Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis
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{"title"=>"Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: A systematic review and meta-analysis", "type"=>"generic", "authors"=>[{"first_name"=>"Dick", "last_name"=>"Menzies", "scopus_author_id"=>"7006221407"}, {"first_name"=>"Andrea", "last_name"=>"Benedetti", "scopus_author_id"=>"20833376700"}, {"first_name"=>"Anita", "last_name"=>"Paydar", "scopus_author_id"=>"35168073000"}, {"first_name"=>"Ian", "last_name"=>"Martin", "scopus_author_id"=>"55574238061"}, {"first_name"=>"Sarah", "last_name"=>"Royce", "scopus_author_id"=>"6701708823"}, {"first_name"=>"Madhukar", "last_name"=>"Pai", "scopus_author_id"=>"14054425400"}, {"first_name"=>"Andrew", "last_name"=>"Vernon", "scopus_author_id"=>"7005532201"}, {"first_name"=>"Christian", "last_name"=>"Lienhardt", "scopus_author_id"=>"7003944694"}, {"first_name"=>"William", "last_name"=>"Burman", "scopus_author_id"=>"7005482634"}], "year"=>2009, "source"=>"PLoS Medicine", "identifiers"=>{"issn"=>"15491277", "isbn"=>"1549-1277", "pmid"=>"19753109", "scopus"=>"2-s2.0-70349634546", "doi"=>"10.1371/journal.pmed.1000146", "sgr"=>"70349634546", "pui"=>"355369596"}, "id"=>"29a91ec7-e923-3d3b-b624-cfdd1c4290c1", "abstract"=>"BACKGROUND: Treatment regimens for active tuberculosis (TB) that are intermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacy has been questioned. We conducted a systematic review of treatment regimens for active TB, to assess the effect of duration and intermittency of rifampin use on TB treatment outcomes. METHODS AND FINDINGS: PubMed, Embase, and the Cochrane CENTRAL database for clinical trials were searched for randomized controlled trials, published in English, French, or Spanish, between 1965 and June 2008. Selected studies utilized standardized treatment with rifampin-containing regimens. Studies reported bacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologically confirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with risk factors were computed with stratified random effects meta-analyses. Meta-regression was performed using a negative binomial regression model. A total of 57 trials with 312 arms and 21,472 participants were included in the analysis. Regimens utilizing rifampin only for the first 1-2 mo had significantly higher rates of failure, relapse, and acquired drug resistance, as compared to regimens that used rifampin for 6 mo. This was particularly evident when there was initial drug resistance to isoniazid, streptomycin, or both. On the other hand, there was little evidence of difference in failure or relapse with daily or intermittent schedules of treatment administration, although there was insufficient published evidence of the efficacy of twice-weekly rifampin administration throughout therapy. CONCLUSIONS: TB treatment outcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance to isoniazid and/or streptomycin. Treatment outcomes were similar with all intermittent schedules evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy.", "link"=>"http://www.mendeley.com/research/effect-duration-intermittency-rifampin-tuberculosis-treatment-outcomes-systematic-review-metaanalysi-1", "reader_count"=>103, "reader_count_by_academic_status"=>{"Unspecified"=>6, "Professor > Associate Professor"=>2, "Researcher"=>21, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>6, "Student > Master"=>26, "Other"=>12, "Student > Bachelor"=>6, "Professor"=>7}, "reader_count_by_user_role"=>{"Unspecified"=>6, "Professor > Associate Professor"=>2, "Researcher"=>21, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>6, "Student > Master"=>26, "Other"=>12, "Student > Bachelor"=>6, "Professor"=>7}, "reader_count_by_subject_area"=>{"Unspecified"=>14, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Nursing and Health Professions"=>2, "Medicine and Dentistry"=>58, "Agricultural and Biological Sciences"=>15, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Business, Management and Accounting"=>2, "Chemical Engineering"=>1, "Chemistry"=>2, "Social Sciences"=>1, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>58}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>14}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Chemical Engineering"=>{"Chemical Engineering"=>1}}, "reader_count_by_country"=>{"Armenia"=>1, "Sweden"=>1, "United States"=>2, "South Africa"=>1, "Switzerland"=>2, "India"=>2, "Russia"=>1, "Spain"=>1}, "group_count"=>6}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/883987"], "description"=>"a<p>Acquired drug resistance in both failure and relapse cases combined.</p>b<p>Adjusted estimates of Incidence Rate Ratios (IRR) from multivariate negative binomial regression with model that included all variables indicated, plus length of follow-up after end of treatment (for relapse and acquired drug resistance), supervision of therapy (DOT), and non-completion of therapy because of protocol violations, patient refusal, default, moved, or lost. Estimates that are statistically significant are in bold.</p>c<p>Overall significance of each factor in multi-variate models, from log likelihood ratio test.</p>d<p>Adjusted estimates of IRR from second model that included initial drug resistance, and all the same factors, but not the number of sensitive drugs in initial or continuation phases. These could not be included because of substantial co-linearity with drug resistance.</p>", "links"=>[], "tags"=>["incidence", "ratios", "acquired", "binomial"], "article_id"=>554432, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.t009", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Adjusted_incidence_rate_ratios_of_failure_relapse_and_acquired_drug_resistance_from_negative_binomial_regression_/554432", "title"=>"Adjusted incidence rate ratios of failure, relapse, and acquired drug resistance (from negative binomial regression).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-15 01:13:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/883704"], "description"=>"<p>Eighteen head-to-head comparisons of rifampin duration. For one study <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000146#pmed.1000146-British2\" target=\"_blank\">[54]</a>,<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000146#pmed.1000146-British3\" target=\"_blank\">[55]</a>, results with 9-, 12-, and 18-mo regimens were the same so they were combined.</p>a<p>Regimen abbreviations: H, isoniazid; R, rifampin; Z, pyrazinamide; E, ethambutol; S, streptomycin.</p><p>Letters to left of “/” indicate regimen in initial intensive phase; letters to right of “/” indicate regimen in continuation phase. First number signifies the months of initial phase of treatment and the second number signifies the months of continuation phase treatment. [ ] indicates intermittent therapy; subscript number after [ ] indicates number of doses per week.</p>", "links"=>[], "tags"=>["differences", "head-to-head", "comparisons", "rifampin", "duration", "intermittent", "schedules"], "article_id"=>554145, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.t003", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pooled_risk_differences_from_direct_head_to_head_comparisons_of_rifampin_duration_or_intermittent_schedules_in_otherwise_comparable_regimens_Relapse_/554145", "title"=>"Pooled risk differences from direct head-to-head comparisons of rifampin duration or intermittent schedules in otherwise comparable regimens: Relapse.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-15 01:09:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/883752"], "description"=>"<p>Eleven head-to-head comparisons of rifampin duration. For one study <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000146#pmed.1000146-British2\" target=\"_blank\">[54]</a>,<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000146#pmed.1000146-British3\" target=\"_blank\">[55]</a>—results with 9-, 12-, and 18-mo regimens were the same—so they were combined.</p>a<p>Regimen abbreviations: H, isoniazid; R, rifampin; Z, pyrazinamide; E, ethambutol; S, streptomycin.</p><p>Letters to left of “/” indicate regimen in initial intensive phase; letters to right of “/” indicate regimen in continuation phase. First number signifies the months of initial phase of treatment and the second number signifies the months of continuation phase treatment. [ ] indicates intermittent therapy; subscript number after [ ] indicates number of doses per week.</p>", "links"=>[], "tags"=>["differences", "head-to-head", "comparisons", "rifampin", "duration", "intermittent", "schedules", "acquired"], "article_id"=>554196, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.t004", "stats"=>{"downloads"=>2, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pooled_risk_differences_from_direct_head_to_head_comparisons_of_rifampin_duration_or_intermittent_schedules_in_otherwise_comparable_regimens_Acquired_drug_resistance_/554196", "title"=>"Pooled risk differences from direct head-to-head comparisons of rifampin duration or intermittent schedules in otherwise comparable regimens: Acquired drug resistance.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-15 01:09:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/883801"], "description"=>"<p>Treatment outcomes are from five studies with direct head-to head-comparisons of intermittency schedules (and otherwise comparable regimens). Meta-analysis not done, as no schedules were the same.</p>a<p>Regimen abbreviations: H, isoniazid; R, rifampin; Z, pyrazinamide; E, ethambutol; S, streptomycin.</p><p>Letters to left of “/” indicate regimen in initial intensive phase; letters to right of “/” indicate regimen in continuation phase. First number signifies the months of initial phase of treatment and the second number signifies the months of continuation phase treatment. [ ] indicate intermittent therapy; subscript number after [ ] indicates number of doses per week.</p>a<p>n/a, not available, meaning relapse and/or acquired drug resistance (ADR) not measured.</p><p>INH, isoniazid resistant; STREP, streptomycin resistant; PDR, poly-drug resistant (streptomycin+isoniazid resistant); FDC, fixed drug combinations.</p>", "links"=>[], "tags"=>["differences", "head-to-head", "comparisons", "rifampin", "duration", "intermittent", "schedules"], "article_id"=>554246, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.t005", "stats"=>{"downloads"=>7, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pooled_risk_differences_from_direct_head_to_head_comparisons_of_rifampin_duration_or_intermittent_schedules_otherwise_comparable_regimens_/554246", "title"=>"Pooled risk differences from direct head-to-head comparisons of rifampin duration or intermittent schedules otherwise comparable regimens.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-15 01:10:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/883613"], "description"=>"<p>Summary of studies reviewed (all randomized controlled trials with rifampin-containing regimens in new cases).</p>", "links"=>[], "tags"=>["studies", "reviewed", "randomized", "controlled", "trials", "rifampin-containing", "regimens"], "article_id"=>554055, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.t001", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_studies_reviewed_all_randomized_controlled_trials_with_rifampin_containing_regimens_in_new_cases_/554055", "title"=>"Summary of studies reviewed (all randomized controlled trials with rifampin-containing regimens in new cases).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-15 01:07:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/883520"], "description"=>"<p>Summary of literature search and study selection.</p>", "links"=>[], "tags"=>["infectious diseases/epidemiology and control of infectious diseases", "infectious diseases/neglected tropical diseases", "public health and epidemiology/global health"], "article_id"=>553967, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.g001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_literature_search_and_study_selection_/553967", "title"=>"Summary of literature search and study selection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-15 01:06:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/883944"], "description"=>"<p>Event rate and 95% CI are in bold if confidence intervals for two or more strata do not overlap.</p>a<p>In all but one trial, if therapy was intermittent initially, the same schedule was continued throughout therapy.</p>b<p>In a few trials the number of drugs was the same throughout—these were classified according to the starting regimen.</p>", "links"=>[], "tags"=>["estimates", "acquired", "rct"], "article_id"=>554385, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.t008", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Stratified_estimates_of_acquired_drug_resistance_in_RCT_in_new_cases_/554385", "title"=>"Stratified estimates of acquired drug resistance in RCT in new cases.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-15 01:13:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/438192", "https://ndownloader.figshare.com/files/438250"], "description"=>"<div><h3>Background</h3><p>Treatment regimens for active tuberculosis (TB) that are intermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacy has been questioned. We conducted a systematic review of treatment regimens for active TB, to assess the effect of duration and intermittency of rifampin use on TB treatment outcomes.</p><h3>Methods and Findings</h3><p>PubMed, Embase, and the Cochrane CENTRAL database for clinical trials were searched for randomized controlled trials, published in English, French, or Spanish, between 1965 and June 2008. Selected studies utilized standardized treatment with rifampin-containing regimens. Studies reported bacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologically confirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with risk factors were computed with stratified random effects meta-analyses. Meta-regression was performed using a negative binomial regression model. A total of 57 trials with 312 arms and 21,472 participants were included in the analysis. Regimens utilizing rifampin only for the first 1–2 mo had significantly higher rates of failure, relapse, and acquired drug resistance, as compared to regimens that used rifampin for 6 mo. This was particularly evident when there was initial drug resistance to isoniazid, streptomycin, or both. On the other hand, there was little evidence of difference in failure or relapse with daily or intermittent schedules of treatment administration, although there was insufficient published evidence of the efficacy of twice-weekly rifampin administration throughout therapy.</p><h3>Conclusions</h3><p>TB treatment outcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance to isoniazid and/or streptomycin. Treatment outcomes were similar with all intermittent schedules evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy.</p><h3></h3><p><em>Please see later in the article for the Editors' Summary</em></p></div>", "links"=>[], "tags"=>["duration", "intermittency", "rifampin", "tuberculosis", "systematic", "meta-analysis"], "article_id"=>146386, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1000146.s001", "https://dx.doi.org/10.1371/journal.pmed.1000146.s002"], "stats"=>{"downloads"=>12, "page_views"=>32, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Effect_of_Duration_and_Intermittency_of_Rifampin_on_Tuberculosis_Treatment_Outcomes_A_Systematic_Review_and_Meta_Analysis/146386", "title"=>"Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-09-15 01:46:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/883655"], "description"=>"<p>Seventeen head-to-head comparisons of rifampin duration. For one study <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000146#pmed.1000146-British2\" target=\"_blank\">[54]</a>,<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000146#pmed.1000146-British3\" target=\"_blank\">[55]</a>, results with 9-, 12-, and 18-mo regimens were the same so they were combined.</p>a<p>Regimen abbreviations: H, isoniazid; R, rifampin; Z, pyrazinamide; E, ethambutol; S, streptomycin.</p><p>Letters to left of “/” indicate regimen in initial intensive phase; letters to right of “/” indicate regimen in continuation phase. First number signifies the months of initial phase of treatment and the second number signifies the months of continuation phase treatment. [ ] indicates intermittent therapy; subscript number after [ ] indicates number of doses per week.</p>", "links"=>[], "tags"=>["differences", "head-to-head", "comparisons", "rifampin", "duration", "intermittent", "schedules"], "article_id"=>554100, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.t002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pooled_risk_differences_from_direct_head_to_head_comparisons_of_rifampin_duration_or_intermittent_schedules_in_otherwise_comparable_regimens_Failure_/554100", "title"=>"Pooled risk differences from direct head-to-head comparisons of rifampin duration or intermittent schedules in otherwise comparable regimens: Failure.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-15 01:08:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/883883"], "description"=>"<p>Event rate and 95% CI are in bold if confidence intervals for two or more strata do not overlap.</p>a<p>In all but one trial, if therapy was intermittent initially, the same schedule was continued throughout therapy.</p>b<p>In a few trials the number of drugs was the same throughout—these were classified according to the starting regimen.</p>", "links"=>[], "tags"=>["estimates", "relapse", "rct"], "article_id"=>554329, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.t007", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Stratified_estimates_of_relapse_in_RCT_in_new_cases_/554329", "title"=>"Stratified estimates of relapse in RCT in new cases.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-15 01:12:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/883841"], "description"=>"<p>Event rate and 95% CI are in bold if confidence intervals for two or more strata do not overlap.</p>a<p>In all but one trial, if therapy was intermittent initially, the same schedule was continued throughout therapy.</p>b<p>In a few trials, the number of drugs was the same throughout—these were classified according to the starting regimen.</p>", "links"=>[], "tags"=>["estimates", "failures", "rct"], "article_id"=>554292, "categories"=>["Medicine", "Cancer"], "users"=>["Dick Menzies", "Andrea Benedetti", "Anita Paydar", "Ian Martin", "Sarah Royce", "Madhukar Pai", "Andrew Vernon", "Christian Lienhardt", "William Burman"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000146.t006", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Stratified_estimates_of_treatment_failures_in_RCT_in_new_cases_/554292", "title"=>"Stratified estimates of treatment failures in RCT in new cases.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-15 01:11:32"}

PMC Usage Stats | Further Information

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Relative Metric

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