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{"title"=>"Homocysteine and coronary heart disease: Meta-analysis of MTHFR case-control studies, avoiding publication bias", "type"=>"journal", "authors"=>[{"first_name"=>"Robert", "last_name"=>"Clarke", "scopus_author_id"=>"55248074700"}, {"first_name"=>"Derrick A.", "last_name"=>"Bennett", "scopus_author_id"=>"35420095800"}, {"first_name"=>"Sarah", "last_name"=>"Parish", "scopus_author_id"=>"7007050848"}, {"first_name"=>"Petra", "last_name"=>"Verhoef", "scopus_author_id"=>"7004384631"}, {"first_name"=>"Mariska", "last_name"=>"Dötsch-Klerk", "scopus_author_id"=>"24437473500"}, {"first_name"=>"Mark", "last_name"=>"Lathrop", "scopus_author_id"=>"7006495387"}, {"first_name"=>"Peng", "last_name"=>"Xu", "scopus_author_id"=>"14055231100"}, {"first_name"=>"Børge G.", "last_name"=>"Nordestgaard", "scopus_author_id"=>"7007170557"}, {"first_name"=>"Hilma", "last_name"=>"Holm", "scopus_author_id"=>"25822221000"}, {"first_name"=>"Jemma C.", "last_name"=>"Hopewell", "scopus_author_id"=>"26767851800"}, {"first_name"=>"Danish", "last_name"=>"Saleheen", "scopus_author_id"=>"57191531896"}, {"first_name"=>"Toshihiro", "last_name"=>"Tanaka", "scopus_author_id"=>"55535827200"}, {"first_name"=>"Sonia S.", "last_name"=>"Anand", "scopus_author_id"=>"7201522674"}, {"first_name"=>"John C.", "last_name"=>"Chambers", "scopus_author_id"=>"56676464600"}, {"first_name"=>"Marcus E.", "last_name"=>"Kleber", "scopus_author_id"=>"34872560400"}, {"first_name"=>"Willem H.", "last_name"=>"Ouwehand", "scopus_author_id"=>"55801267700"}, {"first_name"=>"Yoshiji", "last_name"=>"Yamada", "scopus_author_id"=>"7407166277"}, {"first_name"=>"Clara", "last_name"=>"Elbers", "scopus_author_id"=>"15724836800"}, {"first_name"=>"Bas", "last_name"=>"Peters", "scopus_author_id"=>"25121750400"}, {"first_name"=>"Alexandre F.R.", "last_name"=>"Stewart", "scopus_author_id"=>"56962727600"}, {"first_name"=>"Muredach M.", "last_name"=>"Reilly", "scopus_author_id"=>"55276207000"}, {"first_name"=>"Barbara", "last_name"=>"Thorand", "scopus_author_id"=>"6603102917"}, {"first_name"=>"Salim", "last_name"=>"Yusuf", "scopus_author_id"=>"7202749318"}, {"first_name"=>"James C.", "last_name"=>"Engert", "scopus_author_id"=>"56962776000"}, {"first_name"=>"Themistocles L.", "last_name"=>"Assimes", "scopus_author_id"=>"56425902800"}, {"first_name"=>"Jaspal", "last_name"=>"Kooner", "scopus_author_id"=>"56188131900"}, {"first_name"=>"John", "last_name"=>"Danesh", "scopus_author_id"=>"7006642150"}, {"first_name"=>"Hugh", "last_name"=>"Watkins", "scopus_author_id"=>"7004286059"}, {"first_name"=>"Nilesh J.", "last_name"=>"Samani", "scopus_author_id"=>"7004345054"}, {"first_name"=>"Rory", "last_name"=>"Collins", "scopus_author_id"=>"7403350771"}, {"first_name"=>"Richard", "last_name"=>"Peto", "scopus_author_id"=>"34572276000"}], "year"=>2012, "source"=>"PLoS Medicine", "identifiers"=>{"scopus"=>"2-s2.0-84857711683", "doi"=>"10.1371/journal.pmed.1001177", "sgr"=>"84857711683", "isbn"=>"1549-1676 (Electronic)\\r1549-1277 (Linking)", "pmid"=>"22363213", "issn"=>"15491277", "pui"=>"364370612"}, "id"=>"18ae3b28-53b7-3377-afe3-a987a349167d", "abstract"=>"BACKGROUND: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so \"Mendelian randomization\" studies using this variant as an instrumental variable could help test causality.\\n\\nMETHODS AND FINDINGS: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09-1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04-1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09-1.28) in the 72 smaller ones (total 15,498 cases).\\n\\nCONCLUSIONS: The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.", "link"=>"http://www.mendeley.com/research/homocysteine-coronary-heart-disease-metaanalysis-mthfr-casecontrol-studies-avoiding-publication-bias", "reader_count"=>112, "reader_count_by_academic_status"=>{"Unspecified"=>5, "Professor > Associate Professor"=>7, "Librarian"=>3, "Researcher"=>24, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>16, "Student > Postgraduate"=>8, "Student > Master"=>19, "Other"=>5, "Student > Bachelor"=>13, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>3, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>5, "Professor > Associate Professor"=>7, "Librarian"=>3, "Researcher"=>24, "Student > Doctoral Student"=>2, "Student > Ph. D. 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Figshare

• {"files"=>["https://ndownloader.figshare.com/files/346304", "https://ndownloader.figshare.com/files/346345", "https://ndownloader.figshare.com/files/346381", "https://ndownloader.figshare.com/files/346448", "https://ndownloader.figshare.com/files/346516", "https://ndownloader.figshare.com/files/346589"], "description"=>"<div><h3>Background</h3><p>Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (<em>MTHFR</em>) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality.</p> <h3>Methods and Findings</h3><p>Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including <em>MTHFR</em> C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; <em>p</em> = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (<em>p</em> = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases).</p> <h3>Conclusions</h3><p>The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.</p> <h3></h3><p> <em>Please see later in the article for the Editors' Summary</em></p> </div>", "links"=>[], "tags"=>["homocysteine", "coronary", "meta-analysis", "case-control", "avoiding"], "article_id"=>128436, "categories"=>["Medicine"], "users"=>["Robert Clarke", "Derrick A. Bennett", "Sarah Parish", "Petra Verhoef", "Mariska Dötsch-Klerk", "Mark Lathrop", "Peng Xu", "Børge G. Nordestgaard", "Hilma Holm", "Jemma C. Hopewell", "Danish Saleheen", "Toshihiro Tanaka", "Sonia S. Anand", "John C. Chambers", "Marcus E. Kleber", "Willem H. Ouwehand", "Yoshiji Yamada", "Clara Elbers", "Bas Peters", "Alexandre F. R. Stewart", "Muredach M. Reilly", "Barbara Thorand", "Salim Yusuf", "James C. Engert", "Themistocles L. Assimes", "Jaspal Kooner", "John Danesh", "Hugh Watkins", "Nilesh J. Samani", "Rory Collins", "Richard Peto"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001177.s001", "https://dx.doi.org/10.1371/journal.pmed.1001177.s002", "https://dx.doi.org/10.1371/journal.pmed.1001177.s003", "https://dx.doi.org/10.1371/journal.pmed.1001177.s004", "https://dx.doi.org/10.1371/journal.pmed.1001177.s005", "https://dx.doi.org/10.1371/journal.pmed.1001177.s006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Homocysteine_and_Coronary_Heart_Disease_Meta_analysis_of_MTHFR_Case_Control_Studies_Avoiding_Publication_Bias/128436", "title"=>"Homocysteine and Coronary Heart Disease: Meta-analysis of <em>MTHFR</em> Case-Control Studies, Avoiding Publication Bias", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-02-21 02:20:36"}
• {"files"=>["https://ndownloader.figshare.com/files/677626"], "description"=>"<p>White squares, no folate supplementation; black squares, after folate supplementation; broken vertical line, 1995–1996, when folate supplementation began in the United States, Canada, Australia, New Zealand (US & ANZ), and some but not all European countries. No Asian surveys were in supplemented populations.</p>", "links"=>[], "tags"=>["serum", "folate", "concentrations", "81"], "article_id"=>348063, "categories"=>["Medicine"], "users"=>["Robert Clarke", "Derrick A. Bennett", "Sarah Parish", "Petra Verhoef", "Mariska Dötsch-Klerk", "Mark Lathrop", "Peng Xu", "Børge G. Nordestgaard", "Hilma Holm", "Jemma C. Hopewell", "Danish Saleheen", "Toshihiro Tanaka", "Sonia S. Anand", "John C. Chambers", "Marcus E. Kleber", "Willem H. Ouwehand", "Yoshiji Yamada", "Clara Elbers", "Bas Peters", "Alexandre F. R. Stewart", "Muredach M. Reilly", "Barbara Thorand", "Salim Yusuf", "James C. Engert", "Themistocles L. Assimes", "Jaspal Kooner", "John Danesh", "Hugh Watkins", "Nilesh J. Samani", "Rory Collins", "Richard Peto"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001177.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mean_serum_folate_concentrations_in_81_population_surveys_by_calendar_year_and_region_/348063", "title"=>"Mean serum folate concentrations in 81 population surveys, by calendar year and region.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-21 02:14:23"}
• {"files"=>["https://ndownloader.figshare.com/files/677792"], "description"=>"<p>For these datasets, being unpublished introduces a negligible bias (less than 0.3% for each OR and about 0.1% for the overall OR: eAppendix 1). Black squares indicate OR (with areas inversely proportional to the variance of log OR), and horizontal lines indicate 99% CIs. The subtotals and their 99% CIs are indicated by black diamonds. The overall OR and its 95% CI is indicated by a white diamond. The weight (defined as the inverse of the variance of the maximum likelihood estimate of the log OR) and the product of the weight times OR indicates how much each study has contributed to the subtotals and totals. Because the weights and products are approximately additive, they can be used to estimate the effects of ignoring particular studies, or of grouping studies in different ways.</p>", "links"=>[], "tags"=>["chd", "cc", "c677t", "19", "unpublished", "yielding", "24", "parts", "classified", "genotyping"], "article_id"=>348216, "categories"=>["Medicine"], "users"=>["Robert Clarke", "Derrick A. Bennett", "Sarah Parish", "Petra Verhoef", "Mariska Dötsch-Klerk", "Mark Lathrop", "Peng Xu", "Børge G. Nordestgaard", "Hilma Holm", "Jemma C. Hopewell", "Danish Saleheen", "Toshihiro Tanaka", "Sonia S. Anand", "John C. Chambers", "Marcus E. Kleber", "Willem H. Ouwehand", "Yoshiji Yamada", "Clara Elbers", "Bas Peters", "Alexandre F. R. Stewart", "Muredach M. Reilly", "Barbara Thorand", "Salim Yusuf", "James C. Engert", "Themistocles L. Assimes", "Jaspal Kooner", "John Danesh", "Hugh Watkins", "Nilesh J. Samani", "Rory Collins", "Richard Peto"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001177.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Homozygote_CHD_OR_TT_versus_CC_MTHFR_C677T_genotype_in_19_unpublished_datasets_yielding_24_parts_that_are_classified_by_genotyping_panel_size_/348216", "title"=>"Homozygote CHD OR (TT versus CC <i>MTHFR</i> C677T genotype) in 19 unpublished datasets, yielding 24 parts that are classified by genotyping panel size.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-21 02:16:56"}
• {"files"=>["https://ndownloader.figshare.com/files/678023"], "description"=>"<p>Average homocysteine difference (in the non-CHD general population) for all areas and periods is weighted in proportion to the numbers of TT CHD cases in all 19 unpublished datasets. Nonpublication involves negligible bias: Appendix S2 in <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001177#pmed.1001177.s006\" target=\"_blank\">Text S1</a>.</p>", "links"=>[], "tags"=>["chd", "cc", "c677t", "probable", "folate", "meta-analyses", "19", "unpublished", "datasets"], "article_id"=>348456, "categories"=>["Medicine"], "users"=>["Robert Clarke", "Derrick A. Bennett", "Sarah Parish", "Petra Verhoef", "Mariska Dötsch-Klerk", "Mark Lathrop", "Peng Xu", "Børge G. Nordestgaard", "Hilma Holm", "Jemma C. Hopewell", "Danish Saleheen", "Toshihiro Tanaka", "Sonia S. Anand", "John C. Chambers", "Marcus E. Kleber", "Willem H. Ouwehand", "Yoshiji Yamada", "Clara Elbers", "Bas Peters", "Alexandre F. R. Stewart", "Muredach M. Reilly", "Barbara Thorand", "Salim Yusuf", "James C. Engert", "Themistocles L. Assimes", "Jaspal Kooner", "John Danesh", "Hugh Watkins", "Nilesh J. Samani", "Rory Collins", "Richard Peto"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001177.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Homozygote_CHD_OR_TT_versus_CC_MTHFR_C677T_genotype_in_each_probable_folate_status_category_from_meta_analyses_of_19_unpublished_datasets_all_large_/348456", "title"=>"Homozygote CHD OR (TT versus CC <i>MTHFR</i> C677T genotype) in each probable folate status category, from meta-analyses of 19 unpublished datasets (all large).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-21 02:20:56"}
• {"files"=>["https://ndownloader.figshare.com/files/678276"], "description"=>"<p>Black squares indicate OR (with areas inversely proportional to the variance of log OR in each subdivision), and horizontal lines indicate 99% CIs. The overall OR and its 95% CI are indicated by a black diamond. Average homocysteine difference (in the non-CHD general population) for all areas and periods is weighted in proportion to the numbers of TT CHD cases in all 86 studies.</p>", "links"=>[], "tags"=>["chd", "cc", "c677t", "probable", "folate", "meta-analyses", "86", "published", "14", "variance", "72", "smaller"], "article_id"=>348701, "categories"=>["Medicine"], "users"=>["Robert Clarke", "Derrick A. Bennett", "Sarah Parish", "Petra Verhoef", "Mariska Dötsch-Klerk", "Mark Lathrop", "Peng Xu", "Børge G. Nordestgaard", "Hilma Holm", "Jemma C. Hopewell", "Danish Saleheen", "Toshihiro Tanaka", "Sonia S. Anand", "John C. Chambers", "Marcus E. Kleber", "Willem H. Ouwehand", "Yoshiji Yamada", "Clara Elbers", "Bas Peters", "Alexandre F. R. Stewart", "Muredach M. Reilly", "Barbara Thorand", "Salim Yusuf", "James C. Engert", "Themistocles L. Assimes", "Jaspal Kooner", "John Danesh", "Hugh Watkins", "Nilesh J. Samani", "Rory Collins", "Richard Peto"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001177.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Homozygote_CHD_OR_TT_versus_CC_MTHFR_C677T_genotype_in_each_probable_folate_status_category_from_meta_analyses_of_86_published_studies_14_large_i_e_variance_of_log_OR_less_than_0_05_and_72_smaller_studies_/348701", "title"=>"Homozygote CHD OR (TT versus CC <i>MTHFR</i> C677T genotype) in each probable folate status category, from meta-analyses of 86 published studies, 14 large (i.e., variance of log OR less than 0.05) and 72 smaller studies.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-21 02:25:01"}
• {"files"=>["https://ndownloader.figshare.com/files/678448"], "description"=>"<p>Data for the VITATOPS trial are for myocardial infarction only. Data for FAVORIT are for all cardiovascular disease outcomes. Symbols and conventions as in <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001177#pmed-1001177-g002\" target=\"_blank\">Figure 2</a>.</p>", "links"=>[], "tags"=>["folic", "coronary", "events", "myocardial", "infarction", "meta-analysis", "published", "randomized", "trials", "homocysteine"], "article_id"=>348882, "categories"=>["Medicine"], "users"=>["Robert Clarke", "Derrick A. Bennett", "Sarah Parish", "Petra Verhoef", "Mariska Dötsch-Klerk", "Mark Lathrop", "Peng Xu", "Børge G. Nordestgaard", "Hilma Holm", "Jemma C. Hopewell", "Danish Saleheen", "Toshihiro Tanaka", "Sonia S. Anand", "John C. Chambers", "Marcus E. Kleber", "Willem H. Ouwehand", "Yoshiji Yamada", "Clara Elbers", "Bas Peters", "Alexandre F. R. Stewart", "Muredach M. Reilly", "Barbara Thorand", "Salim Yusuf", "James C. Engert", "Themistocles L. Assimes", "Jaspal Kooner", "John Danesh", "Hugh Watkins", "Nilesh J. Samani", "Rory Collins", "Richard Peto"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001177.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_folic_acid_on_major_coronary_events_nonfatal_myocardial_infarction_or_coronary_death_in_a_meta_analysis_of_the_published_results_of_all_large_randomized_trials_of_homocysteine_reduction_/348882", "title"=>"Effects of folic acid on major coronary events (nonfatal myocardial infarction or coronary death) in a meta-analysis of the published results of all large randomized trials of homocysteine reduction.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-21 02:28:02"}
• {"files"=>["https://ndownloader.figshare.com/files/678672"], "description"=>"a<p>Mean folate levels average all who were surveyed; SE denotes the standard error due only to within-survey variation. Between-survey variation in folate levels is illustrated in <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001177#pmed-1001177-g001\" target=\"_blank\">Figure 1</a>.</p>b<p>From inverse-variance-weighted averages of within-study differences in log homocysteine; <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001177#pmed.1001177.s001\" target=\"_blank\">Figure S1</a>, Table S2 in <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001177#pmed.1001177.s006\" target=\"_blank\">Text S1</a>.</p>c<p>Mainly of Japanese, Chinese, or Korean populations; none of South Asians.</p>", "links"=>[], "tags"=>["surveys", "serum", "folate", "excess", "plasma", "homocysteine", "tt", "cc", "c677t"], "article_id"=>349114, "categories"=>["Medicine"], "users"=>["Robert Clarke", "Derrick A. Bennett", "Sarah Parish", "Petra Verhoef", "Mariska Dötsch-Klerk", "Mark Lathrop", "Peng Xu", "Børge G. Nordestgaard", "Hilma Holm", "Jemma C. Hopewell", "Danish Saleheen", "Toshihiro Tanaka", "Sonia S. Anand", "John C. Chambers", "Marcus E. Kleber", "Willem H. Ouwehand", "Yoshiji Yamada", "Clara Elbers", "Bas Peters", "Alexandre F. R. Stewart", "Muredach M. Reilly", "Barbara Thorand", "Salim Yusuf", "James C. Engert", "Themistocles L. Assimes", "Jaspal Kooner", "John Danesh", "Hugh Watkins", "Nilesh J. Samani", "Rory Collins", "Richard Peto"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001177.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relevance_in_population_surveys_of_study_place_and_time_to_i_the_mean_general_population_serum_folate_level_and_ii_the_excess_plasma_homocysteine_level_in_the_TT_versus_CC_MTHFR_C677T_genotype_/349114", "title"=>"Relevance in population surveys of study place and time to (i) the mean general population serum folate level, and (ii) the excess plasma homocysteine level in the TT versus CC <i>MTHFR</i> C677T genotype.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-02-21 02:31:54"}

PMC Usage Stats | Further Information

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Relative Metric

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