Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's disease
The association between the 6-thioguanine nucleotide (6-TGN) level and clinical remission in Crohn's disease (CD) remains controversial. Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with NUDT15 genetic variants. T...
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| description | The association between the 6-thioguanine nucleotide (6-TGN) level and clinical remission in Crohn's disease (CD) remains controversial. Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with NUDT15 genetic variants. This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of NUDT15, TPMT, and thiopurine metabolites with leukopenia in patients with CD. We enrolled 165 adult patients with CD undergoing thiopurine treatment. Clinical evaluation and laboratory examinations were carried out every 2-3 months. We measured thiopurine metabolites levels and genotyped NUDT15 and TPMT. During the median 12-month observational period, 95 (67.9%) patients exhibited clinical response and 45 (32.1%) did not respond to the treatment. The median 6-TGN level was significantly higher in responders than in non-responders (P < 0.001). The odds ratio of patients with a 6-TGN level ≥230 pmol/8 × 108 red blood cells for showing a clinical response was 4.63 (95% CI 1.62-11.9). NUDT15 variant types were strongly associated with developing leukopenia. Patients with NUDT15 homozygous variant genotype developed severe early leukopenia with an average reduction of 88.2% (range, 84-94%) from the baseline white blood cell count at 4 weeks. Our findings support the role of therapeutic drug monitoring in thiopurine maintenance treatment to optimize thiopurine therapy, especially, for non-responding CD patients. Thiopurine treatment should not be recommended to patients with NUDT15 homozygous variant genotype due to severe early leukopenia. |
| doi_str_mv | 10.1371/journal.pone.0188925 |
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Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with NUDT15 genetic variants. This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of NUDT15, TPMT, and thiopurine metabolites with leukopenia in patients with CD. We enrolled 165 adult patients with CD undergoing thiopurine treatment. Clinical evaluation and laboratory examinations were carried out every 2-3 months. We measured thiopurine metabolites levels and genotyped NUDT15 and TPMT. During the median 12-month observational period, 95 (67.9%) patients exhibited clinical response and 45 (32.1%) did not respond to the treatment. The median 6-TGN level was significantly higher in responders than in non-responders (P < 0.001). The odds ratio of patients with a 6-TGN level ≥230 pmol/8 × 108 red blood cells for showing a clinical response was 4.63 (95% CI 1.62-11.9). NUDT15 variant types were strongly associated with developing leukopenia. Patients with NUDT15 homozygous variant genotype developed severe early leukopenia with an average reduction of 88.2% (range, 84-94%) from the baseline white blood cell count at 4 weeks. Our findings support the role of therapeutic drug monitoring in thiopurine maintenance treatment to optimize thiopurine therapy, especially, for non-responding CD patients. Thiopurine treatment should not be recommended to patients with NUDT15 homozygous variant genotype due to severe early leukopenia.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0188925</identifier><identifier>PMID: 29206869</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Biology and Life Sciences ; Blood ; Blood cells ; Complications and side effects ; Crohn Disease - blood ; Crohn Disease - genetics ; Crohn's disease ; Dosage and administration ; Erythrocytes ; Female ; Genetic aspects ; Genetic diversity ; Genetic variance ; Genotypes ; Genotyping ; Guanine Nucleotides - blood ; Health aspects ; Humans ; Inflammatory bowel disease ; Laboratories ; Leukocytes ; Leukopenia ; Male ; Measurement ; Medicine and Health Sciences ; Metabolites ; Methyltransferases - genetics ; Middle Aged ; Mutation ; Patients ; Pyrophosphatases - genetics ; Remission ; Retrospective Studies ; Therapeutic drug monitoring ; Thioguanine ; Thionucleotides - blood ; White blood cell count</subject><ispartof>PloS one, 2017-12, Vol.12 (12), p.e0188925-e0188925</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Lee et al 2017 Lee et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-cd42cf6e9510b34aeb9f9bcefbfac9e9ffd387855c686a6486a29e18025aafb93</citedby><cites>FETCH-LOGICAL-c692t-cd42cf6e9510b34aeb9f9bcefbfac9e9ffd387855c686a6486a29e18025aafb93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716599/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716599/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29206869$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Green, John</contributor><creatorcontrib>Lee, Ji Hyeon</creatorcontrib><creatorcontrib>Kim, Tae Jun</creatorcontrib><creatorcontrib>Kim, Eun Ran</creatorcontrib><creatorcontrib>Hong, Sung Noh</creatorcontrib><creatorcontrib>Chang, Dong Kyung</creatorcontrib><creatorcontrib>Choi, Li-Hwa</creatorcontrib><creatorcontrib>Woo, Hye In</creatorcontrib><creatorcontrib>Lee, Soo-Youn</creatorcontrib><creatorcontrib>Kim, Young-Ho</creatorcontrib><title>Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's disease</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The association between the 6-thioguanine nucleotide (6-TGN) level and clinical remission in Crohn's disease (CD) remains controversial. Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with NUDT15 genetic variants. This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of NUDT15, TPMT, and thiopurine metabolites with leukopenia in patients with CD. We enrolled 165 adult patients with CD undergoing thiopurine treatment. Clinical evaluation and laboratory examinations were carried out every 2-3 months. We measured thiopurine metabolites levels and genotyped NUDT15 and TPMT. During the median 12-month observational period, 95 (67.9%) patients exhibited clinical response and 45 (32.1%) did not respond to the treatment. The median 6-TGN level was significantly higher in responders than in non-responders (P < 0.001). The odds ratio of patients with a 6-TGN level ≥230 pmol/8 × 108 red blood cells for showing a clinical response was 4.63 (95% CI 1.62-11.9). NUDT15 variant types were strongly associated with developing leukopenia. Patients with NUDT15 homozygous variant genotype developed severe early leukopenia with an average reduction of 88.2% (range, 84-94%) from the baseline white blood cell count at 4 weeks. Our findings support the role of therapeutic drug monitoring in thiopurine maintenance treatment to optimize thiopurine therapy, especially, for non-responding CD patients. Thiopurine treatment should not be recommended to patients with NUDT15 homozygous variant genotype due to severe early leukopenia.</description><subject>Adult</subject><subject>Biology and Life Sciences</subject><subject>Blood</subject><subject>Blood cells</subject><subject>Complications and side effects</subject><subject>Crohn Disease - blood</subject><subject>Crohn Disease - genetics</subject><subject>Crohn's disease</subject><subject>Dosage and administration</subject><subject>Erythrocytes</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>Genotypes</subject><subject>Genotyping</subject><subject>Guanine Nucleotides - blood</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Inflammatory bowel disease</subject><subject>Laboratories</subject><subject>Leukocytes</subject><subject>Leukopenia</subject><subject>Male</subject><subject>Measurement</subject><subject>Medicine and Health Sciences</subject><subject>Metabolites</subject><subject>Methyltransferases - genetics</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Patients</subject><subject>Pyrophosphatases - genetics</subject><subject>Remission</subject><subject>Retrospective Studies</subject><subject>Therapeutic drug monitoring</subject><subject>Thioguanine</subject><subject>Thionucleotides - blood</subject><subject>White blood cell count</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1tv0zAUxyMEYmPwDRBEmsTlocWOYyd-QZrKrdLGEHS8Wo5znLpK7RA7g3173DabWrQHZMm27N_5n4t9kuQ5RlNMCvxu5YbeynbaOQtThMuSZ_RBcow5ySYsQ-Th3v4oeeL9CiFKSsYeJ0cZzxArGT9OuguQfuhhDTb41OmUTcLSuGaQ1lhI7aBacMHUkLZwDa1Pf5uwTBffLhaptHX69erDAtO0AevCTWdskxqbdjKYrdyWnfVuaV_7tDY-uoKnySMtWw_PxvUkufr0cTH7Mjm__DyfnZ1PFONZmKg6z5RmwClGFcklVFzzSoGutFQcuNY1KYuSUhXzkCyPU8YBlyijUuqKk5Pk5U63a50XY7G8wLwgKCsIpZGY74jayZXoerOW_Y1w0ojtgesbIftgYgEEZRnOOGYABHIkZYkkITmouuZ5rnQVtd6P3oZqDbWK6feyPRA9vLFmKRp3LWiBGeWbcN-MAr37NYAPYm28graVFtywizunBSuKiJ7-g96f3Ug1MiZgrHbRr9qIijOKC5rnKMeRmt5DxVHD2qj4s7SJ5wcGbw8MIhPgT2jk4L2Y__j-_-zlz0P21R67BNmGpXftEIyz_hDMd6Dqnfc96LsiYyQ2jXFbDbFpDDE2RjR7sf9Ad0a3nUD-Apl7CV4</recordid><startdate>20171205</startdate><enddate>20171205</enddate><creator>Lee, Ji Hyeon</creator><creator>Kim, Tae Jun</creator><creator>Kim, Eun Ran</creator><creator>Hong, Sung Noh</creator><creator>Chang, Dong Kyung</creator><creator>Choi, Li-Hwa</creator><creator>Woo, Hye In</creator><creator>Lee, Soo-Youn</creator><creator>Kim, Young-Ho</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20171205</creationdate><title>Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's disease</title><author>Lee, Ji Hyeon ; Kim, Tae Jun ; Kim, Eun Ran ; Hong, Sung Noh ; Chang, Dong Kyung ; Choi, Li-Hwa ; Woo, Hye In ; Lee, Soo-Youn ; Kim, Young-Ho</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-cd42cf6e9510b34aeb9f9bcefbfac9e9ffd387855c686a6486a29e18025aafb93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adult</topic><topic>Biology and Life Sciences</topic><topic>Blood</topic><topic>Blood cells</topic><topic>Complications and side effects</topic><topic>Crohn Disease - blood</topic><topic>Crohn Disease - genetics</topic><topic>Crohn's disease</topic><topic>Dosage and administration</topic><topic>Erythrocytes</topic><topic>Female</topic><topic>Genetic aspects</topic><topic>Genetic diversity</topic><topic>Genetic variance</topic><topic>Genotypes</topic><topic>Genotyping</topic><topic>Guanine Nucleotides - blood</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Inflammatory bowel disease</topic><topic>Laboratories</topic><topic>Leukocytes</topic><topic>Leukopenia</topic><topic>Male</topic><topic>Measurement</topic><topic>Medicine and Health Sciences</topic><topic>Metabolites</topic><topic>Methyltransferases - genetics</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Patients</topic><topic>Pyrophosphatases - genetics</topic><topic>Remission</topic><topic>Retrospective Studies</topic><topic>Therapeutic drug monitoring</topic><topic>Thioguanine</topic><topic>Thionucleotides - blood</topic><topic>White blood cell count</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Ji Hyeon</creatorcontrib><creatorcontrib>Kim, Tae Jun</creatorcontrib><creatorcontrib>Kim, Eun Ran</creatorcontrib><creatorcontrib>Hong, Sung Noh</creatorcontrib><creatorcontrib>Chang, Dong Kyung</creatorcontrib><creatorcontrib>Choi, Li-Hwa</creatorcontrib><creatorcontrib>Woo, Hye In</creatorcontrib><creatorcontrib>Lee, Soo-Youn</creatorcontrib><creatorcontrib>Kim, Young-Ho</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Ji Hyeon</au><au>Kim, Tae Jun</au><au>Kim, Eun Ran</au><au>Hong, Sung Noh</au><au>Chang, Dong Kyung</au><au>Choi, Li-Hwa</au><au>Woo, Hye In</au><au>Lee, Soo-Youn</au><au>Kim, Young-Ho</au><au>Green, John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's disease</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-12-05</date><risdate>2017</risdate><volume>12</volume><issue>12</issue><spage>e0188925</spage><epage>e0188925</epage><pages>e0188925-e0188925</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The association between the 6-thioguanine nucleotide (6-TGN) level and clinical remission in Crohn's disease (CD) remains controversial. Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with NUDT15 genetic variants. This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of NUDT15, TPMT, and thiopurine metabolites with leukopenia in patients with CD. We enrolled 165 adult patients with CD undergoing thiopurine treatment. Clinical evaluation and laboratory examinations were carried out every 2-3 months. We measured thiopurine metabolites levels and genotyped NUDT15 and TPMT. During the median 12-month observational period, 95 (67.9%) patients exhibited clinical response and 45 (32.1%) did not respond to the treatment. The median 6-TGN level was significantly higher in responders than in non-responders (P < 0.001). The odds ratio of patients with a 6-TGN level ≥230 pmol/8 × 108 red blood cells for showing a clinical response was 4.63 (95% CI 1.62-11.9). NUDT15 variant types were strongly associated with developing leukopenia. Patients with NUDT15 homozygous variant genotype developed severe early leukopenia with an average reduction of 88.2% (range, 84-94%) from the baseline white blood cell count at 4 weeks. Our findings support the role of therapeutic drug monitoring in thiopurine maintenance treatment to optimize thiopurine therapy, especially, for non-responding CD patients. Thiopurine treatment should not be recommended to patients with NUDT15 homozygous variant genotype due to severe early leukopenia.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29206869</pmid><doi>10.1371/journal.pone.0188925</doi><tpages>e0188925</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | PloS one, 2017-12, Vol.12 (12), p.e0188925-e0188925 |
| issn | 1932-6203 1932-6203 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Biology and Life Sciences Blood Blood cells Complications and side effects Crohn Disease - blood Crohn Disease - genetics Crohn's disease Dosage and administration Erythrocytes Female Genetic aspects Genetic diversity Genetic variance Genotypes Genotyping Guanine Nucleotides - blood Health aspects Humans Inflammatory bowel disease Laboratories Leukocytes Leukopenia Male Measurement Medicine and Health Sciences Metabolites Methyltransferases - genetics Middle Aged Mutation Patients Pyrophosphatases - genetics Remission Retrospective Studies Therapeutic drug monitoring Thioguanine Thionucleotides - blood White blood cell count |
| title | Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-29T12%3A16%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Measurements%20of%206-thioguanine%20nucleotide%20levels%20with%20TPMT%20and%20NUDT15%20genotyping%20in%20patients%20with%20Crohn's%20disease&rft.jtitle=PloS%20one&rft.au=Lee,%20Ji%20Hyeon&rft.date=2017-12-05&rft.volume=12&rft.issue=12&rft.spage=e0188925&rft.epage=e0188925&rft.pages=e0188925-e0188925&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0188925&rft_dat=%3Cgale_plos_%3EA517544041%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1973027355&rft_id=info:pmid/29206869&rft_galeid=A517544041&rft_doaj_id=oai_doaj_org_article_56212916ee3e40aa80a334ecdd944cfb&rfr_iscdi=true |