Prognostic Value of Procalcitonin in Adult Patients with Sepsis: A Systematic Review and Meta-Analysis
Procalcitonin (PCT) has been widely investigated for its prognostic value in septic patients. However, studies have produced conflicting results. The purpose of the present meta-analysis is to explore the diagnostic accuracy of a single PCT concentration and PCT non-clearance in predicting all-cause...
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| description | Procalcitonin (PCT) has been widely investigated for its prognostic value in septic patients. However, studies have produced conflicting results. The purpose of the present meta-analysis is to explore the diagnostic accuracy of a single PCT concentration and PCT non-clearance in predicting all-cause sepsis mortality. We searched PubMed, Embase, Web of Knowledge and the Cochrane Library. Articles written in English were included. A 2 × 2 contingency table was constructed based on all-cause mortality and PCT level or PCT non-clearance in septic patients. Two authors independently evaluated study eligibility and extracted data. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. We used the Q-test and I2 index to test heterogeneity. Twenty-three studies with 3,994 patients were included. An elevated PCT level was associated with a higher risk of death. The pooled relative risk (RR) was 2.60 (95% confidence interval (CI), 2.05-3.30) using a random-effects model (I(2) = 63.5%). The overall area under the summary receiver operator characteristic (SROC) curve was 0.77 (95% CI, 0.73-0.80), with a sensitivity and specificity of 0.76 (95% CI, 0.67-0.82) and 0.64 (95% CI, 0.52-0.74), respectively. There was significant evidence of heterogeneity for the PCT testing time (P = 0.020). Initial PCT values were of limited prognostic value in patients with sepsis. PCT non-clearance was a prognostic factor of death in patients with sepsis. The pooled RR was 3.05 (95% CI, 2.35-3.95) using a fixed-effects model (I(2) = 37.9%). The overall area under the SROC curve was 0.79 (95% CI, 0.75-0.83), with a sensitivity and specificity of 0.72 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.55-0.90), respectively. Elevated PCT concentrations and PCT non-clearance are strongly associated with all-cause mortality in septic patients. Further studies are needed to define the optimal cut-off point and the optimal definition of PCT non-clearance for accurate risk assessment. |
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However, studies have produced conflicting results. The purpose of the present meta-analysis is to explore the diagnostic accuracy of a single PCT concentration and PCT non-clearance in predicting all-cause sepsis mortality. We searched PubMed, Embase, Web of Knowledge and the Cochrane Library. Articles written in English were included. A 2 × 2 contingency table was constructed based on all-cause mortality and PCT level or PCT non-clearance in septic patients. Two authors independently evaluated study eligibility and extracted data. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. We used the Q-test and I2 index to test heterogeneity. Twenty-three studies with 3,994 patients were included. An elevated PCT level was associated with a higher risk of death. The pooled relative risk (RR) was 2.60 (95% confidence interval (CI), 2.05-3.30) using a random-effects model (I(2) = 63.5%). The overall area under the summary receiver operator characteristic (SROC) curve was 0.77 (95% CI, 0.73-0.80), with a sensitivity and specificity of 0.76 (95% CI, 0.67-0.82) and 0.64 (95% CI, 0.52-0.74), respectively. There was significant evidence of heterogeneity for the PCT testing time (P = 0.020). Initial PCT values were of limited prognostic value in patients with sepsis. PCT non-clearance was a prognostic factor of death in patients with sepsis. The pooled RR was 3.05 (95% CI, 2.35-3.95) using a fixed-effects model (I(2) = 37.9%). The overall area under the SROC curve was 0.79 (95% CI, 0.75-0.83), with a sensitivity and specificity of 0.72 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.55-0.90), respectively. Elevated PCT concentrations and PCT non-clearance are strongly associated with all-cause mortality in septic patients. Further studies are needed to define the optimal cut-off point and the optimal definition of PCT non-clearance for accurate risk assessment.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0129450</identifier><identifier>PMID: 26076027</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Biomarkers ; Bivariate analysis ; Calcitonin - blood ; Calcitonin Gene-Related Peptide ; Cognitive biases ; Confidence intervals ; Contingency ; Critical care ; Diagnostic systems ; Emergency Service, Hospital ; Health aspects ; Heterogeneity ; Hospitals ; Humans ; Infectious diseases ; Intensive care ; Intensive Care Units ; Mathematical models ; Medical diagnosis ; Medical ethics ; Medical prognosis ; Medicine ; Meta-analysis ; Mortality ; Odds Ratio ; Patients ; Pneumonia ; Procalcitonin ; Protein Precursors - blood ; Proteins ; Risk assessment ; Sensitivity ; Sepsis ; Sepsis - blood ; Sepsis - diagnosis ; Sepsis - mortality ; Statistical analysis ; Studies ; Systematic review ; Testing time</subject><ispartof>PloS one, 2015-06, Vol.10 (6), p.e0129450-e0129450</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Liu 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>2015 Liu et al 2015 Liu et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-a9a6147f4360f7d26df7564e0836567ee5e9129a73b598a6a7df34b871e7b9fd3</citedby><cites>FETCH-LOGICAL-c692t-a9a6147f4360f7d26df7564e0836567ee5e9129a73b598a6a7df34b871e7b9fd3</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/PMC4468164/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468164/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26076027$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Dan</creatorcontrib><creatorcontrib>Su, Longxiang</creatorcontrib><creatorcontrib>Han, Gencheng</creatorcontrib><creatorcontrib>Yan, Peng</creatorcontrib><creatorcontrib>Xie, Lixin</creatorcontrib><title>Prognostic Value of Procalcitonin in Adult Patients with Sepsis: A Systematic Review and Meta-Analysis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Procalcitonin (PCT) has been widely investigated for its prognostic value in septic patients. However, studies have produced conflicting results. The purpose of the present meta-analysis is to explore the diagnostic accuracy of a single PCT concentration and PCT non-clearance in predicting all-cause sepsis mortality. We searched PubMed, Embase, Web of Knowledge and the Cochrane Library. Articles written in English were included. A 2 × 2 contingency table was constructed based on all-cause mortality and PCT level or PCT non-clearance in septic patients. Two authors independently evaluated study eligibility and extracted data. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. We used the Q-test and I2 index to test heterogeneity. Twenty-three studies with 3,994 patients were included. An elevated PCT level was associated with a higher risk of death. The pooled relative risk (RR) was 2.60 (95% confidence interval (CI), 2.05-3.30) using a random-effects model (I(2) = 63.5%). The overall area under the summary receiver operator characteristic (SROC) curve was 0.77 (95% CI, 0.73-0.80), with a sensitivity and specificity of 0.76 (95% CI, 0.67-0.82) and 0.64 (95% CI, 0.52-0.74), respectively. There was significant evidence of heterogeneity for the PCT testing time (P = 0.020). Initial PCT values were of limited prognostic value in patients with sepsis. PCT non-clearance was a prognostic factor of death in patients with sepsis. The pooled RR was 3.05 (95% CI, 2.35-3.95) using a fixed-effects model (I(2) = 37.9%). The overall area under the SROC curve was 0.79 (95% CI, 0.75-0.83), with a sensitivity and specificity of 0.72 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.55-0.90), respectively. Elevated PCT concentrations and PCT non-clearance are strongly associated with all-cause mortality in septic patients. Further studies are needed to define the optimal cut-off point and the optimal definition of PCT non-clearance for accurate risk assessment.</description><subject>Analysis</subject><subject>Biomarkers</subject><subject>Bivariate analysis</subject><subject>Calcitonin - blood</subject><subject>Calcitonin Gene-Related Peptide</subject><subject>Cognitive biases</subject><subject>Confidence intervals</subject><subject>Contingency</subject><subject>Critical care</subject><subject>Diagnostic systems</subject><subject>Emergency Service, Hospital</subject><subject>Health aspects</subject><subject>Heterogeneity</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Intensive care</subject><subject>Intensive Care Units</subject><subject>Mathematical models</subject><subject>Medical diagnosis</subject><subject>Medical ethics</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Meta-analysis</subject><subject>Mortality</subject><subject>Odds Ratio</subject><subject>Patients</subject><subject>Pneumonia</subject><subject>Procalcitonin</subject><subject>Protein Precursors - blood</subject><subject>Proteins</subject><subject>Risk assessment</subject><subject>Sensitivity</subject><subject>Sepsis</subject><subject>Sepsis - blood</subject><subject>Sepsis - diagnosis</subject><subject>Sepsis - mortality</subject><subject>Statistical analysis</subject><subject>Studies</subject><subject>Systematic review</subject><subject>Testing time</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk99v0zAQxyMEYmPwHyCIhITgocWJHTvhAama-FFpaNMKe7Wuzrl15cZd7Gz0v8dZu6lBe0C2ZOv8ua_vzr4keZ2RcUZF9mnlurYBO964BsckyytWkCfJcVbRfMRzQp8e7I-SF96vCCloyfnz5CjnRHCSi-NEX7Ru0TgfjEqvwHaYOp1GmwKrTHCNadI4J3VnQ3oBwWATfHprwjKd4cYb_zmdpLOtD7iGXuISbwzeptDU6U8MMJrECLcRe5k802A9vtqvJ8nvb19_nf4YnZ1_n55OzkaKV3kYQQU8Y0IzyokWdc5rLQrOkJSUF1wgFljFTEHQeVGVwEHUmrJ5KTIU80rX9CR5u9PdWOflvkReZrwsCyaoKCMx3RG1g5XctGYN7VY6MPLO4NqFhDamYlEWBEADFFlZcUZBlZUmBOd9hLWqFYtaX_a3dfM11ioWpwU7EB2eNGYpF-5GMsbLjPcCH_YCrbvu0Ae5Nl6htdCg6-7irnhOSd6j7_5BH89uTy0gJmAa7eK9qheVE5aVhFRUiEiNH6HiqHFtVPxP2kT7wOHjwCEyAf-EBXTey-ns8v_Z86sh-_6AXSLYsPTOdsG4xg9BtgNV67xvUT8UOSOyb4f7asi-HeS-HaLbm8MHenC6___0L4TZBMA</recordid><startdate>20150615</startdate><enddate>20150615</enddate><creator>Liu, Dan</creator><creator>Su, Longxiang</creator><creator>Han, Gencheng</creator><creator>Yan, Peng</creator><creator>Xie, Lixin</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>AEUYN</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150615</creationdate><title>Prognostic Value of Procalcitonin in Adult Patients with Sepsis: A Systematic Review and Meta-Analysis</title><author>Liu, Dan ; Su, Longxiang ; Han, Gencheng ; Yan, Peng ; Xie, Lixin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-a9a6147f4360f7d26df7564e0836567ee5e9129a73b598a6a7df34b871e7b9fd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Analysis</topic><topic>Biomarkers</topic><topic>Bivariate analysis</topic><topic>Calcitonin - blood</topic><topic>Calcitonin Gene-Related Peptide</topic><topic>Cognitive biases</topic><topic>Confidence intervals</topic><topic>Contingency</topic><topic>Critical care</topic><topic>Diagnostic systems</topic><topic>Emergency Service, Hospital</topic><topic>Health aspects</topic><topic>Heterogeneity</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Intensive care</topic><topic>Intensive Care Units</topic><topic>Mathematical models</topic><topic>Medical diagnosis</topic><topic>Medical ethics</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Meta-analysis</topic><topic>Mortality</topic><topic>Odds Ratio</topic><topic>Patients</topic><topic>Pneumonia</topic><topic>Procalcitonin</topic><topic>Protein Precursors - blood</topic><topic>Proteins</topic><topic>Risk assessment</topic><topic>Sensitivity</topic><topic>Sepsis</topic><topic>Sepsis - blood</topic><topic>Sepsis - diagnosis</topic><topic>Sepsis - mortality</topic><topic>Statistical analysis</topic><topic>Studies</topic><topic>Systematic review</topic><topic>Testing time</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Dan</creatorcontrib><creatorcontrib>Su, Longxiang</creatorcontrib><creatorcontrib>Han, Gencheng</creatorcontrib><creatorcontrib>Yan, Peng</creatorcontrib><creatorcontrib>Xie, Lixin</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 One Sustainability</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>Liu, Dan</au><au>Su, Longxiang</au><au>Han, Gencheng</au><au>Yan, Peng</au><au>Xie, Lixin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prognostic Value of Procalcitonin in Adult Patients with Sepsis: A Systematic Review and Meta-Analysis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-06-15</date><risdate>2015</risdate><volume>10</volume><issue>6</issue><spage>e0129450</spage><epage>e0129450</epage><pages>e0129450-e0129450</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Procalcitonin (PCT) has been widely investigated for its prognostic value in septic patients. However, studies have produced conflicting results. The purpose of the present meta-analysis is to explore the diagnostic accuracy of a single PCT concentration and PCT non-clearance in predicting all-cause sepsis mortality. We searched PubMed, Embase, Web of Knowledge and the Cochrane Library. Articles written in English were included. A 2 × 2 contingency table was constructed based on all-cause mortality and PCT level or PCT non-clearance in septic patients. Two authors independently evaluated study eligibility and extracted data. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. We used the Q-test and I2 index to test heterogeneity. Twenty-three studies with 3,994 patients were included. An elevated PCT level was associated with a higher risk of death. The pooled relative risk (RR) was 2.60 (95% confidence interval (CI), 2.05-3.30) using a random-effects model (I(2) = 63.5%). The overall area under the summary receiver operator characteristic (SROC) curve was 0.77 (95% CI, 0.73-0.80), with a sensitivity and specificity of 0.76 (95% CI, 0.67-0.82) and 0.64 (95% CI, 0.52-0.74), respectively. There was significant evidence of heterogeneity for the PCT testing time (P = 0.020). Initial PCT values were of limited prognostic value in patients with sepsis. PCT non-clearance was a prognostic factor of death in patients with sepsis. The pooled RR was 3.05 (95% CI, 2.35-3.95) using a fixed-effects model (I(2) = 37.9%). The overall area under the SROC curve was 0.79 (95% CI, 0.75-0.83), with a sensitivity and specificity of 0.72 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.55-0.90), respectively. Elevated PCT concentrations and PCT non-clearance are strongly associated with all-cause mortality in septic patients. Further studies are needed to define the optimal cut-off point and the optimal definition of PCT non-clearance for accurate risk assessment.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26076027</pmid><doi>10.1371/journal.pone.0129450</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Analysis Biomarkers Bivariate analysis Calcitonin - blood Calcitonin Gene-Related Peptide Cognitive biases Confidence intervals Contingency Critical care Diagnostic systems Emergency Service, Hospital Health aspects Heterogeneity Hospitals Humans Infectious diseases Intensive care Intensive Care Units Mathematical models Medical diagnosis Medical ethics Medical prognosis Medicine Meta-analysis Mortality Odds Ratio Patients Pneumonia Procalcitonin Protein Precursors - blood Proteins Risk assessment Sensitivity Sepsis Sepsis - blood Sepsis - diagnosis Sepsis - mortality Statistical analysis Studies Systematic review Testing time |
| title | Prognostic Value of Procalcitonin in Adult Patients with Sepsis: A Systematic Review and Meta-Analysis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T10%3A20%3A42IST&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=Prognostic%20Value%20of%20Procalcitonin%20in%20Adult%20Patients%20with%20Sepsis:%20A%20Systematic%20Review%20and%20Meta-Analysis&rft.jtitle=PloS%20one&rft.au=Liu,%20Dan&rft.date=2015-06-15&rft.volume=10&rft.issue=6&rft.spage=e0129450&rft.epage=e0129450&rft.pages=e0129450-e0129450&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0129450&rft_dat=%3Cgale_plos_%3EA418009377%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=1688547378&rft_id=info:pmid/26076027&rft_galeid=A418009377&rft_doaj_id=oai_doaj_org_article_50aafaa5189643ac89f00eb6147dcdc4&rfr_iscdi=true |