With over 5 million attributed deaths per year, physical inactivity is a major global public health issue. Although the importance of physical activity is well recognized within the scope of obesity and cardiometabolic disease prevention and control, its broader benefits for the health of individuals and societies are yet to be fully harnessed. Furthermore, the role of active leisure, active transport and active labor-primary domains of physical activity-in supporting or hindering social and health equity has been largely overlooked. Here we (1) used a health equity lens to describe global domain-specific physical activity inequalities through an analysis of World Health Organization STEPwise approach to NCD risk factor surveillance (WHO STEPS) data from 68 countries; (2) summarized evidence linking physical activity with health outcomes beyond cardiometabolic disease, including immunity and infectious disease, depression and cancer; and (3) developed a new model reconceptualizing physical activity to better respond to 21st-century public health challenges. Our global, intersectional analysis of gender and socioeconomic physical activity inequalities revealed a 40-percentage-point gap in active leisure-the only domain consistently driven by choice-between historically privileged groups (wealthy men in high-income countries) and historically disadvantaged ones (poor women in low-income countries). Robust evidence supports the benefits of physical activity for immunity and infectious disease, depression and cancer. Our reconceptualized model recognizes the influence of social identities, norms, policies and structures on physical activity for health and wellbeing and emphasizes the urgent need to develop and roll out policies and programs that disseminate and harness the full benefits of physical activity for human, societal and planetary health.
{"title":"Physical activity for public health in the 21st century.","authors":"Deborah Salvo,Inacio Crochemore-Silva,Andrea Wendt,Jakob Tarp,Eric J Shiroma,Richard J Simpson,I-Min Lee,Ulf Ekelund,Ester Cerin,Youssouf Keita,Adrian Bauman,Pedro C Hallal,Andrea Ramirez Varela,Michael Pratt,Rodrigo Reis,Erica Hinckson,Ding Ding,Harold W Kohl,James Sallis","doi":"10.1038/s41591-026-04237-5","DOIUrl":"https://doi.org/10.1038/s41591-026-04237-5","url":null,"abstract":"With over 5 million attributed deaths per year, physical inactivity is a major global public health issue. Although the importance of physical activity is well recognized within the scope of obesity and cardiometabolic disease prevention and control, its broader benefits for the health of individuals and societies are yet to be fully harnessed. Furthermore, the role of active leisure, active transport and active labor-primary domains of physical activity-in supporting or hindering social and health equity has been largely overlooked. Here we (1) used a health equity lens to describe global domain-specific physical activity inequalities through an analysis of World Health Organization STEPwise approach to NCD risk factor surveillance (WHO STEPS) data from 68 countries; (2) summarized evidence linking physical activity with health outcomes beyond cardiometabolic disease, including immunity and infectious disease, depression and cancer; and (3) developed a new model reconceptualizing physical activity to better respond to 21st-century public health challenges. Our global, intersectional analysis of gender and socioeconomic physical activity inequalities revealed a 40-percentage-point gap in active leisure-the only domain consistently driven by choice-between historically privileged groups (wealthy men in high-income countries) and historically disadvantaged ones (poor women in low-income countries). Robust evidence supports the benefits of physical activity for immunity and infectious disease, depression and cancer. Our reconceptualized model recognizes the influence of social identities, norms, policies and structures on physical activity for health and wellbeing and emphasizes the urgent need to develop and roll out policies and programs that disseminate and harness the full benefits of physical activity for human, societal and planetary health.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"7 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381170","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 : 2026-03-05DOI: 10.1038/s41591-026-04273-1
Catherine J. Mummery, Arthur J. Mayorga, Adam Simmons, Tiffany W. Chow, Brady Burgess, Tuan Nguyen, Jingjing Gao, Balasubrahmanyam Budda, Lovingly Quitania Park, Ruchi Gupta, Caiyan Li, Li Shi, Sara Kenkare-Mitra, Arnon Rosenthal, Robert Paul, Michael Ward, Derk D. Purcell, Stephen Salloway, Michael Grundman, Gary Romano, Giacomo Salvadore
Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial function and is implicated in Alzheimer’s disease (AD) pathogenesis. Here we conducted a phase 2, randomized, double-blind, placebo-controlled trial of a humanized TREM2 agonistic monoclonal antibody in 381 participants with early AD. Participants were randomized (1:1:1:1) to receive AL002 (15 mg kg−1, 40 mg kg−1 or 60 mg kg−1) or placebo intravenously every 4 weeks for 48−96 weeks. AL002 demonstrated sustained target engagement and pharmacodynamic responses in the central nervous system, as demonstrated by reductions in soluble TREM2 and increases in osteopontin in cerebrospinal fluid, respectively. The study did not meet the primary endpoint of change from baseline in the Clinical Dementia Rating-Sum of Boxes score (versus placebo) (least squares mean difference versus placebo (95% confidence interval) at week 96: 15 mg kg−1 −0.31 (−1.61 to 0.98), 40 mg kg−1 0.13 (−1.18 to 1.43) and 60 mg kg−1 −0.17 (−1.49 to 1.15); P > 0.05 from mixed-effects model for repeated measures). The most frequent treatment-emergent adverse events were magnetic resonance imaging changes resembling amyloid-related imaging abnormalities (ARIA). This first trial of a TREM2 agonistic antibody in early AD was negative but provides findings relevant to the study of TREM2 therapeutics and ARIA. ClinicalTrials.gov: NCT04592874.
髓样细胞上表达的触发受体2 （TREM2）调节小胶质细胞功能并参与阿尔茨海默病（AD）的发病机制。在这里，我们进行了一项2期、随机、双盲、安慰剂对照试验，在381名早期AD患者中使用人源化TREM2激动性单克隆抗体。参与者随机（1:1:1:1）接受AL002 （15 mg kg - 1、40 mg kg - 1或60 mg kg - 1）或安慰剂，每4周静脉注射一次，持续48 - 96周。AL002在中枢神经系统中表现出持续的靶标作用和药效学反应，分别表现为脑脊液中可溶性TREM2的减少和骨桥蛋白的增加。该研究未达到临床痴呆评分-盒和评分（与安慰剂相比）基线变化的主要终点(96周时与安慰剂的最小二乘平均差异（95%置信区间）：15 mg kg - 1 - 0.31(- 1.61至0.98),40 mg kg - 1 - 0.13（- 1.18至1.43）和60 mg kg - 1 - 0.17(- 1.49至1.15)；重复测量的混合效应模型P < 0.05)。最常见的治疗不良事件是类似淀粉样蛋白相关成像异常（ARIA）的磁共振成像改变。TREM2激动抗体在早期AD中的首次试验结果为阴性，但提供了与TREM2治疗和ARIA研究相关的发现。ClinicalTrials.gov: NCT04592874。
{"title":"The TREM2 agonistic antibody AL002 in early Alzheimer’s disease: a phase 2 randomized trial","authors":"Catherine J. Mummery, Arthur J. Mayorga, Adam Simmons, Tiffany W. Chow, Brady Burgess, Tuan Nguyen, Jingjing Gao, Balasubrahmanyam Budda, Lovingly Quitania Park, Ruchi Gupta, Caiyan Li, Li Shi, Sara Kenkare-Mitra, Arnon Rosenthal, Robert Paul, Michael Ward, Derk D. Purcell, Stephen Salloway, Michael Grundman, Gary Romano, Giacomo Salvadore","doi":"10.1038/s41591-026-04273-1","DOIUrl":"https://doi.org/10.1038/s41591-026-04273-1","url":null,"abstract":"Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial function and is implicated in Alzheimer’s disease (AD) pathogenesis. Here we conducted a phase 2, randomized, double-blind, placebo-controlled trial of a humanized TREM2 agonistic monoclonal antibody in 381 participants with early AD. Participants were randomized (1:1:1:1) to receive AL002 (15 mg kg−1, 40 mg kg−1 or 60 mg kg−1) or placebo intravenously every 4 weeks for 48−96 weeks. AL002 demonstrated sustained target engagement and pharmacodynamic responses in the central nervous system, as demonstrated by reductions in soluble TREM2 and increases in osteopontin in cerebrospinal fluid, respectively. The study did not meet the primary endpoint of change from baseline in the Clinical Dementia Rating-Sum of Boxes score (versus placebo) (least squares mean difference versus placebo (95% confidence interval) at week 96: 15 mg kg−1 −0.31 (−1.61 to 0.98), 40 mg kg−1 0.13 (−1.18 to 1.43) and 60 mg kg−1 −0.17 (−1.49 to 1.15); P > 0.05 from mixed-effects model for repeated measures). The most frequent treatment-emergent adverse events were magnetic resonance imaging changes resembling amyloid-related imaging abnormalities (ARIA). This first trial of a TREM2 agonistic antibody in early AD was negative but provides findings relevant to the study of TREM2 therapeutics and ARIA. ClinicalTrials.gov: NCT04592874.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"135 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350667","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 : 2026-03-04DOI: 10.1038/s41591-026-04276-y
Hamad Ali,Barrak Alahmad,Abdullah Alibrahim,Dana Marafi,Hind Alsharhan,Salman Al Sabah,Almundher Al-Maawali,Khalid A Fakhro,Hilal A Lashuel,Fowzan S Alkuraya,Omer S Alkhnbashi,Alawi Alsheikh-Ali,Fahd Al-Mulla,Ahmad Abou Tayoun
{"title":"A genomics health strategy for the Arabian Gulf.","authors":"Hamad Ali,Barrak Alahmad,Abdullah Alibrahim,Dana Marafi,Hind Alsharhan,Salman Al Sabah,Almundher Al-Maawali,Khalid A Fakhro,Hilal A Lashuel,Fowzan S Alkuraya,Omer S Alkhnbashi,Alawi Alsheikh-Ali,Fahd Al-Mulla,Ahmad Abou Tayoun","doi":"10.1038/s41591-026-04276-y","DOIUrl":"https://doi.org/10.1038/s41591-026-04276-y","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"54 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350798","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}
{"title":"Advancing a new generation of heat-health warning system in China.","authors":"Tiantian Li,Runmei Ma,Qing Wang,Taiyuan Zhang,Hui Chen,Lin Wang,Xiaoming Shi,Hongbing Shen","doi":"10.1038/s41591-026-04240-w","DOIUrl":"https://doi.org/10.1038/s41591-026-04240-w","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"1 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350802","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 : 2026-03-04DOI: 10.1038/s41591-026-04255-3
Esper G. Kallás, José A. Moreira, Elizabeth G. Patiño, Patricia Emilia Braga, Juliana C. V. Tenório, Lucas Bassolli de Oliveira Alves, Vanessa Infante, Daniela Haydee Ramos Silveira, João Luiz Miraglia, Monica A. T. Cintra, Dhelio Batista Pereira, Allex Jardim da Fonseca, Ricardo Queiroz Gurgel, Ivo Castelo-Branco Coelho, Cor Jesus Fernandes Fontes, Ernesto T. A. Marques, Gustavo Adolfo Sierra Romero, Mauro Martins Teixeira, André M. Siqueira, Viviane Sampaio Boaventura, Fabiano Ramos, Erivaldo Elias Júnior, José Cassio de Moraes, Cássia Fernanda Estofolete, Angela Carvalho Freitas, Cecilia Luiza Simoes dos Santos, Maria do Carmo S. T. Timenetsky, Stephen S. Whitehead, Anna P. Durbin, Alejandra Esteves-Jaramillo, Tulin Shekar, Jung-Jin Lee, Qiuxu Chen, Julieta Macey, Sanskruti Vaidya, Beth-Ann G. Coller, Fernanda Castro Boulos, Mauricio L. Nogueira, Marcus Vínicius Guimarães de Lacerda
In individuals with prior dengue virus (DENV) exposure, subsequent heterotypic infection can increase the risk of severe disease. A single-dose dengue vaccine that protects against the four DENV serotypes across a wide age range and regardless of DENV serostatus is needed. Here we report the long-term safety and efficacy of Butantan dengue vaccine (Butantan-DV), a live, attenuated, tetravalent dengue vaccine, among participants ages 2–59 who were randomized 2:1 in a double-blind, placebo-controlled, phase 3 trial in Brazil. A primary objective was to evaluate vaccine efficacy (VE) against reverse transcription–PCR-positive symptomatic dengue 28 days after vaccination because of any DENV serotype, regardless of serostatus. Prespecified secondary endpoints included VE by serotype, by serostatus and against severe dengue or dengue with warning signs (combined). The primary and secondary objectives were met if the lower bound of the two-sided 95% confidence interval (CI) for VE was above 25%. Between 2016 and 2019, 16,235 participants received Butantan-DV (n = 10,259) or placebo (n = 5,976). The trial met the primary and secondary objectives. During the 5 years of follow-up, between 2016 and 2024, overall VE (95% CI) was 65.0% (57.8–71.0%). Secondary VE endpoints (95% CI) were 77.1% (67.6–83.9%) in dengue-experienced participants, 58.9% (48.0–67.6%) in dengue-naive participants, 73.0% (64.3–79.7%) against DENV-1 and 55.7% (42.3–66.1%) against DENV-2. Cases of DENV-3 or DENV-4 were not observed. VE (95% CI) against dengue with warning signs or severe dengue (secondary endpoint) was 80.5% (50.8–92.4%). The most commonly reported solicited systemic adverse event (AE) was headache (36.7% of vaccine recipients and 31.1% of placebo recipients), most of which were grade 1. The proportions of participants with unsolicited vaccine-related AEs (including serious AEs) were comparable between intervention groups. A single dose of Butantan-DV was efficacious against symptomatic virologically confirmed dengue because of DENV-1 or DENV-2, regardless of dengue serostatus at baseline, with no safety concerns observed during the 5-year follow-up (ClinicalTrials.gov: NCT02406729).
{"title":"Long-term efficacy and safety of the single-dose tetravalent Butantan dengue vaccine","authors":"Esper G. Kallás, José A. Moreira, Elizabeth G. Patiño, Patricia Emilia Braga, Juliana C. V. Tenório, Lucas Bassolli de Oliveira Alves, Vanessa Infante, Daniela Haydee Ramos Silveira, João Luiz Miraglia, Monica A. T. Cintra, Dhelio Batista Pereira, Allex Jardim da Fonseca, Ricardo Queiroz Gurgel, Ivo Castelo-Branco Coelho, Cor Jesus Fernandes Fontes, Ernesto T. A. Marques, Gustavo Adolfo Sierra Romero, Mauro Martins Teixeira, André M. Siqueira, Viviane Sampaio Boaventura, Fabiano Ramos, Erivaldo Elias Júnior, José Cassio de Moraes, Cássia Fernanda Estofolete, Angela Carvalho Freitas, Cecilia Luiza Simoes dos Santos, Maria do Carmo S. T. Timenetsky, Stephen S. Whitehead, Anna P. Durbin, Alejandra Esteves-Jaramillo, Tulin Shekar, Jung-Jin Lee, Qiuxu Chen, Julieta Macey, Sanskruti Vaidya, Beth-Ann G. Coller, Fernanda Castro Boulos, Mauricio L. Nogueira, Marcus Vínicius Guimarães de Lacerda","doi":"10.1038/s41591-026-04255-3","DOIUrl":"https://doi.org/10.1038/s41591-026-04255-3","url":null,"abstract":"In individuals with prior dengue virus (DENV) exposure, subsequent heterotypic infection can increase the risk of severe disease. A single-dose dengue vaccine that protects against the four DENV serotypes across a wide age range and regardless of DENV serostatus is needed. Here we report the long-term safety and efficacy of Butantan dengue vaccine (Butantan-DV), a live, attenuated, tetravalent dengue vaccine, among participants ages 2–59 who were randomized 2:1 in a double-blind, placebo-controlled, phase 3 trial in Brazil. A primary objective was to evaluate vaccine efficacy (VE) against reverse transcription–PCR-positive symptomatic dengue 28 days after vaccination because of any DENV serotype, regardless of serostatus. Prespecified secondary endpoints included VE by serotype, by serostatus and against severe dengue or dengue with warning signs (combined). The primary and secondary objectives were met if the lower bound of the two-sided 95% confidence interval (CI) for VE was above 25%. Between 2016 and 2019, 16,235 participants received Butantan-DV (n = 10,259) or placebo (n = 5,976). The trial met the primary and secondary objectives. During the 5 years of follow-up, between 2016 and 2024, overall VE (95% CI) was 65.0% (57.8–71.0%). Secondary VE endpoints (95% CI) were 77.1% (67.6–83.9%) in dengue-experienced participants, 58.9% (48.0–67.6%) in dengue-naive participants, 73.0% (64.3–79.7%) against DENV-1 and 55.7% (42.3–66.1%) against DENV-2. Cases of DENV-3 or DENV-4 were not observed. VE (95% CI) against dengue with warning signs or severe dengue (secondary endpoint) was 80.5% (50.8–92.4%). The most commonly reported solicited systemic adverse event (AE) was headache (36.7% of vaccine recipients and 31.1% of placebo recipients), most of which were grade 1. The proportions of participants with unsolicited vaccine-related AEs (including serious AEs) were comparable between intervention groups. A single dose of Butantan-DV was efficacious against symptomatic virologically confirmed dengue because of DENV-1 or DENV-2, regardless of dengue serostatus at baseline, with no safety concerns observed during the 5-year follow-up (ClinicalTrials.gov: NCT02406729).","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"48 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346789","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 : 2026-03-03DOI: 10.1038/s41591-026-04220-0
Robert S Rosenson,Sascha N Goonewardena
{"title":"Base editing milestone for familial hypercholesterolemia.","authors":"Robert S Rosenson,Sascha N Goonewardena","doi":"10.1038/s41591-026-04220-0","DOIUrl":"https://doi.org/10.1038/s41591-026-04220-0","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"198 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346524","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 : 2026-03-03DOI: 10.1038/s41591-026-04268-y
Dylan P Reichert,Aaron D Levine
{"title":"The rise and fall of US federally funded human fetal tissue research.","authors":"Dylan P Reichert,Aaron D Levine","doi":"10.1038/s41591-026-04268-y","DOIUrl":"https://doi.org/10.1038/s41591-026-04268-y","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"402 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346525","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}
Antimicrobial resistance (AMR) poses a major global health threat, yet the effectiveness of national action plans (NAPs) remains uncertain. Here we developed a multidimensional One Health governance index through a structured Delphi expert consultation to evaluate AMR governance across 193 countries (2017-2022), integrating 269 policy documents, expert-weighted indicators and multinational survey and surveillance datasets. Difference-in-differences and joinpoint regression analyses were used to link governance to antimicrobial use, AMR prevalence and AMR-related mortality. Global governance scores improved from 30.7 to 44.5/100, although implementation and monitoring lagged behind policy design, particularly in animal and environmental sectors. A significant increase in AMR prevalence scores was observed only 5 years after NAP adoption (two-stage difference-in-differences, β = 2.43, 95% confidence interval (CI) 1.02-3.85, P < 0.05), underscoring the delayed impact of policy. Multisector engagement (early-adopting countries, β = 0.05, 95% CI 0.02-0.08, P < 0.01) and antimicrobial use surveillance system (early-adopting countries, β = 0.05, 95% CI 0.03-0.07, P < 0.01) showed the strongest associations with improvement in AMR outcomes. As the 2026 Global Action Plan update approaches, sustained financing and integrated One Health surveillance, with stronger environmental and agricultural engagement, are essential for translating NAPs into sustained reductions in resistance.
抗菌素耐药性（AMR）对全球健康构成重大威胁，但国家行动计划（nap）的有效性仍不确定。在这里，我们通过结构化的德尔菲专家咨询，开发了一个多维度的“同一个健康”治理指数，以评估193个国家（2017-2022年）的抗生素耐药性治理，整合了269份政策文件、专家加权指标和跨国调查和监测数据集。使用差异中的差异和连接点回归分析将治理与抗菌素使用、抗菌素耐药性流行率和抗菌素耐药性相关死亡率联系起来。全球治理得分从30.7分提高到44.5分，尽管实施和监测落后于政策设计，特别是在动物和环境部门。采用NAP后仅5年，AMR患病率得分显著增加（两阶段差异中的差异，β = 2.43, 95%置信区间（CI） 1.02-3.85, P < 0.05），强调政策的延迟影响。多部门参与（早期采用的国家，β = 0.05, 95% CI 0.02-0.08, P < 0.01）和抗菌药物使用监测系统（早期采用的国家，β = 0.05, 95% CI 0.03-0.07, P < 0.01）显示出与抗生素耐药性结果改善的最强关联。随着2026年全球行动计划更新的临近，持续的融资和一体化的“同一个健康”监测，以及加强环境和农业参与，对于将国家行动计划转化为持续减少耐药性至关重要。
{"title":"Evaluation of antimicrobial resistance governance across 193 countries to inform the 2026 Global Action Plan update.","authors":"Weiye Chen,Yige Zeng,Jinxin Zheng,Jing Wang,Wei Gu,Min Li,Zile Cheng,Jing Qian,Xiaoxi Zhang,Emmanuel Kabali,Chao Lv,Yiwen Chen,Guangrui Yang,Nan Zhou,Xiao Tan,Chendi Zhu,Hein Min Tun,Mashkoor Mohsin,Tanvir Rahman,Zhemin Zhou,Yonghong Xiao,Hong Chen,Chunlei Shi,Robert Bergquist,J Ross Fitzgerald,Sheng Chen,Yung-Fu Chang,Zhaojun Wang,Xiaonong Zhou,Xiaokui Guo,Jürg Utzinger,Junxia Song,Yongzhang Zhu","doi":"10.1038/s41591-026-04257-1","DOIUrl":"https://doi.org/10.1038/s41591-026-04257-1","url":null,"abstract":"Antimicrobial resistance (AMR) poses a major global health threat, yet the effectiveness of national action plans (NAPs) remains uncertain. Here we developed a multidimensional One Health governance index through a structured Delphi expert consultation to evaluate AMR governance across 193 countries (2017-2022), integrating 269 policy documents, expert-weighted indicators and multinational survey and surveillance datasets. Difference-in-differences and joinpoint regression analyses were used to link governance to antimicrobial use, AMR prevalence and AMR-related mortality. Global governance scores improved from 30.7 to 44.5/100, although implementation and monitoring lagged behind policy design, particularly in animal and environmental sectors. A significant increase in AMR prevalence scores was observed only 5 years after NAP adoption (two-stage difference-in-differences, β = 2.43, 95% confidence interval (CI) 1.02-3.85, P < 0.05), underscoring the delayed impact of policy. Multisector engagement (early-adopting countries, β = 0.05, 95% CI 0.02-0.08, P < 0.01) and antimicrobial use surveillance system (early-adopting countries, β = 0.05, 95% CI 0.03-0.07, P < 0.01) showed the strongest associations with improvement in AMR outcomes. As the 2026 Global Action Plan update approaches, sustained financing and integrated One Health surveillance, with stronger environmental and agricultural engagement, are essential for translating NAPs into sustained reductions in resistance.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"10 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346505","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}
Heterozygous familial hypercholesterolemia is a common genetic disorder characterized by lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. YOLT-101 is an investigational in vivo gene therapy that uses adenine base-editing technology, delivered via GalNAc-modified lipid nanoparticles to inactivate PCSK9 and achieve sustained LDL-C reduction. Here we report interim results from an ongoing clinical trial evaluating primary (safety and tolerability) and secondary (lowering of PCSK9 and LDL-C levels) outcomes of a single intravenous dose of YOLT-101 in adults with heterozygous familial hypercholesterolemia and uncontrolled LDL-C. Six participants (three men and three women) received escalating doses of YOLT-101 (0.2, 0.4 or 0.6 mg kg-1). No grade ≥3 adverse events occurred. Transient and self-limited infusion-related reactions and elevations in liver enzymes were the most common adverse events. A single infusion of YOLT-101 induced dose-dependent and durable reductions in circulating PCSK9 and LDL-C, with sustained reductions of 74.4% and 52.3%, respectively, at 24 weeks in the 0.6 mg kg-1 cohort (n = 3), demonstrating promise for future clinical development. ClinicalTrials.gov registration: NCT06458010 .
{"title":"In vivo base editing gene therapy for heterozygous familial hypercholesterolemia: a phase 1 trial.","authors":"Ping Wan,Siyuan Tang,Dongni Lin,Yuming Lu,Mei Long,Ling Xiao,Yanhong Jiang,Jiaoyang Liao,Xiaoying Ma,Ying Liu,Wensu Yu,Michael Ott,Zi Jun Wang,Yuxuan Wu,Taihua Yang,Qiang Xia","doi":"10.1038/s41591-026-04254-4","DOIUrl":"https://doi.org/10.1038/s41591-026-04254-4","url":null,"abstract":"Heterozygous familial hypercholesterolemia is a common genetic disorder characterized by lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. YOLT-101 is an investigational in vivo gene therapy that uses adenine base-editing technology, delivered via GalNAc-modified lipid nanoparticles to inactivate PCSK9 and achieve sustained LDL-C reduction. Here we report interim results from an ongoing clinical trial evaluating primary (safety and tolerability) and secondary (lowering of PCSK9 and LDL-C levels) outcomes of a single intravenous dose of YOLT-101 in adults with heterozygous familial hypercholesterolemia and uncontrolled LDL-C. Six participants (three men and three women) received escalating doses of YOLT-101 (0.2, 0.4 or 0.6 mg kg-1). No grade ≥3 adverse events occurred. Transient and self-limited infusion-related reactions and elevations in liver enzymes were the most common adverse events. A single infusion of YOLT-101 induced dose-dependent and durable reductions in circulating PCSK9 and LDL-C, with sustained reductions of 74.4% and 52.3%, respectively, at 24 weeks in the 0.6 mg kg-1 cohort (n = 3), demonstrating promise for future clinical development. ClinicalTrials.gov registration: NCT06458010 .","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"60 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346506","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 : 2026-03-03DOI: 10.1038/s41591-026-04229-5
Sully F Chen,Anton Alyakin,Andreas Seas,Eunice Yang,Joanne J Choi,Jin Vivian Lee,Amelia L Chen,Pranav I Warman,Rochelle T Bitolas,Robert J Steele,Daniel A Alber,Eric K Oermann
Clinical evaluations of large language models (LLMs) have rapidly expanded since 2022, yet their evidence base remains opaque. The overwhelming volume of studies creates challenges for manual curation and review. However, LLMs themselves offer the scalability and capability to evaluate the ever-growing evidence base. This LLM-assisted review identified 4,609 peer-reviewed studies in clinical medicine between January 2022 and September 2025, equating to roughly 3.2 papers per day. Only 1,048 studies used real-world patient data and of these only 19 were prospective randomized trials; most addressed simulated scenarios (n = 1,857) or exam-style tasks (n = 1,704). ChatGPT and related OpenAI models constitute 65.7% of evaluated models, with Gemini/Bard a distant second constituting 13.1% of evaluated models. Patient-facing communication and education comprised 17% of tasks, followed by knowledge retrieval, and education and assessment simulation. Across 1,046 head-to-head comparisons, LLMs outperformed humans in 33% of comparisons, with a strong dependency on task realism and level of training. At least 25% of studies had sample sizes less than 30. Despite the growth of LLMs in medicine, rigorous, patient-centered evidence remains scarce, underscoring the need for larger prospective trials before clinical adoption.
{"title":"LLM-assisted systematic review of large language models in clinical medicine.","authors":"Sully F Chen,Anton Alyakin,Andreas Seas,Eunice Yang,Joanne J Choi,Jin Vivian Lee,Amelia L Chen,Pranav I Warman,Rochelle T Bitolas,Robert J Steele,Daniel A Alber,Eric K Oermann","doi":"10.1038/s41591-026-04229-5","DOIUrl":"https://doi.org/10.1038/s41591-026-04229-5","url":null,"abstract":"Clinical evaluations of large language models (LLMs) have rapidly expanded since 2022, yet their evidence base remains opaque. The overwhelming volume of studies creates challenges for manual curation and review. However, LLMs themselves offer the scalability and capability to evaluate the ever-growing evidence base. This LLM-assisted review identified 4,609 peer-reviewed studies in clinical medicine between January 2022 and September 2025, equating to roughly 3.2 papers per day. Only 1,048 studies used real-world patient data and of these only 19 were prospective randomized trials; most addressed simulated scenarios (n = 1,857) or exam-style tasks (n = 1,704). ChatGPT and related OpenAI models constitute 65.7% of evaluated models, with Gemini/Bard a distant second constituting 13.1% of evaluated models. Patient-facing communication and education comprised 17% of tasks, followed by knowledge retrieval, and education and assessment simulation. Across 1,046 head-to-head comparisons, LLMs outperformed humans in 33% of comparisons, with a strong dependency on task realism and level of training. At least 25% of studies had sample sizes less than 30. Despite the growth of LLMs in medicine, rigorous, patient-centered evidence remains scarce, underscoring the need for larger prospective trials before clinical adoption.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"43 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346523","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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