Validation of scores of PRO‐C3 to predict liver‐related events in alcohol‐related liver disease
Background and Aims Risk prediction in alcohol‐related liver disease (ArLD) is an unmet need. We aimed to assess PRO‐C3 models to predict liver‐related events (LRE) in patients with a history of excessive alcohol use without an established diagnosis of chronic liver disease. Methods A prospective co...
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| Veröffentlicht in: | Liver international 2023-07, Vol.43 (7), p.1486-1496 |
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| creator | Johansen, Stine Israelsen, Mads Villesen, Ida F. Torp, Nikolaj Nielsen, Mette J. Kjærgaard, Maria Lindvig, Katrine P. Hansen, Camilla D. Andersen, Peter Rasmussen, Ditlev N. Detlefsen, Sönke Leeming, Diana J. Thiele, Maja Karsdal, Morten Krag, Aleksander Anastasiadou, Ema Arumugam, Manimozhian Bork, Peer Hansen, Torben Henrar, Roland Israelsen, Hans Karsdal, Morten Legido‐Quigley, Cristina Melberg, Hans Olav Thiele, Maja Trebicka, Jonel Krag, Aleksander Bork, Peer Mann, Mathias Matthijnssens, Jelle Krag, Aleksander Hansen, Torben |
| description | Background and Aims
Risk prediction in alcohol‐related liver disease (ArLD) is an unmet need. We aimed to assess PRO‐C3 models to predict liver‐related events (LRE) in patients with a history of excessive alcohol use without an established diagnosis of chronic liver disease.
Methods
A prospective cohort study of 462 patients with ArLD, split into a derivation cohort of 221 secondary care patients and a validation cohort of 241 primary care patients. Baseline variables, including fibrogenesis marker PRO‐C3, were used to develop a prediction model. Prognostic accuracy was compared to enhanced liver fibrosis (ELF), fibrosis‐4‐index (FIB‐4), transient elastography (TE) and ADAPT.
Results
In the derivation and validation cohorts, 67 (30%) and 19 (8%) experienced an LRE during a median follow‐up of 5.2 years (IQR: 3.2‐6.8) and 4.0 years (IQR: 2.7‐5.6). On top of PRO‐C3 and ADAPT score, we generated a model (ALPACA) of independent predictors of LREs (PRO‐C3, AST/ALT, platelets). ALPACA had high prognostic accuracy with a C‐statistic of 0.85 in the derivation cohort, comparable to ELF (0.83) and TE (0.84) and significantly higher than FIB‐4 (0.78), PRO‐C3 (0.80) and ADAPT (0.81). In the validation cohort, all tests had comparable C‐statistics. Compared to low‐risk patients (ALPACA ≤11), high‐risk patients (>11) had a subhazard ratio for LREs of 12.6 (95% CI 5.9‐26.8, p |
| doi_str_mv | 10.1111/liv.15595 |
| format | Article |
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Risk prediction in alcohol‐related liver disease (ArLD) is an unmet need. We aimed to assess PRO‐C3 models to predict liver‐related events (LRE) in patients with a history of excessive alcohol use without an established diagnosis of chronic liver disease.
Methods
A prospective cohort study of 462 patients with ArLD, split into a derivation cohort of 221 secondary care patients and a validation cohort of 241 primary care patients. Baseline variables, including fibrogenesis marker PRO‐C3, were used to develop a prediction model. Prognostic accuracy was compared to enhanced liver fibrosis (ELF), fibrosis‐4‐index (FIB‐4), transient elastography (TE) and ADAPT.
Results
In the derivation and validation cohorts, 67 (30%) and 19 (8%) experienced an LRE during a median follow‐up of 5.2 years (IQR: 3.2‐6.8) and 4.0 years (IQR: 2.7‐5.6). On top of PRO‐C3 and ADAPT score, we generated a model (ALPACA) of independent predictors of LREs (PRO‐C3, AST/ALT, platelets). ALPACA had high prognostic accuracy with a C‐statistic of 0.85 in the derivation cohort, comparable to ELF (0.83) and TE (0.84) and significantly higher than FIB‐4 (0.78), PRO‐C3 (0.80) and ADAPT (0.81). In the validation cohort, all tests had comparable C‐statistics. Compared to low‐risk patients (ALPACA ≤11), high‐risk patients (>11) had a subhazard ratio for LREs of 12.6 (95% CI 5.9‐26.8, p < .001) and higher cumulative incidence (57% vs. 7%, p < .001; derivation cohort). We observed similar subhazard ratio in the validation cohort.
Conclusions
PRO‐C3‐based scores are reliable tools to predict LREs in ArLD patients and are suitable for risk stratification in primary and secondary care.</description><identifier>ISSN: 1478-3223</identifier><identifier>EISSN: 1478-3231</identifier><identifier>DOI: 10.1111/liv.15595</identifier><identifier>PMID: 37183542</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Alcohol ; alcoholic liver disease ; Animals ; biomarkers ; Camelids, New World ; Complement C3 ; Derivation ; extracellular matrix ; Fibrosis ; Health care ; Health risks ; Humans ; Liver ; Liver - pathology ; Liver Cirrhosis - complications ; Liver diseases ; Model accuracy ; Non-alcoholic Fatty Liver Disease - complications ; Prediction models ; Primary care ; prognosis ; Prospective Studies ; Risk</subject><ispartof>Liver international, 2023-07, Vol.43 (7), p.1486-1496</ispartof><rights>2023 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2023 The Authors. Liver International published by John Wiley & Sons Ltd.</rights><rights>2023. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3885-6e77cca709a26ec45468b883f6e11851bab1ef8a25cc5dcd4bce1539f321f6e3</citedby><cites>FETCH-LOGICAL-c3885-6e77cca709a26ec45468b883f6e11851bab1ef8a25cc5dcd4bce1539f321f6e3</cites><orcidid>0000-0002-5031-2294 ; 0000-0001-5026-8740 ; 0000-0002-4256-140X ; 0000-0003-1854-1924 ; 0000-0001-7891-7706 ; 0000-0001-9443-5846 ; 0000-0002-4378-6256 ; 0000-0002-3414-5369 ; 0000-0002-9466-2333 ; 0000-0002-9598-4932 ; 0000-0001-7921-9707 ; 0000-0002-5704-2485 ; 0000-0002-4448-8955 ; 0000-0001-8452-1820</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%2Fliv.15595$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fliv.15595$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37183542$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Johansen, Stine</creatorcontrib><creatorcontrib>Israelsen, Mads</creatorcontrib><creatorcontrib>Villesen, Ida F.</creatorcontrib><creatorcontrib>Torp, Nikolaj</creatorcontrib><creatorcontrib>Nielsen, Mette J.</creatorcontrib><creatorcontrib>Kjærgaard, Maria</creatorcontrib><creatorcontrib>Lindvig, Katrine P.</creatorcontrib><creatorcontrib>Hansen, Camilla D.</creatorcontrib><creatorcontrib>Andersen, Peter</creatorcontrib><creatorcontrib>Rasmussen, Ditlev N.</creatorcontrib><creatorcontrib>Detlefsen, Sönke</creatorcontrib><creatorcontrib>Leeming, Diana J.</creatorcontrib><creatorcontrib>Thiele, Maja</creatorcontrib><creatorcontrib>Karsdal, Morten</creatorcontrib><creatorcontrib>Krag, Aleksander</creatorcontrib><creatorcontrib>Anastasiadou, Ema</creatorcontrib><creatorcontrib>Arumugam, Manimozhian</creatorcontrib><creatorcontrib>Bork, Peer</creatorcontrib><creatorcontrib>Hansen, Torben</creatorcontrib><creatorcontrib>Henrar, Roland</creatorcontrib><creatorcontrib>Israelsen, Hans</creatorcontrib><creatorcontrib>Karsdal, Morten</creatorcontrib><creatorcontrib>Legido‐Quigley, Cristina</creatorcontrib><creatorcontrib>Melberg, Hans Olav</creatorcontrib><creatorcontrib>Thiele, Maja</creatorcontrib><creatorcontrib>Trebicka, Jonel</creatorcontrib><creatorcontrib>Krag, Aleksander</creatorcontrib><creatorcontrib>Bork, Peer</creatorcontrib><creatorcontrib>Mann, Mathias</creatorcontrib><creatorcontrib>Matthijnssens, Jelle</creatorcontrib><creatorcontrib>Krag, Aleksander</creatorcontrib><creatorcontrib>Hansen, Torben</creatorcontrib><creatorcontrib>GALAXY and MicrobLiver consortia</creatorcontrib><creatorcontrib>the GALAXY and MicrobLiver consortia</creatorcontrib><title>Validation of scores of PRO‐C3 to predict liver‐related events in alcohol‐related liver disease</title><title>Liver international</title><addtitle>Liver Int</addtitle><description>Background and Aims
Risk prediction in alcohol‐related liver disease (ArLD) is an unmet need. We aimed to assess PRO‐C3 models to predict liver‐related events (LRE) in patients with a history of excessive alcohol use without an established diagnosis of chronic liver disease.
Methods
A prospective cohort study of 462 patients with ArLD, split into a derivation cohort of 221 secondary care patients and a validation cohort of 241 primary care patients. Baseline variables, including fibrogenesis marker PRO‐C3, were used to develop a prediction model. Prognostic accuracy was compared to enhanced liver fibrosis (ELF), fibrosis‐4‐index (FIB‐4), transient elastography (TE) and ADAPT.
Results
In the derivation and validation cohorts, 67 (30%) and 19 (8%) experienced an LRE during a median follow‐up of 5.2 years (IQR: 3.2‐6.8) and 4.0 years (IQR: 2.7‐5.6). On top of PRO‐C3 and ADAPT score, we generated a model (ALPACA) of independent predictors of LREs (PRO‐C3, AST/ALT, platelets). ALPACA had high prognostic accuracy with a C‐statistic of 0.85 in the derivation cohort, comparable to ELF (0.83) and TE (0.84) and significantly higher than FIB‐4 (0.78), PRO‐C3 (0.80) and ADAPT (0.81). In the validation cohort, all tests had comparable C‐statistics. Compared to low‐risk patients (ALPACA ≤11), high‐risk patients (>11) had a subhazard ratio for LREs of 12.6 (95% CI 5.9‐26.8, p < .001) and higher cumulative incidence (57% vs. 7%, p < .001; derivation cohort). We observed similar subhazard ratio in the validation cohort.
Conclusions
PRO‐C3‐based scores are reliable tools to predict LREs in ArLD patients and are suitable for risk stratification in primary and secondary care.</description><subject>Alcohol</subject><subject>alcoholic liver disease</subject><subject>Animals</subject><subject>biomarkers</subject><subject>Camelids, New World</subject><subject>Complement C3</subject><subject>Derivation</subject><subject>extracellular matrix</subject><subject>Fibrosis</subject><subject>Health care</subject><subject>Health risks</subject><subject>Humans</subject><subject>Liver</subject><subject>Liver - pathology</subject><subject>Liver Cirrhosis - complications</subject><subject>Liver diseases</subject><subject>Model accuracy</subject><subject>Non-alcoholic Fatty Liver Disease - complications</subject><subject>Prediction models</subject><subject>Primary care</subject><subject>prognosis</subject><subject>Prospective Studies</subject><subject>Risk</subject><issn>1478-3223</issn><issn>1478-3231</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp10M1KAzEQB_Agih_Vgy8gAS96WLuTbLrZoxQ_CgVFitclm53FSLqpybbSm4_gM_okpq2KCOaSIfnxn2QIOYb0AuLqW7O4ACEKsUX2IctlwhmH7Z-a8T1yEMJzmkJRCNglezwHyUXG9gk-Kmtq1RnXUtfQoJ3HsKruH-4-3t6HnHaOzjzWRnc09kEfTz1a1WFNcYFtF6hpqbLaPTn7625taW0CqoCHZKdRNuDR194jk-uryfA2Gd_djIaX40RzKUUywDzXWuVpodgAdSaygayk5M0AAaSASlWAjVRMaC1qXWeVRhC8aDiDaHiPnG1iZ969zDF05dQEjdaqFt08lExC7CPzDCI9_UOf3dy38XFRMcHzLE9ZVOcbpb0LwWNTzryZKr8sIS1Xoy_jN8v16KM9-UqcV1Osf-T3rCPob8Crsbj8P6kcjx43kZ86CJBh</recordid><startdate>202307</startdate><enddate>202307</enddate><creator>Johansen, Stine</creator><creator>Israelsen, Mads</creator><creator>Villesen, Ida F.</creator><creator>Torp, Nikolaj</creator><creator>Nielsen, Mette J.</creator><creator>Kjærgaard, Maria</creator><creator>Lindvig, 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of scores of PRO‐C3 to predict liver‐related events in alcohol‐related liver disease</title><author>Johansen, Stine ; Israelsen, Mads ; Villesen, Ida F. ; Torp, Nikolaj ; Nielsen, Mette J. ; Kjærgaard, Maria ; Lindvig, Katrine P. ; Hansen, Camilla D. ; Andersen, Peter ; Rasmussen, Ditlev N. ; Detlefsen, Sönke ; Leeming, Diana J. ; Thiele, Maja ; Karsdal, Morten ; Krag, Aleksander ; Anastasiadou, Ema ; Arumugam, Manimozhian ; Bork, Peer ; Hansen, Torben ; Henrar, Roland ; Israelsen, Hans ; Karsdal, Morten ; Legido‐Quigley, Cristina ; Melberg, Hans Olav ; Thiele, Maja ; Trebicka, Jonel ; Krag, Aleksander ; Bork, Peer ; Mann, Mathias ; Matthijnssens, Jelle ; Krag, Aleksander ; Hansen, Torben</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3885-6e77cca709a26ec45468b883f6e11851bab1ef8a25cc5dcd4bce1539f321f6e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Alcohol</topic><topic>alcoholic liver disease</topic><topic>Animals</topic><topic>biomarkers</topic><topic>Camelids, New World</topic><topic>Complement C3</topic><topic>Derivation</topic><topic>extracellular matrix</topic><topic>Fibrosis</topic><topic>Health care</topic><topic>Health risks</topic><topic>Humans</topic><topic>Liver</topic><topic>Liver - pathology</topic><topic>Liver Cirrhosis - complications</topic><topic>Liver diseases</topic><topic>Model accuracy</topic><topic>Non-alcoholic Fatty Liver Disease - complications</topic><topic>Prediction models</topic><topic>Primary care</topic><topic>prognosis</topic><topic>Prospective Studies</topic><topic>Risk</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johansen, Stine</creatorcontrib><creatorcontrib>Israelsen, Mads</creatorcontrib><creatorcontrib>Villesen, Ida F.</creatorcontrib><creatorcontrib>Torp, Nikolaj</creatorcontrib><creatorcontrib>Nielsen, Mette J.</creatorcontrib><creatorcontrib>Kjærgaard, Maria</creatorcontrib><creatorcontrib>Lindvig, Katrine P.</creatorcontrib><creatorcontrib>Hansen, Camilla D.</creatorcontrib><creatorcontrib>Andersen, Peter</creatorcontrib><creatorcontrib>Rasmussen, Ditlev N.</creatorcontrib><creatorcontrib>Detlefsen, Sönke</creatorcontrib><creatorcontrib>Leeming, Diana J.</creatorcontrib><creatorcontrib>Thiele, Maja</creatorcontrib><creatorcontrib>Karsdal, Morten</creatorcontrib><creatorcontrib>Krag, Aleksander</creatorcontrib><creatorcontrib>Anastasiadou, Ema</creatorcontrib><creatorcontrib>Arumugam, Manimozhian</creatorcontrib><creatorcontrib>Bork, 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(Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Liver international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Johansen, Stine</au><au>Israelsen, Mads</au><au>Villesen, Ida F.</au><au>Torp, Nikolaj</au><au>Nielsen, Mette J.</au><au>Kjærgaard, Maria</au><au>Lindvig, Katrine P.</au><au>Hansen, Camilla D.</au><au>Andersen, Peter</au><au>Rasmussen, Ditlev N.</au><au>Detlefsen, Sönke</au><au>Leeming, Diana J.</au><au>Thiele, Maja</au><au>Karsdal, Morten</au><au>Krag, Aleksander</au><au>Anastasiadou, Ema</au><au>Arumugam, Manimozhian</au><au>Bork, Peer</au><au>Hansen, Torben</au><au>Henrar, Roland</au><au>Israelsen, Hans</au><au>Karsdal, Morten</au><au>Legido‐Quigley, Cristina</au><au>Melberg, Hans Olav</au><au>Thiele, Maja</au><au>Trebicka, Jonel</au><au>Krag, Aleksander</au><au>Bork, Peer</au><au>Mann, Mathias</au><au>Matthijnssens, Jelle</au><au>Krag, Aleksander</au><au>Hansen, Torben</au><aucorp>GALAXY and MicrobLiver consortia</aucorp><aucorp>the GALAXY and MicrobLiver consortia</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Validation of scores of PRO‐C3 to predict liver‐related events in alcohol‐related liver disease</atitle><jtitle>Liver international</jtitle><addtitle>Liver Int</addtitle><date>2023-07</date><risdate>2023</risdate><volume>43</volume><issue>7</issue><spage>1486</spage><epage>1496</epage><pages>1486-1496</pages><issn>1478-3223</issn><eissn>1478-3231</eissn><abstract>Background and Aims
Risk prediction in alcohol‐related liver disease (ArLD) is an unmet need. We aimed to assess PRO‐C3 models to predict liver‐related events (LRE) in patients with a history of excessive alcohol use without an established diagnosis of chronic liver disease.
Methods
A prospective cohort study of 462 patients with ArLD, split into a derivation cohort of 221 secondary care patients and a validation cohort of 241 primary care patients. Baseline variables, including fibrogenesis marker PRO‐C3, were used to develop a prediction model. Prognostic accuracy was compared to enhanced liver fibrosis (ELF), fibrosis‐4‐index (FIB‐4), transient elastography (TE) and ADAPT.
Results
In the derivation and validation cohorts, 67 (30%) and 19 (8%) experienced an LRE during a median follow‐up of 5.2 years (IQR: 3.2‐6.8) and 4.0 years (IQR: 2.7‐5.6). On top of PRO‐C3 and ADAPT score, we generated a model (ALPACA) of independent predictors of LREs (PRO‐C3, AST/ALT, platelets). ALPACA had high prognostic accuracy with a C‐statistic of 0.85 in the derivation cohort, comparable to ELF (0.83) and TE (0.84) and significantly higher than FIB‐4 (0.78), PRO‐C3 (0.80) and ADAPT (0.81). In the validation cohort, all tests had comparable C‐statistics. Compared to low‐risk patients (ALPACA ≤11), high‐risk patients (>11) had a subhazard ratio for LREs of 12.6 (95% CI 5.9‐26.8, p < .001) and higher cumulative incidence (57% vs. 7%, p < .001; derivation cohort). We observed similar subhazard ratio in the validation cohort.
Conclusions
PRO‐C3‐based scores are reliable tools to predict LREs in ArLD patients and are suitable for risk stratification in primary and secondary care.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>37183542</pmid><doi>10.1111/liv.15595</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-5031-2294</orcidid><orcidid>https://orcid.org/0000-0001-5026-8740</orcidid><orcidid>https://orcid.org/0000-0002-4256-140X</orcidid><orcidid>https://orcid.org/0000-0003-1854-1924</orcidid><orcidid>https://orcid.org/0000-0001-7891-7706</orcidid><orcidid>https://orcid.org/0000-0001-9443-5846</orcidid><orcidid>https://orcid.org/0000-0002-4378-6256</orcidid><orcidid>https://orcid.org/0000-0002-3414-5369</orcidid><orcidid>https://orcid.org/0000-0002-9466-2333</orcidid><orcidid>https://orcid.org/0000-0002-9598-4932</orcidid><orcidid>https://orcid.org/0000-0001-7921-9707</orcidid><orcidid>https://orcid.org/0000-0002-5704-2485</orcidid><orcidid>https://orcid.org/0000-0002-4448-8955</orcidid><orcidid>https://orcid.org/0000-0001-8452-1820</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1478-3223 |
| ispartof | Liver international, 2023-07, Vol.43 (7), p.1486-1496 |
| issn | 1478-3223 1478-3231 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2813888741 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Alcohol alcoholic liver disease Animals biomarkers Camelids, New World Complement C3 Derivation extracellular matrix Fibrosis Health care Health risks Humans Liver Liver - pathology Liver Cirrhosis - complications Liver diseases Model accuracy Non-alcoholic Fatty Liver Disease - complications Prediction models Primary care prognosis Prospective Studies Risk |
| title | Validation of scores of PRO‐C3 to predict liver‐related events in alcohol‐related liver disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T06%3A41%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Validation%20of%20scores%20of%20PRO%E2%80%90C3%20to%20predict%20liver%E2%80%90related%20events%20in%20alcohol%E2%80%90related%20liver%20disease&rft.jtitle=Liver%20international&rft.au=Johansen,%20Stine&rft.aucorp=GALAXY%20and%20MicrobLiver%20consortia&rft.date=2023-07&rft.volume=43&rft.issue=7&rft.spage=1486&rft.epage=1496&rft.pages=1486-1496&rft.issn=1478-3223&rft.eissn=1478-3231&rft_id=info:doi/10.1111/liv.15595&rft_dat=%3Cproquest_cross%3E2825374702%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2825374702&rft_id=info:pmid/37183542&rfr_iscdi=true |