Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder
This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD p...
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| creator | Arnaldi, Dario Chincarini, Andrea Hu, Michele T Sonka, Karel Boeve, Bradley Miyamoto, Tomoyuki Puligheddu, Monica De Cock, Valérie Cochen Terzaghi, Michele Plazzi, Giuseppe Tachibana, Naoko Morbelli, Silvia Rolinski, Michal Dusek, Petr Lowe, Val Miyamoto, Masayuki Figorilli, Michela Verbizier, Delphine de Bossert, Irene Antelmi, Elena Meli, Riccardo Barber, Thomas R Trnka, Jiří Miyagawa, Toji Serra, Alessandra Pizza, Fabio Bauckneht, Matteo Bradley, Kevin M Zogala, David McGowan, Daniel R Jordan, Lennon Manni, Raffaele Nobili, Flavio |
| description | This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P |
| doi_str_mv | 10.1093/brain/awaa365 |
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Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.</description><identifier>ISSN: 0006-8950</identifier><identifier>EISSN: 1460-2156</identifier><identifier>DOI: 10.1093/brain/awaa365</identifier><identifier>PMID: 33348363</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Aged ; Caudate Nucleus - diagnostic imaging ; Caudate Nucleus - metabolism ; Dopamine Plasma Membrane Transport Proteins - metabolism ; Engineering Sciences ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Original ; Putamen - diagnostic imaging ; Putamen - metabolism ; REM Sleep Behavior Disorder - diagnostic imaging ; REM Sleep Behavior Disorder - metabolism ; Retrospective Studies ; ROC Curve ; Synucleinopathies - diagnostic imaging ; Synucleinopathies - metabolism ; Tomography, Emission-Computed, Single-Photon ; Tropanes</subject><ispartof>Brain (London, England : 1878), 2021-02, Vol.144 (1), p.278-287</ispartof><rights>The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-89237a7e7711b2c8724af2fee5a4d74d84f9f67ed3b7d9f49148c517b36bab7b3</citedby><cites>FETCH-LOGICAL-c421t-89237a7e7711b2c8724af2fee5a4d74d84f9f67ed3b7d9f49148c517b36bab7b3</cites><orcidid>0000-0003-3372-1667 ; 0000-0001-5773-9656 ; 0000-0003-4850-9677 ; 0000-0002-1937-9116 ; 0000-0001-6937-3065 ; 0000-0002-1638-1384 ; 0000-0001-9811-0897 ; 0000-0002-6837-6608 ; 0000-0003-1739-6139</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33348363$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://imt-mines-ales.hal.science/hal-03584080$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Arnaldi, Dario</creatorcontrib><creatorcontrib>Chincarini, Andrea</creatorcontrib><creatorcontrib>Hu, Michele T</creatorcontrib><creatorcontrib>Sonka, Karel</creatorcontrib><creatorcontrib>Boeve, Bradley</creatorcontrib><creatorcontrib>Miyamoto, Tomoyuki</creatorcontrib><creatorcontrib>Puligheddu, Monica</creatorcontrib><creatorcontrib>De Cock, Valérie Cochen</creatorcontrib><creatorcontrib>Terzaghi, Michele</creatorcontrib><creatorcontrib>Plazzi, Giuseppe</creatorcontrib><creatorcontrib>Tachibana, Naoko</creatorcontrib><creatorcontrib>Morbelli, Silvia</creatorcontrib><creatorcontrib>Rolinski, Michal</creatorcontrib><creatorcontrib>Dusek, Petr</creatorcontrib><creatorcontrib>Lowe, Val</creatorcontrib><creatorcontrib>Miyamoto, Masayuki</creatorcontrib><creatorcontrib>Figorilli, Michela</creatorcontrib><creatorcontrib>Verbizier, Delphine de</creatorcontrib><creatorcontrib>Bossert, Irene</creatorcontrib><creatorcontrib>Antelmi, Elena</creatorcontrib><creatorcontrib>Meli, Riccardo</creatorcontrib><creatorcontrib>Barber, Thomas R</creatorcontrib><creatorcontrib>Trnka, Jiří</creatorcontrib><creatorcontrib>Miyagawa, Toji</creatorcontrib><creatorcontrib>Serra, Alessandra</creatorcontrib><creatorcontrib>Pizza, Fabio</creatorcontrib><creatorcontrib>Bauckneht, Matteo</creatorcontrib><creatorcontrib>Bradley, Kevin M</creatorcontrib><creatorcontrib>Zogala, David</creatorcontrib><creatorcontrib>McGowan, Daniel R</creatorcontrib><creatorcontrib>Jordan, Lennon</creatorcontrib><creatorcontrib>Manni, Raffaele</creatorcontrib><creatorcontrib>Nobili, Flavio</creatorcontrib><title>Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder</title><title>Brain (London, England : 1878)</title><addtitle>Brain</addtitle><description>This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.</description><subject>Aged</subject><subject>Caudate Nucleus - diagnostic imaging</subject><subject>Caudate Nucleus - metabolism</subject><subject>Dopamine Plasma Membrane Transport Proteins - metabolism</subject><subject>Engineering Sciences</subject><subject>Female</subject><subject>Humans</subject><subject>Kaplan-Meier Estimate</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Original</subject><subject>Putamen - diagnostic imaging</subject><subject>Putamen - metabolism</subject><subject>REM Sleep Behavior Disorder - diagnostic imaging</subject><subject>REM Sleep Behavior Disorder - metabolism</subject><subject>Retrospective Studies</subject><subject>ROC Curve</subject><subject>Synucleinopathies - diagnostic imaging</subject><subject>Synucleinopathies - metabolism</subject><subject>Tomography, Emission-Computed, Single-Photon</subject><subject>Tropanes</subject><issn>0006-8950</issn><issn>1460-2156</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1vEzEQhi0EomnhyBX5CIel_lzvXpCqtrRIQUgIzmbWHidGG3uxkyD-PRsSKuA00viZ1zN6CHnB2RvOenk5FIjpEn4AyFY_IguuWtYIrtvHZMEYa5uu1-yMnNf6jTGupGifkjMppepkKxfk602eYBMTllV0NG5gFdOKQvLUjTFFByOdCvrotrlUGnKh0xpTdjntsdSYE82Bfrr9QOuIONEB17CPeVeojzUXj-UZeRJgrPj8VC_Il3e3n6_vm-XHu_fXV8vGKcG385ZCGjBoDOeDcJ0RCoIIiBqUN8p3KvShNejlYHwfVM9V5zQ3g2wHGOZyQd4ec6fdsEHvMG0LjHYq803lp80Q7b8vKa7tKu9tp_u-52IOeH0MWP83dn-1tIcek7pTrGN7PrOvTp-V_H2HdWs3sTocR0iYd9UKZcRsR-sD2hxRV3KtBcNDNmf2YND-NmhPBmf-5d93PNB_lMlfgYSbIQ</recordid><startdate>20210212</startdate><enddate>20210212</enddate><creator>Arnaldi, Dario</creator><creator>Chincarini, Andrea</creator><creator>Hu, Michele T</creator><creator>Sonka, Karel</creator><creator>Boeve, Bradley</creator><creator>Miyamoto, Tomoyuki</creator><creator>Puligheddu, Monica</creator><creator>De Cock, Valérie Cochen</creator><creator>Terzaghi, Michele</creator><creator>Plazzi, Giuseppe</creator><creator>Tachibana, Naoko</creator><creator>Morbelli, Silvia</creator><creator>Rolinski, Michal</creator><creator>Dusek, Petr</creator><creator>Lowe, Val</creator><creator>Miyamoto, Masayuki</creator><creator>Figorilli, Michela</creator><creator>Verbizier, Delphine de</creator><creator>Bossert, Irene</creator><creator>Antelmi, Elena</creator><creator>Meli, Riccardo</creator><creator>Barber, Thomas R</creator><creator>Trnka, Jiří</creator><creator>Miyagawa, Toji</creator><creator>Serra, Alessandra</creator><creator>Pizza, Fabio</creator><creator>Bauckneht, Matteo</creator><creator>Bradley, Kevin M</creator><creator>Zogala, David</creator><creator>McGowan, Daniel R</creator><creator>Jordan, Lennon</creator><creator>Manni, Raffaele</creator><creator>Nobili, Flavio</creator><general>Oxford University Press</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>7X8</scope><scope>1XC</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3372-1667</orcidid><orcidid>https://orcid.org/0000-0001-5773-9656</orcidid><orcidid>https://orcid.org/0000-0003-4850-9677</orcidid><orcidid>https://orcid.org/0000-0002-1937-9116</orcidid><orcidid>https://orcid.org/0000-0001-6937-3065</orcidid><orcidid>https://orcid.org/0000-0002-1638-1384</orcidid><orcidid>https://orcid.org/0000-0001-9811-0897</orcidid><orcidid>https://orcid.org/0000-0002-6837-6608</orcidid><orcidid>https://orcid.org/0000-0003-1739-6139</orcidid></search><sort><creationdate>20210212</creationdate><title>Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder</title><author>Arnaldi, Dario ; Chincarini, Andrea ; Hu, Michele T ; Sonka, Karel ; Boeve, Bradley ; Miyamoto, Tomoyuki ; Puligheddu, Monica ; De Cock, Valérie Cochen ; Terzaghi, Michele ; Plazzi, Giuseppe ; Tachibana, Naoko ; Morbelli, Silvia ; Rolinski, Michal ; Dusek, Petr ; Lowe, Val ; Miyamoto, Masayuki ; Figorilli, Michela ; Verbizier, Delphine de ; Bossert, Irene ; Antelmi, Elena ; Meli, Riccardo ; Barber, Thomas R ; Trnka, Jiří ; Miyagawa, Toji ; Serra, Alessandra ; Pizza, Fabio ; Bauckneht, Matteo ; Bradley, Kevin M ; Zogala, David ; McGowan, Daniel R ; Jordan, Lennon ; Manni, Raffaele ; Nobili, Flavio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c421t-89237a7e7711b2c8724af2fee5a4d74d84f9f67ed3b7d9f49148c517b36bab7b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Aged</topic><topic>Caudate Nucleus - 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Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Brain (London, England : 1878)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Arnaldi, Dario</au><au>Chincarini, Andrea</au><au>Hu, Michele T</au><au>Sonka, Karel</au><au>Boeve, Bradley</au><au>Miyamoto, Tomoyuki</au><au>Puligheddu, Monica</au><au>De Cock, Valérie Cochen</au><au>Terzaghi, Michele</au><au>Plazzi, Giuseppe</au><au>Tachibana, Naoko</au><au>Morbelli, Silvia</au><au>Rolinski, Michal</au><au>Dusek, Petr</au><au>Lowe, Val</au><au>Miyamoto, Masayuki</au><au>Figorilli, Michela</au><au>Verbizier, Delphine de</au><au>Bossert, Irene</au><au>Antelmi, Elena</au><au>Meli, Riccardo</au><au>Barber, Thomas R</au><au>Trnka, Jiří</au><au>Miyagawa, Toji</au><au>Serra, Alessandra</au><au>Pizza, Fabio</au><au>Bauckneht, Matteo</au><au>Bradley, Kevin M</au><au>Zogala, David</au><au>McGowan, Daniel R</au><au>Jordan, Lennon</au><au>Manni, Raffaele</au><au>Nobili, Flavio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder</atitle><jtitle>Brain (London, England : 1878)</jtitle><addtitle>Brain</addtitle><date>2021-02-12</date><risdate>2021</risdate><volume>144</volume><issue>1</issue><spage>278</spage><epage>287</epage><pages>278-287</pages><issn>0006-8950</issn><eissn>1460-2156</eissn><abstract>This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>33348363</pmid><doi>10.1093/brain/awaa365</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-3372-1667</orcidid><orcidid>https://orcid.org/0000-0001-5773-9656</orcidid><orcidid>https://orcid.org/0000-0003-4850-9677</orcidid><orcidid>https://orcid.org/0000-0002-1937-9116</orcidid><orcidid>https://orcid.org/0000-0001-6937-3065</orcidid><orcidid>https://orcid.org/0000-0002-1638-1384</orcidid><orcidid>https://orcid.org/0000-0001-9811-0897</orcidid><orcidid>https://orcid.org/0000-0002-6837-6608</orcidid><orcidid>https://orcid.org/0000-0003-1739-6139</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0006-8950 |
| ispartof | Brain (London, England : 1878), 2021-02, Vol.144 (1), p.278-287 |
| issn | 0006-8950 1460-2156 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8599912 |
| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Aged Caudate Nucleus - diagnostic imaging Caudate Nucleus - metabolism Dopamine Plasma Membrane Transport Proteins - metabolism Engineering Sciences Female Humans Kaplan-Meier Estimate Male Middle Aged Original Putamen - diagnostic imaging Putamen - metabolism REM Sleep Behavior Disorder - diagnostic imaging REM Sleep Behavior Disorder - metabolism Retrospective Studies ROC Curve Synucleinopathies - diagnostic imaging Synucleinopathies - metabolism Tomography, Emission-Computed, Single-Photon Tropanes |
| title | Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T08%3A04%3A57IST&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=Dopaminergic%20imaging%20and%20clinical%20predictors%20for%20phenoconversion%20of%20REM%20sleep%20behaviour%20disorder&rft.jtitle=Brain%20(London,%20England%20:%201878)&rft.au=Arnaldi,%20Dario&rft.date=2021-02-12&rft.volume=144&rft.issue=1&rft.spage=278&rft.epage=287&rft.pages=278-287&rft.issn=0006-8950&rft.eissn=1460-2156&rft_id=info:doi/10.1093/brain/awaa365&rft_dat=%3Cproquest_pubme%3E2472109551%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=2472109551&rft_id=info:pmid/33348363&rfr_iscdi=true |