections of human volunteers with a mathematical framework that allows estimation of the parameters that govern the initial generation and subsequent spread of resistance. We show how these parameters are influenced by changes in drug efficacy, timing of treatment, fitness of the resistant strain, and details of virus and immune system dynamics. Our study provides estimates for parameters that can be directly used in mathematical and computational models to study how NI usage might lead to the emergence and spread of resistance in the population. We find that the initial generation of resistant cases is most likely lower than the fraction of resistant cases reported. However, we also show that the results depend strongly on the details of the within-host dynamics of influenza infections, and most importantly, the role the immune system plays. Better knowledge of the quantitative dynamics of the immune response during influenza infections will be crucial to further improve the results.", "link"=>"http://www.mendeley.com/research/neuraminidase-inhibitor-resistance-influenza-assessing-danger-generation-spread", "reader_count"=>72, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>9, "Student > Doctoral Student"=>3, "Researcher"=>21, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>4, "Other"=>4, "Student > Bachelor"=>7, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>9, "Student > Doctoral Student"=>3, "Researcher"=>21, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>4, "Other"=>4, "Student > Bachelor"=>7, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>8, "Engineering"=>3, "Environmental Science"=>3, "Biochemistry, Genetics and Molecular Biology"=>3, "Mathematics"=>10, "Agricultural and Biological Sciences"=>26, "Medicine and Dentistry"=>12, "Physics and Astronomy"=>1, "Psychology"=>1, "Computer Science"=>2, "Immunology and Microbiology"=>2, "Linguistics"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>12}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>26}, "Computer Science"=>{"Computer Science"=>2}, "Linguistics"=>{"Linguistics"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Mathematics"=>{"Mathematics"=>10}, "Unspecified"=>{"Unspecified"=>8}, "Environmental Science"=>{"Environmental Science"=>3}}, "reader_count_by_country"=>{"United States"=>4, "Italy"=>1, "Australia"=>1, "Switzerland"=>1}, "group_count"=>7}

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  • {"month"=>"5", "year"=>"2019", "pdf_views"=>"6", "xml_views"=>"0", "html_views"=>"6"}
  • {"month"=>"6", "year"=>"2019", "pdf_views"=>"9", "xml_views"=>"1", "html_views"=>"4"}
  • {"month"=>"7", "year"=>"2019", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"6"}
  • {"month"=>"8", "year"=>"2019", "pdf_views"=>"4", "xml_views"=>"0", "html_views"=>"3"}
  • {"month"=>"9", "year"=>"2019", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"11"}
  • {"month"=>"10", "year"=>"2019", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"7"}
  • {"month"=>"11", "year"=>"2019", "pdf_views"=>"6", "xml_views"=>"0", "html_views"=>"2"}
  • {"month"=>"12", "year"=>"2019", "pdf_views"=>"16", "xml_views"=>"0", "html_views"=>"8"}
  • {"month"=>"1", "year"=>"2020", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"6"}
  • {"month"=>"2", "year"=>"2020", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"4"}
  • {"month"=>"3", "year"=>"2020", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"14"}
  • {"month"=>"4", "year"=>"2020", "pdf_views"=>"8", "xml_views"=>"1", "html_views"=>"4"}
  • {"month"=>"5", "year"=>"2020", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"5"}
  • {"month"=>"6", "year"=>"2020", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"7"}
  • {"month"=>"7", "year"=>"2020", "pdf_views"=>"6", "xml_views"=>"1", "html_views"=>"12"}
  • {"month"=>"8", "year"=>"2020", "pdf_views"=>"1", "xml_views"=>"0", "html_views"=>"4"}
  • {"month"=>"9", "year"=>"2020", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"10"}

Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/940905"], "description"=>"<p>Schematic of Resistance Generation and Spread</p>", "links"=>[], "tags"=>["immunology", "Infectious diseases", "mathematics", "Virology"], "article_id"=>611330, "categories"=>["Virology", "Mathematics", "Infectious Diseases", "Immunology"], "users"=>["Andreas Handel", "Ira M Longini Jr.", "Rustom Antia"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.0030240.g003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_of_Resistance_Generation_and_Spread_/611330", "title"=>"Schematic of Resistance Generation and Spread", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 11:25:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/940970"], "description"=>"<p>Results are shown for both deterministic and stochastic simulations. Unless varied, treatment starts 24 h post-infection, and the other parameters are as shown in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0030240#pcbi-0030240-t002\" target=\"_blank\">Table 2</a>.</p>", "links"=>[], "tags"=>["td", "ir"], "article_id"=>611396, "categories"=>["Virology", "Mathematics", "Infectious Diseases", "Immunology"], "users"=>["Andreas Handel", "Ira M Longini Jr.", "Rustom Antia"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.0030240.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generation_of_Resistance_as_Measured_by_for_the_TD_Model_No_Immune_Response_and_IR_Model_with_Immune_Response_/611396", "title"=>"Generation of Resistance, as Measured by , for the TD Model (No Immune Response) and IR Model (with Immune Response)", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 11:25:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/941420"], "description"=>"<p>Unless varied, treatment starts 24 h post-infection, and antiviral efficacy is <i>a</i> = 0.99/0.97. Red = TD model, blue = IR model.</p>", "links"=>[], "tags"=>["antiviral"], "article_id"=>611847, "categories"=>["Virology", "Mathematics", "Infectious Diseases", "Immunology"], "users"=>["Andreas Handel", "Ira M Longini Jr.", "Rustom Antia"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.0030240.g008", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_as_a_Function_of_Treatment_Start_and_Antiviral_Efficacy_/611847", "title"=>"as a Function of Treatment Start and Antiviral Efficacy", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 11:28:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/940782"], "description"=>"<p>Data are from [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0030240#pcbi-0030240-b042\" target=\"_blank\">42</a>] (squares) and [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0030240#pcbi-0030240-b043\" target=\"_blank\">43</a>] (circles). Also shown is the best fit for the function <i>s</i> (Equation 1). Note that daily discharge is measured in grams; we make the approximation that one gram corresponds to 1 ml in volume.</p>", "links"=>[], "tags"=>["discharge", "viral"], "article_id"=>611212, "categories"=>["Virology", "Mathematics", "Infectious Diseases", "Immunology"], "users"=>["Andreas Handel", "Ira M Longini Jr.", "Rustom Antia"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.0030240.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nasal_Discharge_Weight_as_a_Function_of_Viral_Load_/611212", "title"=>"Nasal Discharge Weight as a Function of Viral Load", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 11:24:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/941334"], "description"=>"<p>Shown are results for the model without () and with () behavioral component for both the stochastic and the deterministic simulations. Unless varied, treatment starts 24 h post-infection, the fitness cost is <i>c</i> = 0.1, antiviral efficacy is <i>a</i> = 0.97, and the mutation rate is μ = 10<sup>−5</sup>.</p>", "links"=>[], "tags"=>["ir"], "article_id"=>611760, "categories"=>["Virology", "Mathematics", "Infectious Diseases", "Immunology"], "users"=>["Andreas Handel", "Ira M Longini Jr.", "Rustom Antia"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.0030240.g007", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generation_of_Resistance_for_the_IR_Model_/611760", "title"=>"Generation of Resistance for the IR Model", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 11:27:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/941089"], "description"=>"<p>Note that only variation in the fitness cost has an impact on <i>R<sub>r</sub></i> since treatment does not affect the resistant strain.</p>", "links"=>[], "tags"=>["immunology", "Infectious diseases", "mathematics", "Virology"], "article_id"=>611509, "categories"=>["Virology", "Mathematics", "Infectious Diseases", "Immunology"], "users"=>["Andreas Handel", "Ira M Longini Jr.", "Rustom Antia"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.0030240.g005", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Spread_of_Resistance_as_Measured_by_R_r_/611509", "title"=>"Spread of Resistance as Measured by <i>R<sub>r</sub></i>", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 11:26:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/941250"], "description"=>"<p>Data are system symptom score values and viral load from [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0030240#pcbi-0030240-b042\" target=\"_blank\">42</a>] (squares) and [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0030240#pcbi-0030240-b043\" target=\"_blank\">43</a>] (circles). Also shown is the best fit for the function <i>y</i>.</p>", "links"=>[], "tags"=>["viral"], "article_id"=>611673, "categories"=>["Virology", "Mathematics", "Infectious Diseases", "Immunology"], "users"=>["Andreas Handel", "Ira M Longini Jr.", "Rustom Antia"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.0030240.g006", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Symptom_Score_as_a_Function_of_Viral_Load_/611673", "title"=>"Symptom Score as a Function of Viral Load", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 11:27:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/940703"], "description"=>"<p>Symbols in (A) and (B) are data from humans infected with influenza A/Texas/91 (H1N1). Early drug treatment starts at around 29 h, late treatment at around 50 h post-infection. The dotted horizontal line shows the limit of assay sensitivity. The solid lines show total viral load as obtained from (A) the target-cell depletion (TD) model and (B) the immune response (IR) model. The dashed lines show the resistant subpopulation. Further details on the experimental data are given in [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0030240#pcbi-0030240-b027\" target=\"_blank\">27</a>].</p>", "links"=>[], "tags"=>["titer", "nasal"], "article_id"=>611132, "categories"=>["Virology", "Mathematics", "Infectious Diseases", "Immunology"], "users"=>["Andreas Handel", "Ira M Longini Jr.", "Rustom Antia"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.0030240.g001", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Viral_Titer_TCID_50_ml_of_Nasal_Wash_/611132", "title"=>"Viral Titer (TCID<sub>50</sub>/ml of Nasal Wash)", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 11:24:01"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"1"}
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  • {"unique-ip"=>"5", "full-text"=>"3", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"3"}
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  • {"unique-ip"=>"3", "full-text"=>"1", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"5"}
  • {"unique-ip"=>"2", "full-text"=>"2", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"6"}
  • {"unique-ip"=>"1", "full-text"=>"1", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"7"}
  • {"unique-ip"=>"3", "full-text"=>"1", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"8"}
  • {"unique-ip"=>"6", "full-text"=>"5", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"9"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"10"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
  • {"unique-ip"=>"2", "full-text"=>"2", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"12"}
  • {"unique-ip"=>"6", "full-text"=>"3", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"1"}
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  • {"unique-ip"=>"1", "full-text"=>"1", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"6"}
  • {"unique-ip"=>"1", "full-text"=>"1", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"7"}
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  • {"unique-ip"=>"2", "full-text"=>"2", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"7", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"7", "full-text"=>"4", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"23", "full-text"=>"8", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"16", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"24", "full-text"=>"29", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"8", "full-text"=>"6", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"6", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"8", "full-text"=>"10", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"10", "full-text"=>"9", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"9", "full-text"=>"11", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"9", "full-text"=>"15", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"3", "full-text"=>"2", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}

Relative Metric

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