Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant a randomized clinical trial

Mark J. Mulligan, David I. Bernstein, Patricia Winokur, Richard Rupp, Evan Anderson, Nadine Rouphael, Michelle Dickey, Jack T. Stapleton, Srilatha Edupuganti, Paul Spearman, Dilek Ince, Diana L. Noah, Heather Hill, Abbie R. Bellamy, Karen Mask, Allison Beck, Lilin Lai, Nayoka Rimann, Colleen Kelley, Melinda OgilvieEileen Osinski, Dawn Battle, Andres Camacho-Gonzalez, Anita McElroy, Andi Shane, Larry Anderson, Kathy Stephens, Brooke Hartwell, Teresa Ball, Laila Hussani, Theda Gibson, Melanie Johnson, Bethany Sederdahl, Natasha Mann, Robert Frenck, Rebecca Brady, Tara Foltz, Amy Cline, Sarah McCartney, Margery Huron, Jeffrey Meier, Margo Schilling, Nancy Wagner, Geraldine Dull, Kathy Flanders, Dan Zhao, Mary Reidy, Gretchen Cress, Nikki Gerot, Diane Barrett, Carrie Harrington, Amy McMahan, Marianne Shafer, Lori Simon, Barbara Taggart, Valerie Johnson, Donna Bowen, Shixiong Li, Candi Looney, Megan May, Rachel May, Lawanda Parker, Bridgette Myers, Nertaissa Cochran, Michelle Bell, Logan Haller, Claire Stablein, Sara Marshall, Megan McDonough, Fenhua He, Kuo Guo, Linda Lambert, Wendy Buchanan, Valerie Riddle, Suzanne Murray, Richard Gorman

Research output: Contribution to journalArticle

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Abstract

RESULTS Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 μg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95%CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95%CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95%CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 μg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95%CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95%CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 μg doses (n = 34 [35%; 95%CI, 25%-45%] vs n = 47 [47%; 95%CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.

CONCLUSIONS AND RELEVANCE Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59%of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes.

TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01938742.

DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014.

IMPORTANCE Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.

OBJECTIVE To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant.

INTERVENTIONS The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 μg of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700).

MAIN OUTCOMES AND MEASURES Proportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer-40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7.

Original languageEnglish (US)
Pages (from-to)1409-1419
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume312
Issue number14
DOIs
StatePublished - Oct 8 2014

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Influenza in Birds
Vaccines
Randomized Controlled Trials
Hemagglutination
Human Influenza
Antibodies
H7N9 Subtype Influenza A Virus
Antigens
Inactivated Vaccines
Hemagglutinins
MF59 oil emulsion
Neutralizing Antibodies
Seroconversion
China
Vaccination
Outcome Assessment (Health Care)
Morbidity
Safety
Mortality
Infection

ASJC Scopus subject areas

  • Medicine(all)

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Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant a randomized clinical trial. / Mulligan, Mark J.; Bernstein, David I.; Winokur, Patricia; Rupp, Richard; Anderson, Evan; Rouphael, Nadine; Dickey, Michelle; Stapleton, Jack T.; Edupuganti, Srilatha; Spearman, Paul; Ince, Dilek; Noah, Diana L.; Hill, Heather; Bellamy, Abbie R.; Mask, Karen; Beck, Allison; Lai, Lilin; Rimann, Nayoka; Kelley, Colleen; Ogilvie, Melinda; Osinski, Eileen; Battle, Dawn; Camacho-Gonzalez, Andres; McElroy, Anita; Shane, Andi; Anderson, Larry; Stephens, Kathy; Hartwell, Brooke; Ball, Teresa; Hussani, Laila; Gibson, Theda; Johnson, Melanie; Sederdahl, Bethany; Mann, Natasha; Frenck, Robert; Brady, Rebecca; Foltz, Tara; Cline, Amy; McCartney, Sarah; Huron, Margery; Meier, Jeffrey; Schilling, Margo; Wagner, Nancy; Dull, Geraldine; Flanders, Kathy; Zhao, Dan; Reidy, Mary; Cress, Gretchen; Gerot, Nikki; Barrett, Diane; Harrington, Carrie; McMahan, Amy; Shafer, Marianne; Simon, Lori; Taggart, Barbara; Johnson, Valerie; Bowen, Donna; Li, Shixiong; Looney, Candi; May, Megan; May, Rachel; Parker, Lawanda; Myers, Bridgette; Cochran, Nertaissa; Bell, Michelle; Haller, Logan; Stablein, Claire; Marshall, Sara; McDonough, Megan; He, Fenhua; Guo, Kuo; Lambert, Linda; Buchanan, Wendy; Riddle, Valerie; Murray, Suzanne; Gorman, Richard.

In: JAMA - Journal of the American Medical Association, Vol. 312, No. 14, 08.10.2014, p. 1409-1419.

Research output: Contribution to journalArticle

Mulligan, MJ, Bernstein, DI, Winokur, P, Rupp, R, Anderson, E, Rouphael, N, Dickey, M, Stapleton, JT, Edupuganti, S, Spearman, P, Ince, D, Noah, DL, Hill, H, Bellamy, AR, Mask, K, Beck, A, Lai, L, Rimann, N, Kelley, C, Ogilvie, M, Osinski, E, Battle, D, Camacho-Gonzalez, A, McElroy, A, Shane, A, Anderson, L, Stephens, K, Hartwell, B, Ball, T, Hussani, L, Gibson, T, Johnson, M, Sederdahl, B, Mann, N, Frenck, R, Brady, R, Foltz, T, Cline, A, McCartney, S, Huron, M, Meier, J, Schilling, M, Wagner, N, Dull, G, Flanders, K, Zhao, D, Reidy, M, Cress, G, Gerot, N, Barrett, D, Harrington, C, McMahan, A, Shafer, M, Simon, L, Taggart, B, Johnson, V, Bowen, D, Li, S, Looney, C, May, M, May, R, Parker, L, Myers, B, Cochran, N, Bell, M, Haller, L, Stablein, C, Marshall, S, McDonough, M, He, F, Guo, K, Lambert, L, Buchanan, W, Riddle, V, Murray, S & Gorman, R 2014, 'Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant a randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 312, no. 14, pp. 1409-1419. https://doi.org/10.1001/jama.2014.12854
Mulligan, Mark J. ; Bernstein, David I. ; Winokur, Patricia ; Rupp, Richard ; Anderson, Evan ; Rouphael, Nadine ; Dickey, Michelle ; Stapleton, Jack T. ; Edupuganti, Srilatha ; Spearman, Paul ; Ince, Dilek ; Noah, Diana L. ; Hill, Heather ; Bellamy, Abbie R. ; Mask, Karen ; Beck, Allison ; Lai, Lilin ; Rimann, Nayoka ; Kelley, Colleen ; Ogilvie, Melinda ; Osinski, Eileen ; Battle, Dawn ; Camacho-Gonzalez, Andres ; McElroy, Anita ; Shane, Andi ; Anderson, Larry ; Stephens, Kathy ; Hartwell, Brooke ; Ball, Teresa ; Hussani, Laila ; Gibson, Theda ; Johnson, Melanie ; Sederdahl, Bethany ; Mann, Natasha ; Frenck, Robert ; Brady, Rebecca ; Foltz, Tara ; Cline, Amy ; McCartney, Sarah ; Huron, Margery ; Meier, Jeffrey ; Schilling, Margo ; Wagner, Nancy ; Dull, Geraldine ; Flanders, Kathy ; Zhao, Dan ; Reidy, Mary ; Cress, Gretchen ; Gerot, Nikki ; Barrett, Diane ; Harrington, Carrie ; McMahan, Amy ; Shafer, Marianne ; Simon, Lori ; Taggart, Barbara ; Johnson, Valerie ; Bowen, Donna ; Li, Shixiong ; Looney, Candi ; May, Megan ; May, Rachel ; Parker, Lawanda ; Myers, Bridgette ; Cochran, Nertaissa ; Bell, Michelle ; Haller, Logan ; Stablein, Claire ; Marshall, Sara ; McDonough, Megan ; He, Fenhua ; Guo, Kuo ; Lambert, Linda ; Buchanan, Wendy ; Riddle, Valerie ; Murray, Suzanne ; Gorman, Richard. / Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant a randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2014 ; Vol. 312, No. 14. pp. 1409-1419.
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title = "Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant a randomized clinical trial",
abstract = "RESULTS Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 μg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59{\%}; 95{\%}CI, 48{\%}-68{\%}). The peak seroconversion occurred at day 29 in 62 participants (62{\%}; 95{\%}CI, 52{\%}-72{\%}). The day 42 geometric mean titer was 33.0 (95{\%}CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 μg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82{\%}; 95{\%}CI, 73{\%}-89{\%}). The day 42 geometric mean titer was 81.4 (95{\%}CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 μg doses (n = 34 [35{\%}; 95{\%}CI, 25{\%}-45{\%}] vs n = 47 [47{\%}; 95{\%}CI, 37{\%}-58{\%}], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.CONCLUSIONS AND RELEVANCE Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59{\%}of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01938742.DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014.IMPORTANCE Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.OBJECTIVE To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant.INTERVENTIONS The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 μg of hemagglutinin (actual doses approximately 50{\%} higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700).MAIN OUTCOMES AND MEASURES Proportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer-40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7.",
author = "Mulligan, {Mark J.} and Bernstein, {David I.} and Patricia Winokur and Richard Rupp and Evan Anderson and Nadine Rouphael and Michelle Dickey and Stapleton, {Jack T.} and Srilatha Edupuganti and Paul Spearman and Dilek Ince and Noah, {Diana L.} and Heather Hill and Bellamy, {Abbie R.} and Karen Mask and Allison Beck and Lilin Lai and Nayoka Rimann and Colleen Kelley and Melinda Ogilvie and Eileen Osinski and Dawn Battle and Andres Camacho-Gonzalez and Anita McElroy and Andi Shane and Larry Anderson and Kathy Stephens and Brooke Hartwell and Teresa Ball and Laila Hussani and Theda Gibson and Melanie Johnson and Bethany Sederdahl and Natasha Mann and Robert Frenck and Rebecca Brady and Tara Foltz and Amy Cline and Sarah McCartney and Margery Huron and Jeffrey Meier and Margo Schilling and Nancy Wagner and Geraldine Dull and Kathy Flanders and Dan Zhao and Mary Reidy and Gretchen Cress and Nikki Gerot and Diane Barrett and Carrie Harrington and Amy McMahan and Marianne Shafer and Lori Simon and Barbara Taggart and Valerie Johnson and Donna Bowen and Shixiong Li and Candi Looney and Megan May and Rachel May and Lawanda Parker and Bridgette Myers and Nertaissa Cochran and Michelle Bell and Logan Haller and Claire Stablein and Sara Marshall and Megan McDonough and Fenhua He and Kuo Guo and Linda Lambert and Wendy Buchanan and Valerie Riddle and Suzanne Murray and Richard Gorman",
year = "2014",
month = "10",
day = "8",
doi = "10.1001/jama.2014.12854",
language = "English (US)",
volume = "312",
pages = "1409--1419",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "14",

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TY - JOUR

T1 - Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant a randomized clinical trial

AU - Mulligan, Mark J.

AU - Bernstein, David I.

AU - Winokur, Patricia

AU - Rupp, Richard

AU - Anderson, Evan

AU - Rouphael, Nadine

AU - Dickey, Michelle

AU - Stapleton, Jack T.

AU - Edupuganti, Srilatha

AU - Spearman, Paul

AU - Ince, Dilek

AU - Noah, Diana L.

AU - Hill, Heather

AU - Bellamy, Abbie R.

AU - Mask, Karen

AU - Beck, Allison

AU - Lai, Lilin

AU - Rimann, Nayoka

AU - Kelley, Colleen

AU - Ogilvie, Melinda

AU - Osinski, Eileen

AU - Battle, Dawn

AU - Camacho-Gonzalez, Andres

AU - McElroy, Anita

AU - Shane, Andi

AU - Anderson, Larry

AU - Stephens, Kathy

AU - Hartwell, Brooke

AU - Ball, Teresa

AU - Hussani, Laila

AU - Gibson, Theda

AU - Johnson, Melanie

AU - Sederdahl, Bethany

AU - Mann, Natasha

AU - Frenck, Robert

AU - Brady, Rebecca

AU - Foltz, Tara

AU - Cline, Amy

AU - McCartney, Sarah

AU - Huron, Margery

AU - Meier, Jeffrey

AU - Schilling, Margo

AU - Wagner, Nancy

AU - Dull, Geraldine

AU - Flanders, Kathy

AU - Zhao, Dan

AU - Reidy, Mary

AU - Cress, Gretchen

AU - Gerot, Nikki

AU - Barrett, Diane

AU - Harrington, Carrie

AU - McMahan, Amy

AU - Shafer, Marianne

AU - Simon, Lori

AU - Taggart, Barbara

AU - Johnson, Valerie

AU - Bowen, Donna

AU - Li, Shixiong

AU - Looney, Candi

AU - May, Megan

AU - May, Rachel

AU - Parker, Lawanda

AU - Myers, Bridgette

AU - Cochran, Nertaissa

AU - Bell, Michelle

AU - Haller, Logan

AU - Stablein, Claire

AU - Marshall, Sara

AU - McDonough, Megan

AU - He, Fenhua

AU - Guo, Kuo

AU - Lambert, Linda

AU - Buchanan, Wendy

AU - Riddle, Valerie

AU - Murray, Suzanne

AU - Gorman, Richard

PY - 2014/10/8

Y1 - 2014/10/8

N2 - RESULTS Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 μg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95%CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95%CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95%CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 μg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95%CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95%CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 μg doses (n = 34 [35%; 95%CI, 25%-45%] vs n = 47 [47%; 95%CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.CONCLUSIONS AND RELEVANCE Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59%of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01938742.DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014.IMPORTANCE Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.OBJECTIVE To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant.INTERVENTIONS The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 μg of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700).MAIN OUTCOMES AND MEASURES Proportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer-40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7.

AB - RESULTS Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 μg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95%CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95%CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95%CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 μg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95%CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95%CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 μg doses (n = 34 [35%; 95%CI, 25%-45%] vs n = 47 [47%; 95%CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.CONCLUSIONS AND RELEVANCE Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59%of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01938742.DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014.IMPORTANCE Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.OBJECTIVE To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant.INTERVENTIONS The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 μg of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700).MAIN OUTCOMES AND MEASURES Proportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer-40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7.

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U2 - 10.1001/jama.2014.12854

DO - 10.1001/jama.2014.12854

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AN - SCOPUS:84907698232

VL - 312

SP - 1409

EP - 1419

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

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