Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results
Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9...
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| Veröffentlicht in: | Nature medicine 2024-07, Vol.30 (7), p.1898-1904 |
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| creator | Wang, Hui Chen, Yuxin Lv, Jun Cheng, Xiaoting Cao, Qi Wang, Daqi Zhang, Longlong Zhu, Biyun Shen, Min Xu, Chunxin Xun, Mengzhao Wang, Zijing Tang, Honghai Hu, Shaowei Cui, Chong Jiang, Luoying Yin, Yanbo Guo, Luo Zhou, Yi Han, Lei Gao, Ziwen Zhang, Jiajia Yu, Sha Gao, Kaiyu Wang, Jinghan Chen, Bing Wang, Wuqing Chen, Zheng-Yi Li, Huawei Shu, Yilai |
| description | Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human
OTOF
transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration:
ChiCTR2200063181
.
An interim analysis of a single-arm trial in 5 children with hereditary deafness shows that binaural AAV gene therapy is safe and leads to hearing improvement up to 13–26 weeks of follow-up. |
| doi_str_mv | 10.1038/s41591-024-03023-5 |
| format | Article |
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OTOF
transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration:
ChiCTR2200063181
.
An interim analysis of a single-arm trial in 5 children with hereditary deafness shows that binaural AAV gene therapy is safe and leads to hearing improvement up to 13–26 weeks of follow-up.</description><identifier>ISSN: 1078-8956</identifier><identifier>ISSN: 1546-170X</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/s41591-024-03023-5</identifier><identifier>PMID: 38839897</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/208/2489/201 ; 692/699/375 ; Adolescent ; Adverse events ; Auditory system ; Biomedical and Life Sciences ; Biomedicine ; Brain stem ; Cancer Research ; Child ; Child, Preschool ; Cholesterol ; Constraining ; Deafness ; Deafness - genetics ; Deafness - therapy ; Dependovirus - genetics ; Ear ; Effectiveness ; Evoked Potentials, Auditory, Brain Stem ; Female ; Gene therapy ; Genes, Recessive ; Genetic Therapy - methods ; Genetic Vectors - genetics ; Hearing loss ; Humans ; Infectious Diseases ; Localization ; Lymphocytes ; Male ; Metabolic Diseases ; Molecular Medicine ; Neurosciences ; Patients ; Pediatrics ; Perception ; Safety ; Sound localization ; Sound sources ; Speech ; Speech perception ; Toxicity ; Transgenes ; Treatment Outcome</subject><ispartof>Nature medicine, 2024-07, Vol.30 (7), p.1898-1904</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-4e7a41198208b98f039d5f34f0deebf20002d6d4da3a27ab4194f29d6399fda23</citedby><cites>FETCH-LOGICAL-c405t-4e7a41198208b98f039d5f34f0deebf20002d6d4da3a27ab4194f29d6399fda23</cites><orcidid>0000-0002-1452-4193 ; 0000-0001-8893-434X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41591-024-03023-5$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41591-024-03023-5$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38839897$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Chen, Yuxin</creatorcontrib><creatorcontrib>Lv, Jun</creatorcontrib><creatorcontrib>Cheng, Xiaoting</creatorcontrib><creatorcontrib>Cao, Qi</creatorcontrib><creatorcontrib>Wang, Daqi</creatorcontrib><creatorcontrib>Zhang, Longlong</creatorcontrib><creatorcontrib>Zhu, Biyun</creatorcontrib><creatorcontrib>Shen, Min</creatorcontrib><creatorcontrib>Xu, Chunxin</creatorcontrib><creatorcontrib>Xun, Mengzhao</creatorcontrib><creatorcontrib>Wang, Zijing</creatorcontrib><creatorcontrib>Tang, Honghai</creatorcontrib><creatorcontrib>Hu, Shaowei</creatorcontrib><creatorcontrib>Cui, Chong</creatorcontrib><creatorcontrib>Jiang, Luoying</creatorcontrib><creatorcontrib>Yin, Yanbo</creatorcontrib><creatorcontrib>Guo, Luo</creatorcontrib><creatorcontrib>Zhou, Yi</creatorcontrib><creatorcontrib>Han, Lei</creatorcontrib><creatorcontrib>Gao, Ziwen</creatorcontrib><creatorcontrib>Zhang, Jiajia</creatorcontrib><creatorcontrib>Yu, Sha</creatorcontrib><creatorcontrib>Gao, Kaiyu</creatorcontrib><creatorcontrib>Wang, Jinghan</creatorcontrib><creatorcontrib>Chen, Bing</creatorcontrib><creatorcontrib>Wang, Wuqing</creatorcontrib><creatorcontrib>Chen, Zheng-Yi</creatorcontrib><creatorcontrib>Li, Huawei</creatorcontrib><creatorcontrib>Shu, Yilai</creatorcontrib><title>Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human
OTOF
transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration:
ChiCTR2200063181
.
An interim analysis of a single-arm trial in 5 children with hereditary deafness shows that binaural AAV gene therapy is safe and leads to hearing improvement up to 13–26 weeks of follow-up.</description><subject>631/208/2489/201</subject><subject>692/699/375</subject><subject>Adolescent</subject><subject>Adverse events</subject><subject>Auditory system</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain stem</subject><subject>Cancer Research</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Cholesterol</subject><subject>Constraining</subject><subject>Deafness</subject><subject>Deafness - genetics</subject><subject>Deafness - therapy</subject><subject>Dependovirus - genetics</subject><subject>Ear</subject><subject>Effectiveness</subject><subject>Evoked Potentials, Auditory, Brain Stem</subject><subject>Female</subject><subject>Gene therapy</subject><subject>Genes, Recessive</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - genetics</subject><subject>Hearing loss</subject><subject>Humans</subject><subject>Infectious Diseases</subject><subject>Localization</subject><subject>Lymphocytes</subject><subject>Male</subject><subject>Metabolic Diseases</subject><subject>Molecular Medicine</subject><subject>Neurosciences</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Perception</subject><subject>Safety</subject><subject>Sound localization</subject><subject>Sound sources</subject><subject>Speech</subject><subject>Speech perception</subject><subject>Toxicity</subject><subject>Transgenes</subject><subject>Treatment Outcome</subject><issn>1078-8956</issn><issn>1546-170X</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9kc1PFTEUxRuiEUT_ARakiRs21X7OtG4IEL8SEjeauKt909v3SmY6j7aD4b-38hDUhaue5P7u6T05CB0x-ppRod8UyZRhhHJJqKBcELWHDpiSHWE9_fakadproo3q9tHzUq4obZgyz9C-0FoYbfoD9P08jq5CdiNeQwJcN01vb3FMeNjE0WdI-EesG-yWOpd5alyGAUqJN4A9uJCaxuYtLjGtRyAuT7jmeIeVZazlBXoa3Fjg5f17iL6-f_fl4iO5_Pzh08XZJRkkVZVI6J1kzGhO9croQIXxKggZqAdYBd5u577z0jvheO9WkhkZuPGdMCZ4x8UhOt35bpfVBH6AVFsou81xcvnWzi7avycpbux6vrGM8Z4JbZrDyb1Dnq8XKNVOsQwwji7BvBQraKd4z4WkDX31D3o1Lzm1fI3SzY9zoRvFd9SQ51IyhIdrGLW_GrS7Bm1r0N41aFVbOv4zx8PK78oaIHZAaaO0hvz4939sfwJ80af6</recordid><startdate>20240701</startdate><enddate>20240701</enddate><creator>Wang, Hui</creator><creator>Chen, Yuxin</creator><creator>Lv, Jun</creator><creator>Cheng, Xiaoting</creator><creator>Cao, Qi</creator><creator>Wang, Daqi</creator><creator>Zhang, Longlong</creator><creator>Zhu, Biyun</creator><creator>Shen, Min</creator><creator>Xu, Chunxin</creator><creator>Xun, Mengzhao</creator><creator>Wang, Zijing</creator><creator>Tang, Honghai</creator><creator>Hu, Shaowei</creator><creator>Cui, Chong</creator><creator>Jiang, Luoying</creator><creator>Yin, Yanbo</creator><creator>Guo, Luo</creator><creator>Zhou, Yi</creator><creator>Han, Lei</creator><creator>Gao, Ziwen</creator><creator>Zhang, Jiajia</creator><creator>Yu, Sha</creator><creator>Gao, Kaiyu</creator><creator>Wang, Jinghan</creator><creator>Chen, Bing</creator><creator>Wang, Wuqing</creator><creator>Chen, Zheng-Yi</creator><creator>Li, Huawei</creator><creator>Shu, Yilai</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><scope>C6C</scope><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1452-4193</orcidid><orcidid>https://orcid.org/0000-0001-8893-434X</orcidid></search><sort><creationdate>20240701</creationdate><title>Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results</title><author>Wang, Hui ; Chen, Yuxin ; Lv, Jun ; Cheng, Xiaoting ; Cao, Qi ; Wang, Daqi ; Zhang, Longlong ; Zhu, Biyun ; Shen, Min ; Xu, Chunxin ; Xun, Mengzhao ; Wang, Zijing ; Tang, Honghai ; Hu, Shaowei ; Cui, Chong ; Jiang, Luoying ; Yin, Yanbo ; Guo, Luo ; Zhou, Yi ; Han, Lei ; Gao, Ziwen ; Zhang, Jiajia ; Yu, Sha ; Gao, Kaiyu ; Wang, Jinghan ; Chen, Bing ; Wang, Wuqing ; Chen, Zheng-Yi ; Li, Huawei ; Shu, Yilai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-4e7a41198208b98f039d5f34f0deebf20002d6d4da3a27ab4194f29d6399fda23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>631/208/2489/201</topic><topic>692/699/375</topic><topic>Adolescent</topic><topic>Adverse events</topic><topic>Auditory system</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain stem</topic><topic>Cancer Research</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Cholesterol</topic><topic>Constraining</topic><topic>Deafness</topic><topic>Deafness - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Hui</au><au>Chen, Yuxin</au><au>Lv, Jun</au><au>Cheng, Xiaoting</au><au>Cao, Qi</au><au>Wang, Daqi</au><au>Zhang, Longlong</au><au>Zhu, Biyun</au><au>Shen, Min</au><au>Xu, Chunxin</au><au>Xun, Mengzhao</au><au>Wang, Zijing</au><au>Tang, Honghai</au><au>Hu, Shaowei</au><au>Cui, Chong</au><au>Jiang, Luoying</au><au>Yin, Yanbo</au><au>Guo, Luo</au><au>Zhou, Yi</au><au>Han, Lei</au><au>Gao, Ziwen</au><au>Zhang, Jiajia</au><au>Yu, Sha</au><au>Gao, Kaiyu</au><au>Wang, Jinghan</au><au>Chen, Bing</au><au>Wang, Wuqing</au><au>Chen, Zheng-Yi</au><au>Li, Huawei</au><au>Shu, Yilai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2024-07-01</date><risdate>2024</risdate><volume>30</volume><issue>7</issue><spage>1898</spage><epage>1904</epage><pages>1898-1904</pages><issn>1078-8956</issn><issn>1546-170X</issn><eissn>1546-170X</eissn><abstract>Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human
OTOF
transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration:
ChiCTR2200063181
.
An interim analysis of a single-arm trial in 5 children with hereditary deafness shows that binaural AAV gene therapy is safe and leads to hearing improvement up to 13–26 weeks of follow-up.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>38839897</pmid><doi>10.1038/s41591-024-03023-5</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-1452-4193</orcidid><orcidid>https://orcid.org/0000-0001-8893-434X</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1078-8956 |
| ispartof | Nature medicine, 2024-07, Vol.30 (7), p.1898-1904 |
| issn | 1078-8956 1546-170X 1546-170X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11271389 |
| source | MEDLINE; Nature; SpringerLink Journals - AutoHoldings |
| subjects | 631/208/2489/201 692/699/375 Adolescent Adverse events Auditory system Biomedical and Life Sciences Biomedicine Brain stem Cancer Research Child Child, Preschool Cholesterol Constraining Deafness Deafness - genetics Deafness - therapy Dependovirus - genetics Ear Effectiveness Evoked Potentials, Auditory, Brain Stem Female Gene therapy Genes, Recessive Genetic Therapy - methods Genetic Vectors - genetics Hearing loss Humans Infectious Diseases Localization Lymphocytes Male Metabolic Diseases Molecular Medicine Neurosciences Patients Pediatrics Perception Safety Sound localization Sound sources Speech Speech perception Toxicity Transgenes Treatment Outcome |
| title | Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T04%3A25%3A45IST&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=Bilateral%20gene%20therapy%20in%20children%20with%20autosomal%20recessive%20deafness%209:%20single-arm%20trial%20results&rft.jtitle=Nature%20medicine&rft.au=Wang,%20Hui&rft.date=2024-07-01&rft.volume=30&rft.issue=7&rft.spage=1898&rft.epage=1904&rft.pages=1898-1904&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/s41591-024-03023-5&rft_dat=%3Cproquest_pubme%3E3065272340%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=3082712238&rft_id=info:pmid/38839897&rfr_iscdi=true |