Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all‐trans retinoic acid and anthracycline‐based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study
Summary The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid–induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) b...
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| Veröffentlicht in: | British journal of haematology 2014-08, Vol.166 (4), p.540-549 |
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| creator | Lucena‐Araujo, Antonio R. Kim, Haesook T. Jacomo, Rafael H. Melo, Raul A. Bittencourt, Rosane Pasquini, Ricardo Pagnano, Katia Fagundes, Evandro M. Chauffaille, Maria Chiattone, Carlos S. Lima, Ana S. Kwaan, Hau C. Gallagher, Robert Niemeyer, Charlotte M. Schrier, Stanley L. Tallman, Martin S. Grimwade, David Ganser, Arnold Berliner, Nancy Ribeiro, Raul C. Lo‐Coco, Francesco Löwenberg, Bob Sanz, Miguel A. Rego, Eduardo M. |
| description | Summary
The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid–induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline‐based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2‐year overall survival (OS) (P = 0·005) and 2‐year disease‐free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2‐year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71–30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08–0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49–43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05–0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99–1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients. |
| doi_str_mv | 10.1111/bjh.12921 |
| format | Article |
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The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid–induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline‐based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2‐year overall survival (OS) (P = 0·005) and 2‐year disease‐free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2‐year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71–30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08–0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49–43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05–0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99–1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.</description><identifier>ISSN: 0007-1048</identifier><identifier>EISSN: 1365-2141</identifier><identifier>DOI: 10.1111/bjh.12921</identifier><identifier>PMID: 24796963</identifier><identifier>CODEN: BJHEAL</identifier><language>eng</language><publisher>Oxford: Blackwell</publisher><subject>acute promyelocytic leukaemia ; Adolescent ; Adult ; all‐trans retinoic acid ; Anthracyclines - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biological and medical sciences ; Case-Control Studies ; developing countries ; DNA-Binding Proteins - metabolism ; Female ; Hematologic and hematopoietic diseases ; Humans ; International Consortium on Acute Promyelocytic Leukaemia ; KMT2E (MLL5) ; Leukemia, Promyelocytic, Acute - drug therapy ; Leukemia, Promyelocytic, Acute - metabolism ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Male ; Medical sciences ; Middle Aged ; Treatment Outcome ; Tretinoin - administration & dosage ; Tumors ; Young Adult</subject><ispartof>British journal of haematology, 2014-08, Vol.166 (4), p.540-549</ispartof><rights>2014 John Wiley & Sons Ltd</rights><rights>2015 INIST-CNRS</rights><rights>2014 John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbjh.12921$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbjh.12921$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28674007$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24796963$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lucena‐Araujo, Antonio R.</creatorcontrib><creatorcontrib>Kim, Haesook T.</creatorcontrib><creatorcontrib>Jacomo, Rafael H.</creatorcontrib><creatorcontrib>Melo, Raul A.</creatorcontrib><creatorcontrib>Bittencourt, Rosane</creatorcontrib><creatorcontrib>Pasquini, Ricardo</creatorcontrib><creatorcontrib>Pagnano, Katia</creatorcontrib><creatorcontrib>Fagundes, Evandro M.</creatorcontrib><creatorcontrib>Chauffaille, Maria</creatorcontrib><creatorcontrib>Chiattone, Carlos S.</creatorcontrib><creatorcontrib>Lima, Ana S.</creatorcontrib><creatorcontrib>Kwaan, Hau C.</creatorcontrib><creatorcontrib>Gallagher, Robert</creatorcontrib><creatorcontrib>Niemeyer, Charlotte M.</creatorcontrib><creatorcontrib>Schrier, Stanley L.</creatorcontrib><creatorcontrib>Tallman, Martin S.</creatorcontrib><creatorcontrib>Grimwade, David</creatorcontrib><creatorcontrib>Ganser, Arnold</creatorcontrib><creatorcontrib>Berliner, Nancy</creatorcontrib><creatorcontrib>Ribeiro, Raul C.</creatorcontrib><creatorcontrib>Lo‐Coco, Francesco</creatorcontrib><creatorcontrib>Löwenberg, Bob</creatorcontrib><creatorcontrib>Sanz, Miguel A.</creatorcontrib><creatorcontrib>Rego, Eduardo M.</creatorcontrib><title>Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all‐trans retinoic acid and anthracycline‐based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study</title><title>British journal of haematology</title><addtitle>Br J Haematol</addtitle><description>Summary
The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid–induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline‐based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2‐year overall survival (OS) (P = 0·005) and 2‐year disease‐free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2‐year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71–30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08–0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49–43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05–0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99–1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.</description><subject>acute promyelocytic leukaemia</subject><subject>Adolescent</subject><subject>Adult</subject><subject>all‐trans retinoic acid</subject><subject>Anthracyclines - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Case-Control Studies</subject><subject>developing countries</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Female</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>International Consortium on Acute Promyelocytic Leukaemia</subject><subject>KMT2E (MLL5)</subject><subject>Leukemia, Promyelocytic, Acute - drug therapy</subject><subject>Leukemia, Promyelocytic, Acute - metabolism</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Treatment Outcome</subject><subject>Tretinoin - administration & dosage</subject><subject>Tumors</subject><subject>Young Adult</subject><issn>0007-1048</issn><issn>1365-2141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNksFu1DAURSMEotPCgh9A3iCxmdaOHSdhV0aFFgbRRVlHL84L4-LYqe1QZddP4Bv5CpZ4pkMROyxZfpKPr66ub5a9YPSYpXXSXm-OWV7n7FG2YFwWy5wJ9jhbUErLJaOiOsgOQ7imlHFasKfZQS7KWtaSL7Jfl959tS5ErYgeRlCRuJ58_HSVn5HowQbl9RiJwe9oAnGWuCkqN-CWGiFqtDGQWx03BNQUkYzeDTMap-atosHpG-CgIWkhROz2qDE_737s5InHqK1LLCjdEbDbHTce1KyMtpi4FkJ6qDY4uLhBD-P8JjHkwkb0NllwFgxZORucj3oatiZPd14u__GyfvAS4tTNz7InPZiAz_fnUfbl3dnV6ny5_vz-YnW6Xo48hbiURd63Lc9pDVCn1AQvWdGLqswLCTmv87ZvS8lLVEzJrqoE5W0nKQVJO6xA8KPs9b1uSuZmwhCbQQeFxoBFN4WGFVJWghXl_6CiZmUpmEzoyz06tQN2zej1AH5u_nxsAl7tAQgKTJ-yVjr85SpZitSOxJ3cc7fa4Pxwz2izbVaTmtXsmtW8_XC-G_hvgD7H_w</recordid><startdate>201408</startdate><enddate>201408</enddate><creator>Lucena‐Araujo, Antonio R.</creator><creator>Kim, Haesook T.</creator><creator>Jacomo, Rafael H.</creator><creator>Melo, Raul A.</creator><creator>Bittencourt, Rosane</creator><creator>Pasquini, Ricardo</creator><creator>Pagnano, Katia</creator><creator>Fagundes, Evandro M.</creator><creator>Chauffaille, Maria</creator><creator>Chiattone, Carlos S.</creator><creator>Lima, Ana S.</creator><creator>Kwaan, Hau C.</creator><creator>Gallagher, Robert</creator><creator>Niemeyer, Charlotte M.</creator><creator>Schrier, Stanley L.</creator><creator>Tallman, Martin S.</creator><creator>Grimwade, David</creator><creator>Ganser, Arnold</creator><creator>Berliner, Nancy</creator><creator>Ribeiro, Raul C.</creator><creator>Lo‐Coco, Francesco</creator><creator>Löwenberg, Bob</creator><creator>Sanz, Miguel A.</creator><creator>Rego, Eduardo M.</creator><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>201408</creationdate><title>Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all‐trans retinoic acid and anthracycline‐based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study</title><author>Lucena‐Araujo, Antonio R. ; Kim, Haesook T. ; Jacomo, Rafael H. ; Melo, Raul A. ; Bittencourt, Rosane ; Pasquini, Ricardo ; Pagnano, Katia ; Fagundes, Evandro M. ; Chauffaille, Maria ; Chiattone, Carlos S. ; Lima, Ana S. ; Kwaan, Hau C. ; Gallagher, Robert ; Niemeyer, Charlotte M. ; Schrier, Stanley L. ; Tallman, Martin S. ; Grimwade, David ; Ganser, Arnold ; Berliner, Nancy ; Ribeiro, Raul C. ; Lo‐Coco, Francesco ; Löwenberg, Bob ; Sanz, Miguel A. ; Rego, Eduardo M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p3141-652fbb3209aa947943715f487256a2392bfb7637ec1c6d88403bd600a60de8a43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>acute promyelocytic leukaemia</topic><topic>Adolescent</topic><topic>Adult</topic><topic>all‐trans retinoic acid</topic><topic>Anthracyclines - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Case-Control Studies</topic><topic>developing countries</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Female</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>International Consortium on Acute Promyelocytic Leukaemia</topic><topic>KMT2E (MLL5)</topic><topic>Leukemia, Promyelocytic, Acute - drug therapy</topic><topic>Leukemia, Promyelocytic, Acute - metabolism</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Treatment Outcome</topic><topic>Tretinoin - administration & dosage</topic><topic>Tumors</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lucena‐Araujo, Antonio R.</creatorcontrib><creatorcontrib>Kim, Haesook T.</creatorcontrib><creatorcontrib>Jacomo, Rafael H.</creatorcontrib><creatorcontrib>Melo, Raul A.</creatorcontrib><creatorcontrib>Bittencourt, Rosane</creatorcontrib><creatorcontrib>Pasquini, Ricardo</creatorcontrib><creatorcontrib>Pagnano, Katia</creatorcontrib><creatorcontrib>Fagundes, Evandro M.</creatorcontrib><creatorcontrib>Chauffaille, Maria</creatorcontrib><creatorcontrib>Chiattone, Carlos S.</creatorcontrib><creatorcontrib>Lima, Ana S.</creatorcontrib><creatorcontrib>Kwaan, Hau C.</creatorcontrib><creatorcontrib>Gallagher, Robert</creatorcontrib><creatorcontrib>Niemeyer, Charlotte M.</creatorcontrib><creatorcontrib>Schrier, Stanley L.</creatorcontrib><creatorcontrib>Tallman, Martin S.</creatorcontrib><creatorcontrib>Grimwade, David</creatorcontrib><creatorcontrib>Ganser, Arnold</creatorcontrib><creatorcontrib>Berliner, Nancy</creatorcontrib><creatorcontrib>Ribeiro, Raul C.</creatorcontrib><creatorcontrib>Lo‐Coco, Francesco</creatorcontrib><creatorcontrib>Löwenberg, Bob</creatorcontrib><creatorcontrib>Sanz, Miguel A.</creatorcontrib><creatorcontrib>Rego, Eduardo M.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>British journal of haematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lucena‐Araujo, Antonio R.</au><au>Kim, Haesook T.</au><au>Jacomo, Rafael H.</au><au>Melo, Raul A.</au><au>Bittencourt, Rosane</au><au>Pasquini, Ricardo</au><au>Pagnano, Katia</au><au>Fagundes, Evandro M.</au><au>Chauffaille, Maria</au><au>Chiattone, Carlos S.</au><au>Lima, Ana S.</au><au>Kwaan, Hau C.</au><au>Gallagher, Robert</au><au>Niemeyer, Charlotte M.</au><au>Schrier, Stanley L.</au><au>Tallman, Martin S.</au><au>Grimwade, David</au><au>Ganser, Arnold</au><au>Berliner, Nancy</au><au>Ribeiro, Raul C.</au><au>Lo‐Coco, Francesco</au><au>Löwenberg, Bob</au><au>Sanz, Miguel A.</au><au>Rego, Eduardo M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all‐trans retinoic acid and anthracycline‐based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study</atitle><jtitle>British journal of haematology</jtitle><addtitle>Br J Haematol</addtitle><date>2014-08</date><risdate>2014</risdate><volume>166</volume><issue>4</issue><spage>540</spage><epage>549</epage><pages>540-549</pages><issn>0007-1048</issn><eissn>1365-2141</eissn><coden>BJHEAL</coden><abstract>Summary
The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid–induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline‐based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2‐year overall survival (OS) (P = 0·005) and 2‐year disease‐free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2‐year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71–30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08–0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49–43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05–0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99–1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.</abstract><cop>Oxford</cop><pub>Blackwell</pub><pmid>24796963</pmid><doi>10.1111/bjh.12921</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0007-1048 |
| ispartof | British journal of haematology, 2014-08, Vol.166 (4), p.540-549 |
| issn | 0007-1048 1365-2141 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1566841574 |
| source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | acute promyelocytic leukaemia Adolescent Adult all‐trans retinoic acid Anthracyclines - administration & dosage Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Case-Control Studies developing countries DNA-Binding Proteins - metabolism Female Hematologic and hematopoietic diseases Humans International Consortium on Acute Promyelocytic Leukaemia KMT2E (MLL5) Leukemia, Promyelocytic, Acute - drug therapy Leukemia, Promyelocytic, Acute - metabolism Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Male Medical sciences Middle Aged Treatment Outcome Tretinoin - administration & dosage Tumors Young Adult |
| title | Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all‐trans retinoic acid and anthracycline‐based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-19T23%3A43%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Prognostic%20impact%20of%20KMT2E%20transcript%20levels%20on%20outcome%20of%20patients%20with%20acute%20promyelocytic%20leukaemia%20treated%20with%20all%E2%80%90trans%20retinoic%20acid%20and%20anthracycline%E2%80%90based%20chemotherapy:%20an%20International%20Consortium%20on%20Acute%20Promyelocytic%20Leukaemia%20study&rft.jtitle=British%20journal%20of%20haematology&rft.au=Lucena%E2%80%90Araujo,%20Antonio%20R.&rft.date=2014-08&rft.volume=166&rft.issue=4&rft.spage=540&rft.epage=549&rft.pages=540-549&rft.issn=0007-1048&rft.eissn=1365-2141&rft.coden=BJHEAL&rft_id=info:doi/10.1111/bjh.12921&rft_dat=%3Cproquest_pubme%3E1549177416%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1549177416&rft_id=info:pmid/24796963&rfr_iscdi=true |