Artemisinin derivative-containing therapies and abnormal hemoglobin: Do we need to adapt the treatment?
Background: Artemisinin-based treatment in malaria patients with abnormal hemoglobin may be ineffective because of their genetic particularity, which could lead to resistance. The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according t...
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| Veröffentlicht in: | Parasite (Paris) 2021, Vol.28, p.67-67, Article 67 |
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| creator | Gbessi, Eric A. Toure, Offianan A. Gnondjui, Albert Koui, Tossea S. Coulibaly, Baba Ako, Berenger A. Tiacoh, Nguessan L. Assi, Serge-Brice Sanogo, Ibrahima Sokouri, Didier-Paulin Jambou, Ronan |
| description | Background: Artemisinin-based treatment in malaria patients with abnormal hemoglobin may be ineffective because of their genetic particularity, which could lead to resistance. The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according to erythrocyte variants. In vivo response was investigated through retrospective data obtained over a 42-day artemether-lumefantrine/artesunate amodiaquine efficacy protocol conducted from 2012 to 2016. Results: A total of 770 patients in Cote d'Ivoire attending the hospitals of Anonkoua-koute (Abidjan), Petit Paris (Korhogo), Libreville (Man), Dar es salam (Bouake), Ayame and Yamoussoukro with acute uncomplicated falciparum malaria were selected for successful hemoglobin typing. HbAS, HbSS, HbAC, and HbSC genotypes were found. Parasite clearance time was obtained for 414 patients. In the population with abnormal hemoglobin, parasite densities on admission and parasite clearance rates were significantly lower in the HbSC group compared to HbAA (p = 0.02 and p = 0.007, respectively). After PCR correction on day 42, the acute treatment rate was 100% for each group. Parasite half-life and time for initial parasitaemia to decline by 50 and 99% were longer for the HbSC group (p < 0.05). The study also investigated the prevalence of K13-propeller polymorphisms across different hemoglobin genotype groups. A total of 185 and 63 samples were sequenced in the HbAA group and patients with abnormal Hb, respectively. Only two nonsynonymous mutations D559N and V510M were found in the HbAA group. Conclusion: Although this study proved good efficacy of artemether-lumefantrine and artesunate amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in patients with abnormal hemoglobin, the increased delay of parasite clearance may represent a threat to health in these patients in relation with sickle cell crisis, which could support selection of parasites resistant to artemisinin. |
| doi_str_mv | 10.1051/parasite/2021063 |
| format | Article |
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The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according to erythrocyte variants. In vivo response was investigated through retrospective data obtained over a 42-day artemether-lumefantrine/artesunate amodiaquine efficacy protocol conducted from 2012 to 2016. Results: A total of 770 patients in Cote d'Ivoire attending the hospitals of Anonkoua-koute (Abidjan), Petit Paris (Korhogo), Libreville (Man), Dar es salam (Bouake), Ayame and Yamoussoukro with acute uncomplicated falciparum malaria were selected for successful hemoglobin typing. HbAS, HbSS, HbAC, and HbSC genotypes were found. Parasite clearance time was obtained for 414 patients. In the population with abnormal hemoglobin, parasite densities on admission and parasite clearance rates were significantly lower in the HbSC group compared to HbAA (p = 0.02 and p = 0.007, respectively). After PCR correction on day 42, the acute treatment rate was 100% for each group. Parasite half-life and time for initial parasitaemia to decline by 50 and 99% were longer for the HbSC group (p < 0.05). The study also investigated the prevalence of K13-propeller polymorphisms across different hemoglobin genotype groups. A total of 185 and 63 samples were sequenced in the HbAA group and patients with abnormal Hb, respectively. Only two nonsynonymous mutations D559N and V510M were found in the HbAA group. Conclusion: Although this study proved good efficacy of artemether-lumefantrine and artesunate amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in patients with abnormal hemoglobin, the increased delay of parasite clearance may represent a threat to health in these patients in relation with sickle cell crisis, which could support selection of parasites resistant to artemisinin.</description><identifier>ISSN: 1252-607X</identifier><identifier>ISSN: 1776-1042</identifier><identifier>EISSN: 1776-1042</identifier><identifier>DOI: 10.1051/parasite/2021063</identifier><identifier>PMID: 34569928</identifier><language>eng</language><publisher>LES ULIS CEDEX A: Edp Sciences S A</publisher><subject>Amodiaquine ; Antimalarials - therapeutic use ; Artemether ; Artemether - therapeutic use ; Artemether, Lumefantrine Drug Combination ; Artemisinin ; artemisinin containing therapy ; Artemisinins - therapeutic use ; Artesunate ; Cote d'Ivoire - epidemiology ; Drug Combinations ; Erythrocytes ; Ethanolamines - therapeutic use ; Genotypes ; Health risks ; Hemoglobin ; hemoglobinopathy ; Hemoglobins, Abnormal - therapeutic use ; Human health and pathology ; Humans ; In vivo methods and tests ; Infectious diseases ; ivory coast ; Life Sciences ; Life Sciences & Biomedicine ; Malaria ; Malaria, Falciparum - drug therapy ; Malaria, Falciparum - epidemiology ; Mutation ; Parasite resistance ; Parasites ; Parasitology ; Patients ; Pharmaceutical sciences ; Pharmacology ; Plasmodium falciparum ; Plasmodium falciparum - genetics ; Retrospective Studies ; Science & Technology ; Treatment Outcome ; Vector-borne diseases</subject><ispartof>Parasite (Paris), 2021, Vol.28, p.67-67, Article 67</ispartof><rights>E. Gbessi et al., published by EDP Sciences, 2021.</rights><rights>2021. This work is licensed under https://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>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>E. Gbessi et al., published by EDP Sciences, 2021 2021 E. Gbessi et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>2</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000700215200001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c482t-38b7ce8a4703d285d5dc1358cd4ace45689af2d243fda57fa0cf42bfaa74b7bd3</citedby><cites>FETCH-LOGICAL-c482t-38b7ce8a4703d285d5dc1358cd4ace45689af2d243fda57fa0cf42bfaa74b7bd3</cites><orcidid>0000-0003-0626-101X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475499/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475499/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2115,4025,27928,27929,27930,39263,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34569928$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03356316$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Gbessi, Eric A.</creatorcontrib><creatorcontrib>Toure, Offianan A.</creatorcontrib><creatorcontrib>Gnondjui, Albert</creatorcontrib><creatorcontrib>Koui, Tossea S.</creatorcontrib><creatorcontrib>Coulibaly, Baba</creatorcontrib><creatorcontrib>Ako, Berenger A.</creatorcontrib><creatorcontrib>Tiacoh, Nguessan L.</creatorcontrib><creatorcontrib>Assi, Serge-Brice</creatorcontrib><creatorcontrib>Sanogo, Ibrahima</creatorcontrib><creatorcontrib>Sokouri, Didier-Paulin</creatorcontrib><creatorcontrib>Jambou, Ronan</creatorcontrib><title>Artemisinin derivative-containing therapies and abnormal hemoglobin: Do we need to adapt the treatment?</title><title>Parasite (Paris)</title><addtitle>PARASITE</addtitle><addtitle>Parasite</addtitle><description>Background: Artemisinin-based treatment in malaria patients with abnormal hemoglobin may be ineffective because of their genetic particularity, which could lead to resistance. The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according to erythrocyte variants. In vivo response was investigated through retrospective data obtained over a 42-day artemether-lumefantrine/artesunate amodiaquine efficacy protocol conducted from 2012 to 2016. Results: A total of 770 patients in Cote d'Ivoire attending the hospitals of Anonkoua-koute (Abidjan), Petit Paris (Korhogo), Libreville (Man), Dar es salam (Bouake), Ayame and Yamoussoukro with acute uncomplicated falciparum malaria were selected for successful hemoglobin typing. HbAS, HbSS, HbAC, and HbSC genotypes were found. Parasite clearance time was obtained for 414 patients. In the population with abnormal hemoglobin, parasite densities on admission and parasite clearance rates were significantly lower in the HbSC group compared to HbAA (p = 0.02 and p = 0.007, respectively). After PCR correction on day 42, the acute treatment rate was 100% for each group. Parasite half-life and time for initial parasitaemia to decline by 50 and 99% were longer for the HbSC group (p < 0.05). The study also investigated the prevalence of K13-propeller polymorphisms across different hemoglobin genotype groups. A total of 185 and 63 samples were sequenced in the HbAA group and patients with abnormal Hb, respectively. Only two nonsynonymous mutations D559N and V510M were found in the HbAA group. Conclusion: Although this study proved good efficacy of artemether-lumefantrine and artesunate amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in patients with abnormal hemoglobin, the increased delay of parasite clearance may represent a threat to health in these patients in relation with sickle cell crisis, which could support selection of parasites resistant to artemisinin.</description><subject>Amodiaquine</subject><subject>Antimalarials - therapeutic use</subject><subject>Artemether</subject><subject>Artemether - therapeutic use</subject><subject>Artemether, Lumefantrine Drug Combination</subject><subject>Artemisinin</subject><subject>artemisinin containing therapy</subject><subject>Artemisinins - therapeutic use</subject><subject>Artesunate</subject><subject>Cote d'Ivoire - epidemiology</subject><subject>Drug Combinations</subject><subject>Erythrocytes</subject><subject>Ethanolamines - therapeutic use</subject><subject>Genotypes</subject><subject>Health risks</subject><subject>Hemoglobin</subject><subject>hemoglobinopathy</subject><subject>Hemoglobins, Abnormal - therapeutic use</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>In vivo methods and tests</subject><subject>Infectious diseases</subject><subject>ivory coast</subject><subject>Life Sciences</subject><subject>Life Sciences & Biomedicine</subject><subject>Malaria</subject><subject>Malaria, Falciparum - drug therapy</subject><subject>Malaria, Falciparum - epidemiology</subject><subject>Mutation</subject><subject>Parasite resistance</subject><subject>Parasites</subject><subject>Parasitology</subject><subject>Patients</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - genetics</subject><subject>Retrospective Studies</subject><subject>Science & Technology</subject><subject>Treatment Outcome</subject><subject>Vector-borne diseases</subject><issn>1252-607X</issn><issn>1776-1042</issn><issn>1776-1042</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNks1vEzEQxVcIREvhzgmtxAWElvpzvcsBFIWPVorEBSRu1qw9mzjatVOvk4r_HoekEe2Jk63x772xx68oXlLynhJJLzcQYXIJLxlhlNT8UXFOlaorSgR7nPdMsqom6tdZ8Wya1iQTdcOfFmdcyLptWXNeLGcx4egm550vLUa3g-R2WJngE-yLyzKtMMLG4VSCtyV0PsQRhnKFY1gOoXP-Q_k5lLdYekRbplCChU3ay8oUEdKIPn16XjzpYZjwxXG9KH5-_fJjflUtvn-7ns8WlRENSxVvOmWwAaEIt6yRVlpDuWyMFWAw37ppoWeWCd5bkKoHYnrBuh5AiU51ll8U1wdfG2CtN9GNEH_rAE7_LYS41BCTMwNqRbKpsNlXgeh63uXZyL7nuT3Jc4Ls9fHgtdl2I1qT3xFhuGd6_8S7lV6GnW6EkqJts8Hbg8HqgexqttD7GuFc1pzWO5rZN8dmMdxscUo6_4rBYQCPYTtpJlXdUlmLJqOvH6DrsI0-j1WzOiOUK84zRQ6UiWGaIvanG1Ci9-nRd-nRx_Rkyat_H3wS3MUlA80BuMUu9JNx6A2eMEKIItlKsrwjdO5SzlLw87D1KUvf_b-U_wGf0eTm</recordid><startdate>2021</startdate><enddate>2021</enddate><creator>Gbessi, Eric A.</creator><creator>Toure, Offianan A.</creator><creator>Gnondjui, Albert</creator><creator>Koui, Tossea S.</creator><creator>Coulibaly, Baba</creator><creator>Ako, Berenger A.</creator><creator>Tiacoh, Nguessan L.</creator><creator>Assi, Serge-Brice</creator><creator>Sanogo, Ibrahima</creator><creator>Sokouri, Didier-Paulin</creator><creator>Jambou, Ronan</creator><general>Edp Sciences S A</general><general>EDP Sciences</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</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>3V.</scope><scope>7QG</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-0626-101X</orcidid></search><sort><creationdate>2021</creationdate><title>Artemisinin derivative-containing therapies and abnormal hemoglobin: Do we need to adapt the treatment?</title><author>Gbessi, Eric A. ; Toure, Offianan A. ; Gnondjui, Albert ; Koui, Tossea S. ; Coulibaly, Baba ; Ako, Berenger A. ; Tiacoh, Nguessan L. ; Assi, Serge-Brice ; Sanogo, Ibrahima ; Sokouri, Didier-Paulin ; Jambou, Ronan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c482t-38b7ce8a4703d285d5dc1358cd4ace45689af2d243fda57fa0cf42bfaa74b7bd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amodiaquine</topic><topic>Antimalarials - therapeutic use</topic><topic>Artemether</topic><topic>Artemether - therapeutic use</topic><topic>Artemether, Lumefantrine Drug Combination</topic><topic>Artemisinin</topic><topic>artemisinin containing therapy</topic><topic>Artemisinins - therapeutic use</topic><topic>Artesunate</topic><topic>Cote d'Ivoire - epidemiology</topic><topic>Drug Combinations</topic><topic>Erythrocytes</topic><topic>Ethanolamines - therapeutic use</topic><topic>Genotypes</topic><topic>Health risks</topic><topic>Hemoglobin</topic><topic>hemoglobinopathy</topic><topic>Hemoglobins, Abnormal - therapeutic use</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>In vivo methods and tests</topic><topic>Infectious diseases</topic><topic>ivory coast</topic><topic>Life Sciences</topic><topic>Life Sciences & Biomedicine</topic><topic>Malaria</topic><topic>Malaria, Falciparum - drug therapy</topic><topic>Malaria, Falciparum - epidemiology</topic><topic>Mutation</topic><topic>Parasite resistance</topic><topic>Parasites</topic><topic>Parasitology</topic><topic>Patients</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacology</topic><topic>Plasmodium falciparum</topic><topic>Plasmodium falciparum - 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Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Parasite (Paris)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gbessi, Eric A.</au><au>Toure, Offianan A.</au><au>Gnondjui, Albert</au><au>Koui, Tossea S.</au><au>Coulibaly, Baba</au><au>Ako, Berenger A.</au><au>Tiacoh, Nguessan L.</au><au>Assi, Serge-Brice</au><au>Sanogo, Ibrahima</au><au>Sokouri, Didier-Paulin</au><au>Jambou, Ronan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Artemisinin derivative-containing therapies and abnormal hemoglobin: Do we need to adapt the treatment?</atitle><jtitle>Parasite (Paris)</jtitle><stitle>PARASITE</stitle><addtitle>Parasite</addtitle><date>2021</date><risdate>2021</risdate><volume>28</volume><spage>67</spage><epage>67</epage><pages>67-67</pages><artnum>67</artnum><issn>1252-607X</issn><issn>1776-1042</issn><eissn>1776-1042</eissn><abstract>Background: Artemisinin-based treatment in malaria patients with abnormal hemoglobin may be ineffective because of their genetic particularity, which could lead to resistance. The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according to erythrocyte variants. In vivo response was investigated through retrospective data obtained over a 42-day artemether-lumefantrine/artesunate amodiaquine efficacy protocol conducted from 2012 to 2016. Results: A total of 770 patients in Cote d'Ivoire attending the hospitals of Anonkoua-koute (Abidjan), Petit Paris (Korhogo), Libreville (Man), Dar es salam (Bouake), Ayame and Yamoussoukro with acute uncomplicated falciparum malaria were selected for successful hemoglobin typing. HbAS, HbSS, HbAC, and HbSC genotypes were found. Parasite clearance time was obtained for 414 patients. In the population with abnormal hemoglobin, parasite densities on admission and parasite clearance rates were significantly lower in the HbSC group compared to HbAA (p = 0.02 and p = 0.007, respectively). After PCR correction on day 42, the acute treatment rate was 100% for each group. Parasite half-life and time for initial parasitaemia to decline by 50 and 99% were longer for the HbSC group (p < 0.05). The study also investigated the prevalence of K13-propeller polymorphisms across different hemoglobin genotype groups. A total of 185 and 63 samples were sequenced in the HbAA group and patients with abnormal Hb, respectively. Only two nonsynonymous mutations D559N and V510M were found in the HbAA group. Conclusion: Although this study proved good efficacy of artemether-lumefantrine and artesunate amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in patients with abnormal hemoglobin, the increased delay of parasite clearance may represent a threat to health in these patients in relation with sickle cell crisis, which could support selection of parasites resistant to artemisinin.</abstract><cop>LES ULIS CEDEX A</cop><pub>Edp Sciences S A</pub><pmid>34569928</pmid><doi>10.1051/parasite/2021063</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-0626-101X</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_proquest_miscellaneous_2576915648 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central Open Access; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; EDP Open; PubMed Central; Alma/SFX Local Collection |
| subjects | Amodiaquine Antimalarials - therapeutic use Artemether Artemether - therapeutic use Artemether, Lumefantrine Drug Combination Artemisinin artemisinin containing therapy Artemisinins - therapeutic use Artesunate Cote d'Ivoire - epidemiology Drug Combinations Erythrocytes Ethanolamines - therapeutic use Genotypes Health risks Hemoglobin hemoglobinopathy Hemoglobins, Abnormal - therapeutic use Human health and pathology Humans In vivo methods and tests Infectious diseases ivory coast Life Sciences Life Sciences & Biomedicine Malaria Malaria, Falciparum - drug therapy Malaria, Falciparum - epidemiology Mutation Parasite resistance Parasites Parasitology Patients Pharmaceutical sciences Pharmacology Plasmodium falciparum Plasmodium falciparum - genetics Retrospective Studies Science & Technology Treatment Outcome Vector-borne diseases |
| title | Artemisinin derivative-containing therapies and abnormal hemoglobin: Do we need to adapt the treatment? |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-13T14%3A06%3A54IST&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=Artemisinin%20derivative-containing%20therapies%20and%20abnormal%20hemoglobin:%20Do%20we%20need%20to%20adapt%20the%20treatment?&rft.jtitle=Parasite%20(Paris)&rft.au=Gbessi,%20Eric%20A.&rft.date=2021&rft.volume=28&rft.spage=67&rft.epage=67&rft.pages=67-67&rft.artnum=67&rft.issn=1252-607X&rft.eissn=1776-1042&rft_id=info:doi/10.1051/parasite/2021063&rft_dat=%3Cproquest_pubme%3E2615613733%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=2615613733&rft_id=info:pmid/34569928&rft_doaj_id=oai_doaj_org_article_70d4a4dace7a4bf3b6835ff3e8a0368a&rfr_iscdi=true |