Pub Date : 2026-01-21DOI: 10.1038/s41591-025-04144-1
Yot Teerawattananon, Kinanti Khansa Chavarina, Jeerath Phannajit, Jiratorn Sutawong, Natcha Yongphiphatwong, Natasha Chawla, Siobhan Botwright, Tanainan Chuanchaiyakul, Thunyarat Anothaisintawee, Fatiu Arogundade, Gloria Ashuntantang, Jadej Thammatacharee, Laura Sola, Piyathida Chuengsaman, Somsak Chunharas, Suwit Wibulpolprasert, Sydney C. W. Tang, Talerngsak Kanjanabuch, Valerie Luyckx, Vuddhidej Ophascharoensuk, Wanrudee Isaranuwatchai, Vivekanand Jha, Kearkiat Praditpornsilpa, Kriang Tungsanga, on behalf of The Nature Medicine Commission on Dialysis Policy in Low- and Middle-Income Countries
An abrupt policy change in 2022 — allowing patients to choose between peritoneal dialysis or hemodialysis — created severe unintended consequences for the Thai health system. A multidisciplinary commission found that interacting factors in the system were overlooked and that future dialysis policies must integrate more-diverse evidence and stakeholder views, prioritizing care quality and ethics while balancing equity and sustainability.
{"title":"The path to safe, equitable and sustainable dialysis provision for people with chronic kidney disease","authors":"Yot Teerawattananon, Kinanti Khansa Chavarina, Jeerath Phannajit, Jiratorn Sutawong, Natcha Yongphiphatwong, Natasha Chawla, Siobhan Botwright, Tanainan Chuanchaiyakul, Thunyarat Anothaisintawee, Fatiu Arogundade, Gloria Ashuntantang, Jadej Thammatacharee, Laura Sola, Piyathida Chuengsaman, Somsak Chunharas, Suwit Wibulpolprasert, Sydney C. W. Tang, Talerngsak Kanjanabuch, Valerie Luyckx, Vuddhidej Ophascharoensuk, Wanrudee Isaranuwatchai, Vivekanand Jha, Kearkiat Praditpornsilpa, Kriang Tungsanga, on behalf of The Nature Medicine Commission on Dialysis Policy in Low- and Middle-Income Countries","doi":"10.1038/s41591-025-04144-1","DOIUrl":"10.1038/s41591-025-04144-1","url":null,"abstract":"An abrupt policy change in 2022 — allowing patients to choose between peritoneal dialysis or hemodialysis — created severe unintended consequences for the Thai health system. A multidisciplinary commission found that interacting factors in the system were overlooked and that future dialysis policies must integrate more-diverse evidence and stakeholder views, prioritizing care quality and ethics while balancing equity and sustainability.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 1","pages":"44-46"},"PeriodicalIF":50.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41591-025-04144-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146007901","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 : 2026-01-21DOI: 10.1038/s41591-025-04142-3
Syarifah Liza Munira
Rising demand for dialysis poses a central challenge to universal health coverage systems: not just whether to expand access, but how to sustain equitable, high-quality kidney failure care. In this Comment, I argue that long-term viability depends on system architecture, rather than modality choice alone.
{"title":"Sustaining kidney failure care under universal health coverage","authors":"Syarifah Liza Munira","doi":"10.1038/s41591-025-04142-3","DOIUrl":"10.1038/s41591-025-04142-3","url":null,"abstract":"Rising demand for dialysis poses a central challenge to universal health coverage systems: not just whether to expand access, but how to sustain equitable, high-quality kidney failure care. In this Comment, I argue that long-term viability depends on system architecture, rather than modality choice alone.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 1","pages":"22-24"},"PeriodicalIF":50.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146007889","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 : 2026-01-21DOI: 10.1038/s41591-025-04187-4
The first Nature Portfolio Commission Report outlines paths to sustainable dialysis policies, robust evidence-to-policy translation and south–south collaboration.
第一份《自然组合委员会报告》概述了实现可持续透析政策、强有力的证据到政策的转化和南南合作的途径。
{"title":"Nature Portfolio Commissions: data-driven solutions to global problems","authors":"","doi":"10.1038/s41591-025-04187-4","DOIUrl":"10.1038/s41591-025-04187-4","url":null,"abstract":"The first Nature Portfolio Commission Report outlines paths to sustainable dialysis policies, robust evidence-to-policy translation and south–south collaboration.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 1","pages":"1-1"},"PeriodicalIF":50.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41591-025-04187-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146007908","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}
While large language models (LLMs) achieve near-perfect scores on medical licensing exams, these evaluations inadequately reflect the complexity and diversity of real-world clinical practice. Here we introduce MedHELM, an extensible evaluation framework with three contributions. First, a clinician-validated taxonomy organizing medical AI applications into five categories that mirror real clinical tasks-clinical decision support (diagnostic decisions, treatment planning), clinical note generation (visit documentation, procedure reports), patient communication (education materials, care instructions), medical research (literature analysis, clinical data analysis) and administration (scheduling, workflow coordination). These encompass 22 subcategories and 121 specific tasks reflecting daily medical practice. Second, a comprehensive benchmark suite of 37 evaluations covering all subcategories. Third, systematic comparison of nine frontier LLMs-Claude 3.5 Sonnet, Claude 3.7 Sonnet, DeepSeek R1, Gemini 1.5 Pro, Gemini 2.0 Flash, GPT-4o, GPT-4o mini, Llama 3.3 and o3-mini-using an automated LLM-jury evaluation method. Our LLM-jury uses multiple AI evaluators to assess model outputs against expert-defined criteria. Advanced reasoning models (DeepSeek R1, o3-mini) demonstrated superior performance with win rates of 66%, although Claude 3.5 Sonnet achieved comparable results at 15% lower computational cost. These results not only highlight current model capabilities but also demonstrate how MedHELM could enable evidence-based selection of medical AI systems for healthcare applications.
{"title":"Holistic evaluation of large language models for medical tasks with MedHELM.","authors":"Suhana Bedi,Hejie Cui,Miguel Fuentes,Alyssa Unell,Michael Wornow,Juan M Banda,Nikesh Kotecha,Timothy Keyes,Yifan Mai,Mert Oez,Hao Qiu,Shrey Jain,Leonardo Schettini,Mehr Kashyap,Jason Alan Fries,Akshay Swaminathan,Philip Chung,Fateme Nateghi Haredasht,Ivan Lopez,Asad Aali,Gabriel Tse,Ashwin Nayak,Shivam Vedak,Sneha S Jain,Birju Patel,Oluseyi Fayanju,Shreya Shah,Ethan Goh,Dong-Han Yao,Brian Soetikno,Eduardo Reis,Sergios Gatidis,Vasu Divi,Robson Capasso,Rachna Saralkar,Chia-Chun Chiang,Jenelle Jindal,Tho Pham,Faraz Ghoddusi,Steven Lin,Albert S Chiou,Hyo Jung Hong,Mohana Roy,Michael F Gensheimer,Hinesh Patel,Kevin Schulman,Dev Dash,Danton Char,Lance Downing,Francois Grolleau,Kameron Black,Bethel Mieso,Aydin Zahedivash,Wen-Wai Yim,Harshita Sharma,Tony Lee,Hannah Kirsch,Jennifer Lee,Nerissa Ambers,Carlene Lugtu,Aditya Sharma,Bilal Mawji,Alex Alekseyev,Vicky Zhou,Vikas Kakkar,Jarrod Helzer,Anurang Revri,Yair Bannett,Roxana Daneshjou,Jonathan Chen,Emily Alsentzer,Keith Morse,Nirmal Ravi,Nima Aghaeepour,Vanessa Kennedy,Akshay Chaudhari,Thomas Wang,Sanmi Koyejo,Matthew P Lungren,Eric Horvitz,Percy Liang,Michael A Pfeffer,Nigam H Shah","doi":"10.1038/s41591-025-04151-2","DOIUrl":"https://doi.org/10.1038/s41591-025-04151-2","url":null,"abstract":"While large language models (LLMs) achieve near-perfect scores on medical licensing exams, these evaluations inadequately reflect the complexity and diversity of real-world clinical practice. Here we introduce MedHELM, an extensible evaluation framework with three contributions. First, a clinician-validated taxonomy organizing medical AI applications into five categories that mirror real clinical tasks-clinical decision support (diagnostic decisions, treatment planning), clinical note generation (visit documentation, procedure reports), patient communication (education materials, care instructions), medical research (literature analysis, clinical data analysis) and administration (scheduling, workflow coordination). These encompass 22 subcategories and 121 specific tasks reflecting daily medical practice. Second, a comprehensive benchmark suite of 37 evaluations covering all subcategories. Third, systematic comparison of nine frontier LLMs-Claude 3.5 Sonnet, Claude 3.7 Sonnet, DeepSeek R1, Gemini 1.5 Pro, Gemini 2.0 Flash, GPT-4o, GPT-4o mini, Llama 3.3 and o3-mini-using an automated LLM-jury evaluation method. Our LLM-jury uses multiple AI evaluators to assess model outputs against expert-defined criteria. Advanced reasoning models (DeepSeek R1, o3-mini) demonstrated superior performance with win rates of 66%, although Claude 3.5 Sonnet achieved comparable results at 15% lower computational cost. These results not only highlight current model capabilities but also demonstrate how MedHELM could enable evidence-based selection of medical AI systems for healthcare applications.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"13 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005451","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 : 2026-01-19DOI: 10.1038/s41591-025-04168-7
Kyungdeok Kim, Ben Title, Jonathan Kipnis
A randomized trial provides direct human evidence that the placebo effect can shape humoral immunity, showing that reward-related brain activity correlates with vaccine-induced antibody production and opening new avenues for treating many medical conditions.
{"title":"Placebo effect influences vaccine responses","authors":"Kyungdeok Kim, Ben Title, Jonathan Kipnis","doi":"10.1038/s41591-025-04168-7","DOIUrl":"10.1038/s41591-025-04168-7","url":null,"abstract":"A randomized trial provides direct human evidence that the placebo effect can shape humoral immunity, showing that reward-related brain activity correlates with vaccine-induced antibody production and opening new avenues for treating many medical conditions.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 2","pages":"416-417"},"PeriodicalIF":50.0,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003851","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 : 2026-01-19DOI: 10.1038/s41591-025-04176-7
Xinge Tao, Shuya Zhou, Kai Ding, Sairan Li, Yanzeng Li, Boyou Wu, Qirui Huang, Wangyue Chen, Muzi Shen, En Meng, Xiaowang Chen, Hong Hu, Jinchao Zhang, Jie Zhou, Lei Zou, Libing Ma, Shasha Han
Patient-facing large language models (LLMs) hold potential to streamline inefficient transitions from primary to specialist care. We developed the preassessment (PreA), an LLM chatbot co-designed with local stakeholders, to perform the general medical consultations for history-taking, preliminary diagnoses, and test ordering that would normally be performed by primary care providers and to generate referral reports for specialists. PreA was tested in a randomized controlled trial involving 111 specialists from 24 medical disciplines across two health centers, where 2,069 patients (1,141 women; 928 men) were randomly assigned to use PreA independently (PreA-only), use it with staff support (PreA-human), or not use it (No-PreA) before specialist consultation. The trial met its primary end points with the PreA-only group showing significantly reduced physician consultation duration (28.7% reduction; 3.14 ± 2.25 min) compared to the No-PreA group (4.41 ± 2.77 min; P < 0.001), alongside significant improvements in physician-perceived care coordination (mean scores 113.1% increase; 3.69 ± 0.90 versus 1.73 ± 0.95; P < 0.001) and patient-reported communication ease (mean scores 16.0% increase; 3.99 ± 0.62 versus 3.44 ± 0.97; P < 0.001). Equivalent outcomes between the PreA-only and PreA-human groups confirmed the autonomous operation capability. Co-designed PreA outperformed the same model with additional fine-tuning on local dialogues across clinical decision-making domains. Co-design with local stakeholders, compared to passive local data collecting, represents a more effective strategy for deploying LLMs to strengthen health systems and enhance patient-centered care in resource-limited settings. Chinese Clinical Trial Registry identifier: ChiCTR2400094159 .
{"title":"An LLM chatbot to facilitate primary-to-specialist care transitions: a randomized controlled trial.","authors":"Xinge Tao, Shuya Zhou, Kai Ding, Sairan Li, Yanzeng Li, Boyou Wu, Qirui Huang, Wangyue Chen, Muzi Shen, En Meng, Xiaowang Chen, Hong Hu, Jinchao Zhang, Jie Zhou, Lei Zou, Libing Ma, Shasha Han","doi":"10.1038/s41591-025-04176-7","DOIUrl":"10.1038/s41591-025-04176-7","url":null,"abstract":"<p><p>Patient-facing large language models (LLMs) hold potential to streamline inefficient transitions from primary to specialist care. We developed the preassessment (PreA), an LLM chatbot co-designed with local stakeholders, to perform the general medical consultations for history-taking, preliminary diagnoses, and test ordering that would normally be performed by primary care providers and to generate referral reports for specialists. PreA was tested in a randomized controlled trial involving 111 specialists from 24 medical disciplines across two health centers, where 2,069 patients (1,141 women; 928 men) were randomly assigned to use PreA independently (PreA-only), use it with staff support (PreA-human), or not use it (No-PreA) before specialist consultation. The trial met its primary end points with the PreA-only group showing significantly reduced physician consultation duration (28.7% reduction; 3.14 ± 2.25 min) compared to the No-PreA group (4.41 ± 2.77 min; P < 0.001), alongside significant improvements in physician-perceived care coordination (mean scores 113.1% increase; 3.69 ± 0.90 versus 1.73 ± 0.95; P < 0.001) and patient-reported communication ease (mean scores 16.0% increase; 3.99 ± 0.62 versus 3.44 ± 0.97; P < 0.001). Equivalent outcomes between the PreA-only and PreA-human groups confirmed the autonomous operation capability. Co-designed PreA outperformed the same model with additional fine-tuning on local dialogues across clinical decision-making domains. Co-design with local stakeholders, compared to passive local data collecting, represents a more effective strategy for deploying LLMs to strengthen health systems and enhance patient-centered care in resource-limited settings. Chinese Clinical Trial Registry identifier: ChiCTR2400094159 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003891","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 : 2026-01-19DOI: 10.1038/s41591-025-04140-5
Nitzan Lubianiker, Tamar Koren, Meshi Djerasi, Margarita Sirotkin, Neomi Singer, Itamar Jalon, Avigail Lerner, Roi Sar-el, Haggai Sharon, Moni Shahar, Hilla Azulay-Debby, Asya Rolls, Talma Hendler
Growing evidence points to a close neurophysiological link between brain and body. Recent rodent studies have shown that the dopaminergic mesolimbic pathway, which underlies expectations of positive outcomes, also modulates immune function. However, it remains unknown whether a similar brain-immune link exists in humans and whether it involves conscious positive expectations. In a preregistered, double-blind randomized controlled trial, we used fMRI neurofeedback (NF) to train healthy participants to increase reward mesolimbic activity through self-chosen mental strategies, followed by an immune challenge with the hepatitis B virus (HBV) vaccine and assessments of HBV antibody (HBVab) levels. Eighty-five participants were randomized to (1) reward mesolimbic upregulation (n = 34), (2) non-mesolimbic control upregulation (n = 34) or (3) no-NF control (n = 17). Prespecified primary outcomes were (1) differences in reward mesolimbic activation between NF groups, (2) correlation between reward mesolimbic upregulation and post-vaccination HBVab changes across both NF groups and (3) group differences in post-vaccination HBVab changes. Both NF groups showed significant increases in reward mesolimbic activation. Notably, greater ventral tegmental area (VTA) upregulation—but not nucleus accumbens or control region activation—was associated with larger post-vaccination increases in HBVab levels (r = 0.31, P = 0.018). Sustained VTA upregulation was further linked to mental strategies involving positive expectations. Post-vaccination antibody levels did not differ between groups, and no adverse effects occurred. Together, these findings suggest that consciously generated positive expectations can engage reward circuitry to influence immune function, a process that may be leveraged for non-invasive immune modulation. ClinicalTrials.gov identifier: NCT03951870 . Upregulation of the ventral tegmental area via neurofeedback is associated with a stronger immune response to hepatitis B virus vaccination, and VTA upregulation is achieved through conscious positive expectations.
{"title":"Upregulation of reward mesolimbic activity and immune response to vaccination: a randomized controlled trial","authors":"Nitzan Lubianiker, Tamar Koren, Meshi Djerasi, Margarita Sirotkin, Neomi Singer, Itamar Jalon, Avigail Lerner, Roi Sar-el, Haggai Sharon, Moni Shahar, Hilla Azulay-Debby, Asya Rolls, Talma Hendler","doi":"10.1038/s41591-025-04140-5","DOIUrl":"10.1038/s41591-025-04140-5","url":null,"abstract":"Growing evidence points to a close neurophysiological link between brain and body. Recent rodent studies have shown that the dopaminergic mesolimbic pathway, which underlies expectations of positive outcomes, also modulates immune function. However, it remains unknown whether a similar brain-immune link exists in humans and whether it involves conscious positive expectations. In a preregistered, double-blind randomized controlled trial, we used fMRI neurofeedback (NF) to train healthy participants to increase reward mesolimbic activity through self-chosen mental strategies, followed by an immune challenge with the hepatitis B virus (HBV) vaccine and assessments of HBV antibody (HBVab) levels. Eighty-five participants were randomized to (1) reward mesolimbic upregulation (n = 34), (2) non-mesolimbic control upregulation (n = 34) or (3) no-NF control (n = 17). Prespecified primary outcomes were (1) differences in reward mesolimbic activation between NF groups, (2) correlation between reward mesolimbic upregulation and post-vaccination HBVab changes across both NF groups and (3) group differences in post-vaccination HBVab changes. Both NF groups showed significant increases in reward mesolimbic activation. Notably, greater ventral tegmental area (VTA) upregulation—but not nucleus accumbens or control region activation—was associated with larger post-vaccination increases in HBVab levels (r = 0.31, P = 0.018). Sustained VTA upregulation was further linked to mental strategies involving positive expectations. Post-vaccination antibody levels did not differ between groups, and no adverse effects occurred. Together, these findings suggest that consciously generated positive expectations can engage reward circuitry to influence immune function, a process that may be leveraged for non-invasive immune modulation. ClinicalTrials.gov identifier: NCT03951870 . Upregulation of the ventral tegmental area via neurofeedback is associated with a stronger immune response to hepatitis B virus vaccination, and VTA upregulation is achieved through conscious positive expectations.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 2","pages":"572-581"},"PeriodicalIF":50.0,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003898","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 : 2026-01-16DOI: 10.1038/s41591-025-04182-9
Anna Morena D'Alise,Jason Willis,Fahriye Duzagac,Michael J Hall,Marcia Cruz-Correa,Gregory E Idos,Selvi Thirumurthi,Veroushka Ballester,Guido Leoni,Irene Garzia,Laura Antonucci,Lorenzo De Marco,Elisa Micarelli,Nan Deng,Laura Seclì,Sven Gogov,Wenli Dong,J Jack Lee,Charles M Bowen,Lana A Vornik,Araceli Garcia-Gonzalez,Laura Reyes-Uribe,Ellen Richmond,Asad Umar,Powel H Brown,Krishna M Sinha,Luz Maria Rodriguez,Elisa Scarselli,Eduardo Vilar
Cancer interception is a preventative approach aiming to reduce cancer incidence by targeting precancers and early-stage cancers. Lynch syndrome (LS) is a prevalent hereditary cancer syndrome affecting ~1 in 300 individuals, with an overall lifetime cancer risk as high as 80%. LS is caused by germline mutations in the DNA mismatch repair genes, leading to microsatellite instability (MSI) and accumulation of shared mutations. When these occur in coding regions, they generate frameshift peptides (FSPs). Nous-209 is a neoantigen-directed immunotherapy based on a heterologous prime boost using great ape adenovirus and modified vaccinia virus Ankara encoding 209 FSPs shared across MSI neoplasms. We present the results from cohort 1 of a phase 1b/2 single-arm trial of Nous-209 for cancer interception in LS carriers (n = 45). Safety and immunogenicity were coprimary endpoints. Safety was assessed in 45 participants. Vaccination was safe with no intervention-related serious adverse events (AEs). The most common AEs were injection-site reactions (any grade in 91% of participants after prime and 76% after boost with no grade 3) and fatigue (any grade in 80% after prime and 53% after boost with 4% grade 3 after prime or after boost). Neoantigen-specific immune responses were observed after vaccination in 100% of evaluable participants (n = 37), with induction of potent T cell immunity (mean response at peak of ~1,100 interferon-γ spot-forming cells per million peripheral blood mononuclear cells). The immune response was durable and detectable at 1 year in 85% of participants. Both CD8+ and CD4+ T cells were induced, recognizing multiple FSPs. Peptide-human leukocyte antigen predictions allowed the identification of >100 immunogenic FSPs with demonstration of cytotoxic activity in vitro. Immunogenic FSPs were found in independent datasets of LS MSI colorectal precancers and cancers. These results highlight Nous-209 ability to efficiently stimulate immunity against neoantigens in LS, supporting its development for cancer interception (ClinicalTrials.gov identifier: NCT05078866 ).
{"title":"Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial.","authors":"Anna Morena D'Alise,Jason Willis,Fahriye Duzagac,Michael J Hall,Marcia Cruz-Correa,Gregory E Idos,Selvi Thirumurthi,Veroushka Ballester,Guido Leoni,Irene Garzia,Laura Antonucci,Lorenzo De Marco,Elisa Micarelli,Nan Deng,Laura Seclì,Sven Gogov,Wenli Dong,J Jack Lee,Charles M Bowen,Lana A Vornik,Araceli Garcia-Gonzalez,Laura Reyes-Uribe,Ellen Richmond,Asad Umar,Powel H Brown,Krishna M Sinha,Luz Maria Rodriguez,Elisa Scarselli,Eduardo Vilar","doi":"10.1038/s41591-025-04182-9","DOIUrl":"https://doi.org/10.1038/s41591-025-04182-9","url":null,"abstract":"Cancer interception is a preventative approach aiming to reduce cancer incidence by targeting precancers and early-stage cancers. Lynch syndrome (LS) is a prevalent hereditary cancer syndrome affecting ~1 in 300 individuals, with an overall lifetime cancer risk as high as 80%. LS is caused by germline mutations in the DNA mismatch repair genes, leading to microsatellite instability (MSI) and accumulation of shared mutations. When these occur in coding regions, they generate frameshift peptides (FSPs). Nous-209 is a neoantigen-directed immunotherapy based on a heterologous prime boost using great ape adenovirus and modified vaccinia virus Ankara encoding 209 FSPs shared across MSI neoplasms. We present the results from cohort 1 of a phase 1b/2 single-arm trial of Nous-209 for cancer interception in LS carriers (n = 45). Safety and immunogenicity were coprimary endpoints. Safety was assessed in 45 participants. Vaccination was safe with no intervention-related serious adverse events (AEs). The most common AEs were injection-site reactions (any grade in 91% of participants after prime and 76% after boost with no grade 3) and fatigue (any grade in 80% after prime and 53% after boost with 4% grade 3 after prime or after boost). Neoantigen-specific immune responses were observed after vaccination in 100% of evaluable participants (n = 37), with induction of potent T cell immunity (mean response at peak of ~1,100 interferon-γ spot-forming cells per million peripheral blood mononuclear cells). The immune response was durable and detectable at 1 year in 85% of participants. Both CD8+ and CD4+ T cells were induced, recognizing multiple FSPs. Peptide-human leukocyte antigen predictions allowed the identification of >100 immunogenic FSPs with demonstration of cytotoxic activity in vitro. Immunogenic FSPs were found in independent datasets of LS MSI colorectal precancers and cancers. These results highlight Nous-209 ability to efficiently stimulate immunity against neoantigens in LS, supporting its development for cancer interception (ClinicalTrials.gov identifier: NCT05078866 ).","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"479 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986430","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 : 2026-01-16DOI: 10.1038/s41591-025-04137-0
Jiseung Kang, Hyeon Jin Kim, Min Seo Kim, GBD 2023 Substance Use Collaborators, Jae Il Shin, Dong Keon Yon
Drug use disorders (DUDs) are emerging global public health challenges. Here we investigated the global and regional estimates of the prevalence and burden of DUDs, including amphetamine, cannabis, cocaine and opioid use disorders, from 1990 to 2023 for 204 countries and territories by using the Global Burden of Disease Study 2023. Overall, trends in global age-standardized disability-adjusted life-years of DUDs increased from 169.3 (95% uncertainty interval (95% UI), 134.4–203.9) per 100,000 people in 1990 to 212.0 (95% UI, 179.2–245.6) in 2023. In 2023, both prevalence and burden of DUDs were higher in high-income countries, particularly in the USA. The most prevalent DUDs in 2023 were cannabis use disorder (age-standardized prevalence, 270.8 (95% UI, 201.7–350.0) per 100,000 people) and opioid use disorder (205.9 (95% UI, 178.7–235.0)). Particularly, opioid use disorder showed a nearly twofold increase in prevalence and burden between 1990 and 2023. In 2023, compared with countries where cannabis use was illegal, countries permitting both recreational and medical cannabis use had higher prevalence rates for all types of DUDs. Proactive and effective policies are essential to mitigate the increasing global burden of DUDs. Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.
{"title":"Global burden of amphetamine, cannabis, cocaine and opioid use in 204 countries, 1990–2023: a Global Burden of Disease Study","authors":"Jiseung Kang, Hyeon Jin Kim, Min Seo Kim, GBD 2023 Substance Use Collaborators, Jae Il Shin, Dong Keon Yon","doi":"10.1038/s41591-025-04137-0","DOIUrl":"10.1038/s41591-025-04137-0","url":null,"abstract":"Drug use disorders (DUDs) are emerging global public health challenges. Here we investigated the global and regional estimates of the prevalence and burden of DUDs, including amphetamine, cannabis, cocaine and opioid use disorders, from 1990 to 2023 for 204 countries and territories by using the Global Burden of Disease Study 2023. Overall, trends in global age-standardized disability-adjusted life-years of DUDs increased from 169.3 (95% uncertainty interval (95% UI), 134.4–203.9) per 100,000 people in 1990 to 212.0 (95% UI, 179.2–245.6) in 2023. In 2023, both prevalence and burden of DUDs were higher in high-income countries, particularly in the USA. The most prevalent DUDs in 2023 were cannabis use disorder (age-standardized prevalence, 270.8 (95% UI, 201.7–350.0) per 100,000 people) and opioid use disorder (205.9 (95% UI, 178.7–235.0)). Particularly, opioid use disorder showed a nearly twofold increase in prevalence and burden between 1990 and 2023. In 2023, compared with countries where cannabis use was illegal, countries permitting both recreational and medical cannabis use had higher prevalence rates for all types of DUDs. Proactive and effective policies are essential to mitigate the increasing global burden of DUDs. Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 2","pages":"527-544"},"PeriodicalIF":50.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986429","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 : 2026-01-16DOI: 10.1038/s41591-026-04211-1
Michael Lattke,Wee Leng Tan,Salil Kalarikkal Sukumaran,Kagistia Hana Utami,Marcos Sintes,Srinivasan Sakthivel,Jonathan Tan,Auriel Lim,Bansal Aysha Vibhavari,Katerina Rekopoulou,Nik Matthews,Ivan Alic,Željka Krsnik,Dean Nizetic,Boaz P Levi,Vincenzo De Paola
Down syndrome (DS), caused by trisomy of chromosome 21, is the leading genetic cause of intellectual disability, yet the mechanisms disrupting fetal brain development remain unclear. We performed single-cell transcriptomic and chromatin accessibility profiling of approximately 250,000 cells from 15 DS and 15 control human fetal cortices (10-20 weeks post-conception). Our analysis revealed a subtype-specific reduction in RORB/FOXP1-expressing excitatory neurons and widespread disruption of neurodevelopmental transcriptional programs. Chromosome 21 transcription factors (TFs) BACH1, PKNOX1, and GABPA emerged as dosage-sensitive hubs regulating genes linked to intellectual disability. Antisense oligonucleotide-mediated normalization of these TFs in human neural progenitors in vitro partially rescued target gene expression. Benchmarking a humanized in vivo model captured additional molecular and cellular signatures of DS, complementing the in vitro model. Together, we present a resource defining the gene-regulatory landscape underlying cortical development in DS and highlight molecular pathways for further investigation.
{"title":"Single-cell atlas of the developing Down syndrome brain cortex.","authors":"Michael Lattke,Wee Leng Tan,Salil Kalarikkal Sukumaran,Kagistia Hana Utami,Marcos Sintes,Srinivasan Sakthivel,Jonathan Tan,Auriel Lim,Bansal Aysha Vibhavari,Katerina Rekopoulou,Nik Matthews,Ivan Alic,Željka Krsnik,Dean Nizetic,Boaz P Levi,Vincenzo De Paola","doi":"10.1038/s41591-026-04211-1","DOIUrl":"https://doi.org/10.1038/s41591-026-04211-1","url":null,"abstract":"Down syndrome (DS), caused by trisomy of chromosome 21, is the leading genetic cause of intellectual disability, yet the mechanisms disrupting fetal brain development remain unclear. We performed single-cell transcriptomic and chromatin accessibility profiling of approximately 250,000 cells from 15 DS and 15 control human fetal cortices (10-20 weeks post-conception). Our analysis revealed a subtype-specific reduction in RORB/FOXP1-expressing excitatory neurons and widespread disruption of neurodevelopmental transcriptional programs. Chromosome 21 transcription factors (TFs) BACH1, PKNOX1, and GABPA emerged as dosage-sensitive hubs regulating genes linked to intellectual disability. Antisense oligonucleotide-mediated normalization of these TFs in human neural progenitors in vitro partially rescued target gene expression. Benchmarking a humanized in vivo model captured additional molecular and cellular signatures of DS, complementing the in vitro model. Together, we present a resource defining the gene-regulatory landscape underlying cortical development in DS and highlight molecular pathways for further investigation.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"269 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986434","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}
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