Pub Date : 2023-10-26DOI: 10.1038/s41591-023-02641-9
Tadele Emiru, Dejene Getachew, Maxwell Murphy, Luigi Sedda, Legesse Alamerie Ejigu, Mikiyas Gebremichael Bulto, Isabel Byrne, Mulugeta Demisse, Melat Abdo, Wakweya Chali, Aaron Elliott, Eric Neubauer Vickers, Andrés Aranda-Díaz, Lina Alemayehu, Sinknesh W. Behaksera, Gutema Jebessa, Hunduma Dinka, Tizita Tsegaye, Hiwot Teka, Sheleme Chibsa, Peter Mumba, Samuel Girma, Jimee Hwang, Melissa Yoshimizu, Alice Sutcliffe, Hiwot Solomon Taffese, Gudissa Aseffa Bayissa, Sarah Zohdy, Jon Eric Tongren, Chris Drakeley, Bryan Greenhouse, Teun Bousema, Fitsum G. Tadesse
Anopheles stephensi, an Asian malaria vector, continues to expand across Africa. The vector is now firmly established in urban settings in the Horn of Africa. Its presence in areas where malaria resurged suggested a possible role in causing malaria outbreaks. Here, using a prospective case–control design, we investigated the role of An. stephensi in transmission following a malaria outbreak in Dire Dawa, Ethiopia in April–July 2022. Screening contacts of patients with malaria and febrile controls revealed spatial clustering of Plasmodium falciparum infections around patients with malaria in strong association with the presence of An. stephensi in the household vicinity. Plasmodium sporozoites were detected in these mosquitoes. This outbreak involved clonal propagation of parasites with molecular signatures of artemisinin and diagnostic resistance. To our knowledge, this study provides the strongest evidence so far for a role of An. stephensi in driving an urban malaria outbreak in Africa, highlighting the major public health threat posed by this fast-spreading mosquito. Evidence that a dry-season outbreak of malaria in Dire Dawa, Ethiopia is caused by Anopheles stephensi carrying Plasmodium falciparum with diagnostic and drug resistance mutations calls for heightened vector surveillance in both urban and rural settings.
{"title":"Evidence for a role of Anopheles stephensi in the spread of drug- and diagnosis-resistant malaria in Africa","authors":"Tadele Emiru, Dejene Getachew, Maxwell Murphy, Luigi Sedda, Legesse Alamerie Ejigu, Mikiyas Gebremichael Bulto, Isabel Byrne, Mulugeta Demisse, Melat Abdo, Wakweya Chali, Aaron Elliott, Eric Neubauer Vickers, Andrés Aranda-Díaz, Lina Alemayehu, Sinknesh W. Behaksera, Gutema Jebessa, Hunduma Dinka, Tizita Tsegaye, Hiwot Teka, Sheleme Chibsa, Peter Mumba, Samuel Girma, Jimee Hwang, Melissa Yoshimizu, Alice Sutcliffe, Hiwot Solomon Taffese, Gudissa Aseffa Bayissa, Sarah Zohdy, Jon Eric Tongren, Chris Drakeley, Bryan Greenhouse, Teun Bousema, Fitsum G. Tadesse","doi":"10.1038/s41591-023-02641-9","DOIUrl":"10.1038/s41591-023-02641-9","url":null,"abstract":"Anopheles stephensi, an Asian malaria vector, continues to expand across Africa. The vector is now firmly established in urban settings in the Horn of Africa. Its presence in areas where malaria resurged suggested a possible role in causing malaria outbreaks. Here, using a prospective case–control design, we investigated the role of An. stephensi in transmission following a malaria outbreak in Dire Dawa, Ethiopia in April–July 2022. Screening contacts of patients with malaria and febrile controls revealed spatial clustering of Plasmodium falciparum infections around patients with malaria in strong association with the presence of An. stephensi in the household vicinity. Plasmodium sporozoites were detected in these mosquitoes. This outbreak involved clonal propagation of parasites with molecular signatures of artemisinin and diagnostic resistance. To our knowledge, this study provides the strongest evidence so far for a role of An. stephensi in driving an urban malaria outbreak in Africa, highlighting the major public health threat posed by this fast-spreading mosquito. Evidence that a dry-season outbreak of malaria in Dire Dawa, Ethiopia is caused by Anopheles stephensi carrying Plasmodium falciparum with diagnostic and drug resistance mutations calls for heightened vector surveillance in both urban and rural settings.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 12","pages":"3203-3211"},"PeriodicalIF":82.9,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10719088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-26DOI: 10.1038/s41591-023-02608-w
Anmol Arora, Joseph E. Alderman, Joanne Palmer, Shaswath Ganapathi, Elinor Laws, Melissa D. McCradden, Lauren Oakden-Rayner, Stephen R. Pfohl, Marzyeh Ghassemi, Francis McKay, Darren Treanor, Negar Rostamzadeh, Bilal Mateen, Jacqui Gath, Adewole O. Adebajo, Stephanie Kuku, Rubeta Matin, Katherine Heller, Elizabeth Sapey, Neil J. Sebire, Heather Cole-Lewis, Melanie Calvert, Alastair Denniston, Xiaoxuan Liu
Artificial intelligence as a medical device is increasingly being applied to healthcare for diagnosis, risk stratification and resource allocation. However, a growing body of evidence has highlighted the risk of algorithmic bias, which may perpetuate existing health inequity. This problem arises in part because of systemic inequalities in dataset curation, unequal opportunity to participate in research and inequalities of access. This study aims to explore existing standards, frameworks and best practices for ensuring adequate data diversity in health datasets. Exploring the body of existing literature and expert views is an important step towards the development of consensus-based guidelines. The study comprises two parts: a systematic review of existing standards, frameworks and best practices for healthcare datasets; and a survey and thematic analysis of stakeholder views of bias, health equity and best practices for artificial intelligence as a medical device. We found that the need for dataset diversity was well described in literature, and experts generally favored the development of a robust set of guidelines, but there were mixed views about how these could be implemented practically. The outputs of this study will be used to inform the development of standards for transparency of data diversity in health datasets (the STANDING Together initiative). A systematic review, combined with a stakeholder survey, presents an overview of current practices and recommendations for dataset curation in health, with specific focuses on data diversity and artificial intelligence-based applications.
{"title":"The value of standards for health datasets in artificial intelligence-based applications","authors":"Anmol Arora, Joseph E. Alderman, Joanne Palmer, Shaswath Ganapathi, Elinor Laws, Melissa D. McCradden, Lauren Oakden-Rayner, Stephen R. Pfohl, Marzyeh Ghassemi, Francis McKay, Darren Treanor, Negar Rostamzadeh, Bilal Mateen, Jacqui Gath, Adewole O. Adebajo, Stephanie Kuku, Rubeta Matin, Katherine Heller, Elizabeth Sapey, Neil J. Sebire, Heather Cole-Lewis, Melanie Calvert, Alastair Denniston, Xiaoxuan Liu","doi":"10.1038/s41591-023-02608-w","DOIUrl":"10.1038/s41591-023-02608-w","url":null,"abstract":"Artificial intelligence as a medical device is increasingly being applied to healthcare for diagnosis, risk stratification and resource allocation. However, a growing body of evidence has highlighted the risk of algorithmic bias, which may perpetuate existing health inequity. This problem arises in part because of systemic inequalities in dataset curation, unequal opportunity to participate in research and inequalities of access. This study aims to explore existing standards, frameworks and best practices for ensuring adequate data diversity in health datasets. Exploring the body of existing literature and expert views is an important step towards the development of consensus-based guidelines. The study comprises two parts: a systematic review of existing standards, frameworks and best practices for healthcare datasets; and a survey and thematic analysis of stakeholder views of bias, health equity and best practices for artificial intelligence as a medical device. We found that the need for dataset diversity was well described in literature, and experts generally favored the development of a robust set of guidelines, but there were mixed views about how these could be implemented practically. The outputs of this study will be used to inform the development of standards for transparency of data diversity in health datasets (the STANDING Together initiative). A systematic review, combined with a stakeholder survey, presents an overview of current practices and recommendations for dataset curation in health, with specific focuses on data diversity and artificial intelligence-based applications.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2929-2938"},"PeriodicalIF":82.9,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-24DOI: 10.1038/s41591-023-02649-1
Joan Ballester, Marcos Quijal-Zamorano, Raúl Fernando Méndez Turrubiates, Ferran Pegenaute, François R. Herrmann, Jean Marie Robine, Xavier Basagaña, Cathryn Tonne, Josep M. Antó, Hicham Achebak
{"title":"Author Correction: Heat-related mortality in Europe during the summer of 2022","authors":"Joan Ballester, Marcos Quijal-Zamorano, Raúl Fernando Méndez Turrubiates, Ferran Pegenaute, François R. Herrmann, Jean Marie Robine, Xavier Basagaña, Cathryn Tonne, Josep M. Antó, Hicham Achebak","doi":"10.1038/s41591-023-02649-1","DOIUrl":"10.1038/s41591-023-02649-1","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 2","pages":"603-603"},"PeriodicalIF":82.9,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-023-02649-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50158398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-24DOI: 10.1038/s41591-023-02648-2
Jonathan J. Lau, Samuel M. S. Cheng, Kathy Leung, Cheuk Kwong Lee, Asmaa Hachim, Leo C. H. Tsang, Kenny W. H. Yam, Sara Chaothai, Kelvin K. H. Kwan, Zacary Y. H. Chai, Tiffany H. K. Lo, Masashi Mori, Chao Wu, Sophie A. Valkenburg, Gaya K. Amarasinghe, Eric H. Y. Lau, David S. C. Hui, Gabriel M. Leung, Malik Peiris, Joseph T. Wu
{"title":"Author Correction: Real-world COVID-19 vaccine effectiveness against the Omicron BA.2 variant in a SARS-CoV-2 infection-naive population","authors":"Jonathan J. Lau, Samuel M. S. Cheng, Kathy Leung, Cheuk Kwong Lee, Asmaa Hachim, Leo C. H. Tsang, Kenny W. H. Yam, Sara Chaothai, Kelvin K. H. Kwan, Zacary Y. H. Chai, Tiffany H. K. Lo, Masashi Mori, Chao Wu, Sophie A. Valkenburg, Gaya K. Amarasinghe, Eric H. Y. Lau, David S. C. Hui, Gabriel M. Leung, Malik Peiris, Joseph T. Wu","doi":"10.1038/s41591-023-02648-2","DOIUrl":"10.1038/s41591-023-02648-2","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 1","pages":"305-305"},"PeriodicalIF":82.9,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10803247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50158400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-24DOI: 10.1038/d41591-023-00092-w
Karen O'Leary
{"title":"Mapping the cellular landscape of the brain.","authors":"Karen O'Leary","doi":"10.1038/d41591-023-00092-w","DOIUrl":"https://doi.org/10.1038/d41591-023-00092-w","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":82.9,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50158401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-24DOI: 10.1038/s41591-023-02652-6
Dominik Sturm, David Capper, Felipe Andreiuolo, Marco Gessi, Christian Kölsche, Annekathrin Reinhardt, Philipp Sievers, Annika K. Wefers, Azadeh Ebrahimi, Abigail K. Suwala, Gerrit H. Gielen, Martin Sill, Daniel Schrimpf, Damian Stichel, Volker Hovestadt, Bjarne Daenekas, Agata Rode, Stefan Hamelmann, Christopher Previti, Natalie Jäger, Ivo Buchhalter, Mirjam Blattner-Johnson, Barbara C. Jones, Monika Warmuth-Metz, Brigitte Bison, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Martin Hasselblatt, Ulrich Schüller, Arend Koch, Nicolas U. Gerber, Christine L. White, Molly K. Buntine, Kathryn Kinross, Elizabeth M. Algar, Jordan R. Hansford, Nicholas G. Gottardo, Martin U. Schuhmann, Ulrich W. Thomale, Pablo Hernáiz Driever, Astrid Gnekow, Olaf Witt, Hermann L. Müller, Gabriele Calaminus, Gudrun Fleischhack, Uwe Kordes, Martin Mynarek, Stefan Rutkowski, Michael C. Frühwald, Christof M. Kramm, Andreas von Deimling, Torsten Pietsch, Felix Sahm, Stefan M. Pfister, David. T. W. Jones
{"title":"Author Correction: Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology","authors":"Dominik Sturm, David Capper, Felipe Andreiuolo, Marco Gessi, Christian Kölsche, Annekathrin Reinhardt, Philipp Sievers, Annika K. Wefers, Azadeh Ebrahimi, Abigail K. Suwala, Gerrit H. Gielen, Martin Sill, Daniel Schrimpf, Damian Stichel, Volker Hovestadt, Bjarne Daenekas, Agata Rode, Stefan Hamelmann, Christopher Previti, Natalie Jäger, Ivo Buchhalter, Mirjam Blattner-Johnson, Barbara C. Jones, Monika Warmuth-Metz, Brigitte Bison, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Martin Hasselblatt, Ulrich Schüller, Arend Koch, Nicolas U. Gerber, Christine L. White, Molly K. Buntine, Kathryn Kinross, Elizabeth M. Algar, Jordan R. Hansford, Nicholas G. Gottardo, Martin U. Schuhmann, Ulrich W. Thomale, Pablo Hernáiz Driever, Astrid Gnekow, Olaf Witt, Hermann L. Müller, Gabriele Calaminus, Gudrun Fleischhack, Uwe Kordes, Martin Mynarek, Stefan Rutkowski, Michael C. Frühwald, Christof M. Kramm, Andreas von Deimling, Torsten Pietsch, Felix Sahm, Stefan M. Pfister, David. T. W. Jones","doi":"10.1038/s41591-023-02652-6","DOIUrl":"10.1038/s41591-023-02652-6","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 1","pages":"306-306"},"PeriodicalIF":82.9,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10803251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50158399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-23DOI: 10.1038/s41591-023-02612-0
Andreas Mackensen, John B.A.G. Haanen, Christian Koenecke, Winfried Alsdorf, Eva Wagner-Drouet, Peter Borchmann, Daniel Heudobler, Barbara Ferstl, Sebastian Klobuch, Carsten Bokemeyer, Alexander Desuki, Florian Lüke, Nadine Kutsch, Fabian Müller, Eveline Smit, Peter Hillemanns, Panagiotis Karagiannis, Erol Wiegert, Ying He, Thang Ho, Qing Kang-Fortner, Anna Melissa Schlitter, Catrine Schulz-Eying, Andrew Finlayson, Carina Flemmig, Klaus Kühlcke, Liane Preußner, Benjamin Rengstl, Özlem Türeci, Uğur Şahin
The oncofetal antigen Claudin 6 (CLDN6) is highly and specifically expressed in many solid tumors, and could be a promising treatment target. We report dose escalation results from the ongoing phase 1/2 BNT211-01 trial evaluating the safety and feasibility of chimeric antigen receptor (CAR) T cells targeting the CLDN6 with or without a CAR-T cell-amplifying RNA vaccine (CARVac) at two dose levels (DLs) in relapsed/refractory CLDN6-positive solid tumors. The primary endpoints were safety and tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR) and disease control rate. We observed manageable toxicity, with 10 out of 22 patients (46%) experiencing cytokine release syndrome including one grade 3 event and 1 out of 22 (5%) with grade 1 immune effector cell-associated neurotoxicity syndrome. Dose-limiting toxicities occurred in two patients at the higher DL, resolving without sequelae. CAR-T cell engraftment was robust, and the addition of CARVac was well tolerated. The unconfirmed ORR in 21 evaluable patients was 33% (7 of 21), including one complete response. The disease control rate was 67% (14 of 21), with stable disease in seven patients. Patients with germ cell tumors treated at the higher DL exhibited the highest response rate (ORR 57% (4 of 7)). The maximum tolerated dose and RP2D were not established as the trial has been amended to utilize an automated manufacturing process. A repeat of the dose escalation is ongoing and will identify a RP2D for pivotal trials. ClinicalTrials.gov Identifier: NCT04503278 . In the ongoing phase 1/2 BNT211-01 trial, CLDN6-specific chimeric antigen receptor (CAR)-T cells given with or without CARVac, a CAR-T cell-amplifying RNA vaccine, were well-tolerated and exhibited encouraging clinical activity in patients with relapsed or refractory CLDN6-positive solid tumors, with the highest response rate in patients with germ cell tumors.
{"title":"CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial","authors":"Andreas Mackensen, John B.A.G. Haanen, Christian Koenecke, Winfried Alsdorf, Eva Wagner-Drouet, Peter Borchmann, Daniel Heudobler, Barbara Ferstl, Sebastian Klobuch, Carsten Bokemeyer, Alexander Desuki, Florian Lüke, Nadine Kutsch, Fabian Müller, Eveline Smit, Peter Hillemanns, Panagiotis Karagiannis, Erol Wiegert, Ying He, Thang Ho, Qing Kang-Fortner, Anna Melissa Schlitter, Catrine Schulz-Eying, Andrew Finlayson, Carina Flemmig, Klaus Kühlcke, Liane Preußner, Benjamin Rengstl, Özlem Türeci, Uğur Şahin","doi":"10.1038/s41591-023-02612-0","DOIUrl":"10.1038/s41591-023-02612-0","url":null,"abstract":"The oncofetal antigen Claudin 6 (CLDN6) is highly and specifically expressed in many solid tumors, and could be a promising treatment target. We report dose escalation results from the ongoing phase 1/2 BNT211-01 trial evaluating the safety and feasibility of chimeric antigen receptor (CAR) T cells targeting the CLDN6 with or without a CAR-T cell-amplifying RNA vaccine (CARVac) at two dose levels (DLs) in relapsed/refractory CLDN6-positive solid tumors. The primary endpoints were safety and tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR) and disease control rate. We observed manageable toxicity, with 10 out of 22 patients (46%) experiencing cytokine release syndrome including one grade 3 event and 1 out of 22 (5%) with grade 1 immune effector cell-associated neurotoxicity syndrome. Dose-limiting toxicities occurred in two patients at the higher DL, resolving without sequelae. CAR-T cell engraftment was robust, and the addition of CARVac was well tolerated. The unconfirmed ORR in 21 evaluable patients was 33% (7 of 21), including one complete response. The disease control rate was 67% (14 of 21), with stable disease in seven patients. Patients with germ cell tumors treated at the higher DL exhibited the highest response rate (ORR 57% (4 of 7)). The maximum tolerated dose and RP2D were not established as the trial has been amended to utilize an automated manufacturing process. A repeat of the dose escalation is ongoing and will identify a RP2D for pivotal trials. ClinicalTrials.gov Identifier: NCT04503278 . In the ongoing phase 1/2 BNT211-01 trial, CLDN6-specific chimeric antigen receptor (CAR)-T cells given with or without CARVac, a CAR-T cell-amplifying RNA vaccine, were well-tolerated and exhibited encouraging clinical activity in patients with relapsed or refractory CLDN6-positive solid tumors, with the highest response rate in patients with germ cell tumors.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2844-2853"},"PeriodicalIF":82.9,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49691567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-23DOI: 10.1038/s41591-023-02596-x
Ahmad N. Abou Tayoun, Alawi Alsheikh-Ali
{"title":"A rapid whole-genome sequencing service for infants with rare diseases in the United Arab Emirates","authors":"Ahmad N. Abou Tayoun, Alawi Alsheikh-Ali","doi":"10.1038/s41591-023-02596-x","DOIUrl":"10.1038/s41591-023-02596-x","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 12","pages":"2979-2980"},"PeriodicalIF":82.9,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49691566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-23DOI: 10.1038/s41591-023-02613-z
Olga V. Britanova, Kseniia R. Lupyr, Dmitry B. Staroverov, Irina A. Shagina, Alexey A. Aleksandrov, Yakov Y. Ustyugov, Dmitry V. Somov, Alesia Klimenko, Nadejda A. Shostak, Ivan V. Zvyagin, Alexey V. Stepanov, Ekaterina M. Merzlyak, Alexey N. Davydov, Mark Izraelson, Evgeniy S. Egorov, Ekaterina A. Bogdanova, Anna K. Vladimirova, Pavel A. Iakovlev, Denis A. Fedorenko, Roman A. Ivanov, Veronika I. Skvortsova, Sergey Lukyanov, Dmitry M. Chudakov
Autoimmunity is intrinsically driven by memory T and B cell clones inappropriately targeted at self-antigens. Selective depletion or suppression of self-reactive T cells remains a holy grail of autoimmune therapy, but disease-associated T cell receptors (TCRs) and cognate antigenic epitopes remained elusive. A TRBV9-containing CD8+ TCR motif was recently associated with the pathogenesis of ankylosing spondylitis, psoriatic arthritis and acute anterior uveitis, and cognate HLA-B*27-presented epitopes were identified. Following successful testing in nonhuman primate models, here we report human TRBV9+ T cell elimination in ankylosing spondylitis. The patient achieved remission within 3 months and ceased anti-TNF therapy after 5 years of continuous use. Complete remission has now persisted for 4 years, with three doses of anti-TRBV9 administered per year. We also observed a profound improvement in spinal mobility metrics and the Bath Ankylosing Spondylitis Metrology Index (BASMI). This represents a possibly curative therapy of an autoimmune disease via selective depletion of a TRBV-defined group of T cells. The anti-TRBV9 therapy could potentially be applicable to other HLA-B*27-associated spondyloarthropathies. Such targeted elimination of the underlying cause of the disease without systemic immunosuppression could offer a new generation of safe and efficient therapies for autoimmunity. Targeted depletion of TRBV9+ T cells induces remission in a single patient with ankylosing spondylitis, with significant improvements in functional and mobility metrics.
{"title":"Targeted depletion of TRBV9+ T cells as immunotherapy in a patient with ankylosing spondylitis","authors":"Olga V. Britanova, Kseniia R. Lupyr, Dmitry B. Staroverov, Irina A. Shagina, Alexey A. Aleksandrov, Yakov Y. Ustyugov, Dmitry V. Somov, Alesia Klimenko, Nadejda A. Shostak, Ivan V. Zvyagin, Alexey V. Stepanov, Ekaterina M. Merzlyak, Alexey N. Davydov, Mark Izraelson, Evgeniy S. Egorov, Ekaterina A. Bogdanova, Anna K. Vladimirova, Pavel A. Iakovlev, Denis A. Fedorenko, Roman A. Ivanov, Veronika I. Skvortsova, Sergey Lukyanov, Dmitry M. Chudakov","doi":"10.1038/s41591-023-02613-z","DOIUrl":"10.1038/s41591-023-02613-z","url":null,"abstract":"Autoimmunity is intrinsically driven by memory T and B cell clones inappropriately targeted at self-antigens. Selective depletion or suppression of self-reactive T cells remains a holy grail of autoimmune therapy, but disease-associated T cell receptors (TCRs) and cognate antigenic epitopes remained elusive. A TRBV9-containing CD8+ TCR motif was recently associated with the pathogenesis of ankylosing spondylitis, psoriatic arthritis and acute anterior uveitis, and cognate HLA-B*27-presented epitopes were identified. Following successful testing in nonhuman primate models, here we report human TRBV9+ T cell elimination in ankylosing spondylitis. The patient achieved remission within 3 months and ceased anti-TNF therapy after 5 years of continuous use. Complete remission has now persisted for 4 years, with three doses of anti-TRBV9 administered per year. We also observed a profound improvement in spinal mobility metrics and the Bath Ankylosing Spondylitis Metrology Index (BASMI). This represents a possibly curative therapy of an autoimmune disease via selective depletion of a TRBV-defined group of T cells. The anti-TRBV9 therapy could potentially be applicable to other HLA-B*27-associated spondyloarthropathies. Such targeted elimination of the underlying cause of the disease without systemic immunosuppression could offer a new generation of safe and efficient therapies for autoimmunity. Targeted depletion of TRBV9+ T cells induces remission in a single patient with ankylosing spondylitis, with significant improvements in functional and mobility metrics.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2731-2736"},"PeriodicalIF":82.9,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49691568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-21DOI: 10.1038/s41591-023-02605-z
Sylvan C. Baca, Ji-Heui Seo, Matthew P. Davidsohn, Brad Fortunato, Karl Semaan, Shahabbedin Sotudian, Gitanjali Lakshminarayanan, Miklos Diossy, Xintao Qiu, Talal El Zarif, Hunter Savignano, John Canniff, Ikenna Madueke, Renee Maria Saliby, Ziwei Zhang, Rong Li, Yijia Jiang, Len Taing, Mark Awad, Cindy H. Chau, James A. DeCaprio, William D. Figg, Tim F. Greten, Aaron N. Hata, F. Stephen Hodi, Melissa E. Hughes, Keith L. Ligon, Nancy Lin, Kimmie Ng, Matthew G. Oser, Catherine Meador, Heather A. Parsons, Mark M. Pomerantz, Arun Rajan, Jerome Ritz, Manisha Thakuria, Sara M. Tolaney, Patrick Y. Wen, Henry Long, Jacob E. Berchuck, Zoltan Szallasi, Toni K. Choueiri, Matthew L. Freedman
Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability to identify the transcriptional programs that govern cancer phenotypes and their dynamic changes during the course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling of cancer from 1 ml of patient plasma. Using an immunoprecipitation-based approach targeting histone modifications and DNA methylation, we measured 1,268 epigenomic profiles in plasma from 433 individuals with one of 15 cancers. Our assay provided a robust proxy for transcriptional activity, allowing us to infer the expression levels of diagnostic markers and drug targets, measure the activity of therapeutically targetable transcription factors and detect epigenetic mechanisms of resistance. This proof-of-concept study in advanced cancers shows how plasma epigenomic profiling has the potential to unlock clinically actionable information that is currently accessible only via direct tissue sampling. In a large multi-cancer cohort, a single liquid biopsy assay enables the detection of four epigenomic modifications, allowing the monitoring of expression of potential drug targets and resistance genes.
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