Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder
Aim Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations...
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| Veröffentlicht in: | British journal of clinical pharmacology 2021-03, Vol.87 (3), p.1069-1081 |
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| creator | Kloosterboer, Sanne Maartje Winter, Brenda C.M. Reichart, Catrien G. Kouijzer, Mirjam E.J. Kroon, Matthias M.J. Daalen, Emma Ester, Wietske A. Rieken, Rob Dieleman, Gwen C. Altena, Daphne Bartelds, Beatrijs Schaik, Ron H.N. Nasserinejad, Kazem Hillegers, Manon H.J. Gelder, Teun Dierckx, Bram Koch, Birgit C.P. |
| description | Aim
Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations and 24‐hour area under the curves (AUCs) with body mass index (BMI) z‐scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness.
Methods
Forty‐two children and adolescents (32 males) aged 6‐18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9‐hydroxyrisperidone concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐hour AUCs were analysed to predict outcomes using generalized and linear mixed‐effects models.
Results
A risperidone two‐compartment model combined with a 9‐hydroxyrisperidone one‐compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z‐scores during follow‐up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01).
Conclusion
Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems. |
| doi_str_mv | 10.1111/bcp.14465 |
| format | Article |
| fullrecord | <record><control><sourceid>wiley_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9328651</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>BCP14465</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4555-1b624164c4bcb025351370c49042abc91d6a0bded788e35a0d487ab0ec5b803f3</originalsourceid><addsrcrecordid>eNp1kU1rFTEUhoNU7PXqwj9Qsu1i2nzfuRtBL2qFgiK6Dvk4402ZSYacuS39E_3NTjtt0YXZJHCe87yEl5B3nJ3x-Zz7MJ5xpYx-QVZcGt0ILvQRWTHJTKOF5sfkNeIVY1xyo1-RYymMkoLLFbn7kXCEmmLJQMfe4eBoKDlAnqqbUslIXQXqEEtIboJIb9K0p5giUOg6CNMM5Pj4TteQAZGmTMM-9bFCfpi6WHrAeyku--4wJRzoHB2mehhoTFhqhPqGvOxcj_D28V6TX58__dxdNJffvnzdfbhsgtJaN9wbobhRQfngmdBSc7lhQW2ZEs6HLY_GMR8hbtoWpHYsqnbjPIOgfctkJ9fk_eIdD36AuHy3t2NNg6u3trhk_53ktLe_y7XdStGaOW1NThdBqAWxQve8y5m9L8XOpdiHUmb25O-wZ_KphRk4X4Cb1MPt_0324-77ovwDaAWblQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder</title><source>Wiley Free Content</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Wiley Online Library All Journals</source><creator>Kloosterboer, Sanne Maartje ; Winter, Brenda C.M. ; Reichart, Catrien G. ; Kouijzer, Mirjam E.J. ; Kroon, Matthias M.J. ; Daalen, Emma ; Ester, Wietske A. ; Rieken, Rob ; Dieleman, Gwen C. ; Altena, Daphne ; Bartelds, Beatrijs ; Schaik, Ron H.N. ; Nasserinejad, Kazem ; Hillegers, Manon H.J. ; Gelder, Teun ; Dierckx, Bram ; Koch, Birgit C.P.</creator><creatorcontrib>Kloosterboer, Sanne Maartje ; Winter, Brenda C.M. ; Reichart, Catrien G. ; Kouijzer, Mirjam E.J. ; Kroon, Matthias M.J. ; Daalen, Emma ; Ester, Wietske A. ; Rieken, Rob ; Dieleman, Gwen C. ; Altena, Daphne ; Bartelds, Beatrijs ; Schaik, Ron H.N. ; Nasserinejad, Kazem ; Hillegers, Manon H.J. ; Gelder, Teun ; Dierckx, Bram ; Koch, Birgit C.P.</creatorcontrib><description>Aim
Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations and 24‐hour area under the curves (AUCs) with body mass index (BMI) z‐scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness.
Methods
Forty‐two children and adolescents (32 males) aged 6‐18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9‐hydroxyrisperidone concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐hour AUCs were analysed to predict outcomes using generalized and linear mixed‐effects models.
Results
A risperidone two‐compartment model combined with a 9‐hydroxyrisperidone one‐compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z‐scores during follow‐up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01).
Conclusion
Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/bcp.14465</identifier><identifier>PMID: 32643213</identifier><language>eng</language><publisher>England: John Wiley and Sons Inc</publisher><subject>adolescent ; antipsychotic ; autism spectrum disorder ; body mass index ; child ; cytochrome P‐450 ; drug monitoring ; Original ; prolactin ; risperidone ; weight gain</subject><ispartof>British journal of clinical pharmacology, 2021-03, Vol.87 (3), p.1069-1081</ispartof><rights>2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society</rights><rights>2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4555-1b624164c4bcb025351370c49042abc91d6a0bded788e35a0d487ab0ec5b803f3</citedby><cites>FETCH-LOGICAL-c4555-1b624164c4bcb025351370c49042abc91d6a0bded788e35a0d487ab0ec5b803f3</cites><orcidid>0000-0002-1202-3643 ; 0000-0003-2573-4636</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbcp.14465$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbcp.14465$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1416,1432,27923,27924,45573,45574,46408,46832</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32643213$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kloosterboer, Sanne Maartje</creatorcontrib><creatorcontrib>Winter, Brenda C.M.</creatorcontrib><creatorcontrib>Reichart, Catrien G.</creatorcontrib><creatorcontrib>Kouijzer, Mirjam E.J.</creatorcontrib><creatorcontrib>Kroon, Matthias M.J.</creatorcontrib><creatorcontrib>Daalen, Emma</creatorcontrib><creatorcontrib>Ester, Wietske A.</creatorcontrib><creatorcontrib>Rieken, Rob</creatorcontrib><creatorcontrib>Dieleman, Gwen C.</creatorcontrib><creatorcontrib>Altena, Daphne</creatorcontrib><creatorcontrib>Bartelds, Beatrijs</creatorcontrib><creatorcontrib>Schaik, Ron H.N.</creatorcontrib><creatorcontrib>Nasserinejad, Kazem</creatorcontrib><creatorcontrib>Hillegers, Manon H.J.</creatorcontrib><creatorcontrib>Gelder, Teun</creatorcontrib><creatorcontrib>Dierckx, Bram</creatorcontrib><creatorcontrib>Koch, Birgit C.P.</creatorcontrib><title>Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>Aim
Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations and 24‐hour area under the curves (AUCs) with body mass index (BMI) z‐scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness.
Methods
Forty‐two children and adolescents (32 males) aged 6‐18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9‐hydroxyrisperidone concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐hour AUCs were analysed to predict outcomes using generalized and linear mixed‐effects models.
Results
A risperidone two‐compartment model combined with a 9‐hydroxyrisperidone one‐compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z‐scores during follow‐up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01).
Conclusion
Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems.</description><subject>adolescent</subject><subject>antipsychotic</subject><subject>autism spectrum disorder</subject><subject>body mass index</subject><subject>child</subject><subject>cytochrome P‐450</subject><subject>drug monitoring</subject><subject>Original</subject><subject>prolactin</subject><subject>risperidone</subject><subject>weight gain</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNp1kU1rFTEUhoNU7PXqwj9Qsu1i2nzfuRtBL2qFgiK6Dvk4402ZSYacuS39E_3NTjtt0YXZJHCe87yEl5B3nJ3x-Zz7MJ5xpYx-QVZcGt0ILvQRWTHJTKOF5sfkNeIVY1xyo1-RYymMkoLLFbn7kXCEmmLJQMfe4eBoKDlAnqqbUslIXQXqEEtIboJIb9K0p5giUOg6CNMM5Pj4TteQAZGmTMM-9bFCfpi6WHrAeyku--4wJRzoHB2mehhoTFhqhPqGvOxcj_D28V6TX58__dxdNJffvnzdfbhsgtJaN9wbobhRQfngmdBSc7lhQW2ZEs6HLY_GMR8hbtoWpHYsqnbjPIOgfctkJ9fk_eIdD36AuHy3t2NNg6u3trhk_53ktLe_y7XdStGaOW1NThdBqAWxQve8y5m9L8XOpdiHUmb25O-wZ_KphRk4X4Cb1MPt_0324-77ovwDaAWblQ</recordid><startdate>202103</startdate><enddate>202103</enddate><creator>Kloosterboer, Sanne Maartje</creator><creator>Winter, Brenda C.M.</creator><creator>Reichart, Catrien G.</creator><creator>Kouijzer, Mirjam E.J.</creator><creator>Kroon, Matthias M.J.</creator><creator>Daalen, Emma</creator><creator>Ester, Wietske A.</creator><creator>Rieken, Rob</creator><creator>Dieleman, Gwen C.</creator><creator>Altena, Daphne</creator><creator>Bartelds, Beatrijs</creator><creator>Schaik, Ron H.N.</creator><creator>Nasserinejad, Kazem</creator><creator>Hillegers, Manon H.J.</creator><creator>Gelder, Teun</creator><creator>Dierckx, Bram</creator><creator>Koch, Birgit C.P.</creator><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1202-3643</orcidid><orcidid>https://orcid.org/0000-0003-2573-4636</orcidid></search><sort><creationdate>202103</creationdate><title>Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder</title><author>Kloosterboer, Sanne Maartje ; Winter, Brenda C.M. ; Reichart, Catrien G. ; Kouijzer, Mirjam E.J. ; Kroon, Matthias M.J. ; Daalen, Emma ; Ester, Wietske A. ; Rieken, Rob ; Dieleman, Gwen C. ; Altena, Daphne ; Bartelds, Beatrijs ; Schaik, Ron H.N. ; Nasserinejad, Kazem ; Hillegers, Manon H.J. ; Gelder, Teun ; Dierckx, Bram ; Koch, Birgit C.P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4555-1b624164c4bcb025351370c49042abc91d6a0bded788e35a0d487ab0ec5b803f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>adolescent</topic><topic>antipsychotic</topic><topic>autism spectrum disorder</topic><topic>body mass index</topic><topic>child</topic><topic>cytochrome P‐450</topic><topic>drug monitoring</topic><topic>Original</topic><topic>prolactin</topic><topic>risperidone</topic><topic>weight gain</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kloosterboer, Sanne Maartje</creatorcontrib><creatorcontrib>Winter, Brenda C.M.</creatorcontrib><creatorcontrib>Reichart, Catrien G.</creatorcontrib><creatorcontrib>Kouijzer, Mirjam E.J.</creatorcontrib><creatorcontrib>Kroon, Matthias M.J.</creatorcontrib><creatorcontrib>Daalen, Emma</creatorcontrib><creatorcontrib>Ester, Wietske A.</creatorcontrib><creatorcontrib>Rieken, Rob</creatorcontrib><creatorcontrib>Dieleman, Gwen C.</creatorcontrib><creatorcontrib>Altena, Daphne</creatorcontrib><creatorcontrib>Bartelds, Beatrijs</creatorcontrib><creatorcontrib>Schaik, Ron H.N.</creatorcontrib><creatorcontrib>Nasserinejad, Kazem</creatorcontrib><creatorcontrib>Hillegers, Manon H.J.</creatorcontrib><creatorcontrib>Gelder, Teun</creatorcontrib><creatorcontrib>Dierckx, Bram</creatorcontrib><creatorcontrib>Koch, Birgit C.P.</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kloosterboer, Sanne Maartje</au><au>Winter, Brenda C.M.</au><au>Reichart, Catrien G.</au><au>Kouijzer, Mirjam E.J.</au><au>Kroon, Matthias M.J.</au><au>Daalen, Emma</au><au>Ester, Wietske A.</au><au>Rieken, Rob</au><au>Dieleman, Gwen C.</au><au>Altena, Daphne</au><au>Bartelds, Beatrijs</au><au>Schaik, Ron H.N.</au><au>Nasserinejad, Kazem</au><au>Hillegers, Manon H.J.</au><au>Gelder, Teun</au><au>Dierckx, Bram</au><au>Koch, Birgit C.P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2021-03</date><risdate>2021</risdate><volume>87</volume><issue>3</issue><spage>1069</spage><epage>1081</epage><pages>1069-1081</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><abstract>Aim
Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations and 24‐hour area under the curves (AUCs) with body mass index (BMI) z‐scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness.
Methods
Forty‐two children and adolescents (32 males) aged 6‐18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9‐hydroxyrisperidone concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐hour AUCs were analysed to predict outcomes using generalized and linear mixed‐effects models.
Results
A risperidone two‐compartment model combined with a 9‐hydroxyrisperidone one‐compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z‐scores during follow‐up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01).
Conclusion
Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems.</abstract><cop>England</cop><pub>John Wiley and Sons Inc</pub><pmid>32643213</pmid><doi>10.1111/bcp.14465</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-1202-3643</orcidid><orcidid>https://orcid.org/0000-0003-2573-4636</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Wiley Free Content; EZB-FREE-00999 freely available EZB journals; Wiley Online Library All Journals |
| subjects | adolescent antipsychotic autism spectrum disorder body mass index child cytochrome P‐450 drug monitoring Original prolactin risperidone weight gain |
| title | Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder |
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