Nature Medicine最新文献

{"title":"Rethinking TREM2 as a target for Alzheimer’s disease after the INVOKE-2 trial failure","authors":"Marco Colonna, David M. Holtzman","doi":"10.1038/s41591-025-03816-2","DOIUrl":"https://doi.org/10.1038/s41591-025-03816-2","url":null,"abstract":"<p>When Alector announced in late 2024 that its phase 2 trial of AL002, a monoclonal antibody that targets TREM2, had failed to slow cognitive decline in Alzheimer’s disease (AD), it reignited debate over the viability of microglial targets in AD. Years of compelling genetic and preclinical research had positioned the microglial receptor TREM2 as a central player in AD pathology. Now, with the first major clinical test of a TREM2-targeting therapy falling short, the obvious question is: is TREM2 still worth pursuing?</p><p>The answer is not a simple yes or no. Instead, it depends on rethinking how this microglial receptor and its adapter, DAP12, are engaged, and recognizing that the INVOKE-2 trial may have tested the idea of TREM2 as a drug target, but not the full potential of what effective activation of TREM2 could look like in the clinic. Also, new technologies and alternative strategies suggest that the story is far from over.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"19 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533151","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":"Peers as humans in the loop in digital mental health","authors":"Anushka R. Patel, Ernesto Isaac Lara","doi":"10.1038/s41591-025-03755-y","DOIUrl":"https://doi.org/10.1038/s41591-025-03755-y","url":null,"abstract":"An explosion of digital tools and AI is catalyzing innovations in the mission to scale up mental health support worldwide. These paradigms currently rely on a ‘human in the loop’ — but who is the human in question, and does it matter?","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"92 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533152","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":"The global rollback of transgender care, science and rights","authors":"Igor Longobardi, Bruna Caruso Mazzolani, Hamilton Roschel, Bruno Gualano, Alexandre Saadeh","doi":"10.1038/s41591-025-03805-5","DOIUrl":"https://doi.org/10.1038/s41591-025-03805-5","url":null,"abstract":"<p>Gender-affirming care for transgender youth is under attack. From Europe to the Americas, governments and professional bodies have imposed sweeping restrictions on essential medical interventions, bypassing scientific and ethical standards. Although framed as protective or cautious, these policies are neither: they misrepresent evidence, disregard international clinical guidelines, and expose vulnerable populations to harm.</p><p>This rollback is not isolated. In 2024–2025, the UK, USA and Brazil — three of the world’s largest democracies — enacted or reinforced limits on gender-affirming care. Despite differing sociopolitical contexts, they share key features: selective use of scientific uncertainty, erosion of clinical autonomy, and marginalization of trans voices in policymaking.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520523","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":"AI-enabled drug discovery reaches clinical milestone","authors":"Marinka Zitnik","doi":"10.1038/s41591-025-03832-2","DOIUrl":"https://doi.org/10.1038/s41591-025-03832-2","url":null,"abstract":"A randomized phase 2a clinical trial of an AI-discovered drug and target combination for idiopathic pulmonary fibrosis shows safety and signs of efficacy, marking a concrete step forward in bringing AI-enabled drug discovery into the clinic.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"23 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520524","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":"Health effects associated with consumption of processed meat, sugar-sweetened beverages and trans fatty acids: a Burden of Proof study","authors":"Demewoz Haile, Kassandra L. Harding, Susan A. McLaughlin, Charlie Ashbaugh, Vanessa Garcia, Nora M. Gilbertson, Hewan Kifle, Marie C. Parent, Reed J. D. Sorensen, Simon I. Hay, Aleksandr Y. Aravkin, Peng Zheng, Jeffrey D. Stanaway, Christopher J. L. Murray, Michael Brauer","doi":"10.1038/s41591-025-03775-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03775-8","url":null,"abstract":"<p>Previous research suggests detrimental health effects associated with consuming processed foods, including processed meats, sugar-sweetened beverages (SSBs) and trans fatty acids (TFAs). However, systematic characterization of the dose–response relationships between these foods and health outcomes is limited. Here, using Burden of Proof meta-regression methods, we evaluated the associations between processed meat, SSBs and TFAs and three chronic diseases: type 2 diabetes, ischemic heart disease (IHD) and colorectal cancer. We conservatively estimated that—relative to zero consumption—consuming processed meat (at 0.6–57 g d⁻¹) was associated with at least an 11% average increase in type 2 diabetes risk and a 7% (at 0.78–55 g d⁻¹) increase in colorectal cancer risk. SSB intake (at 1.5–390 g d⁻¹) was associated with at least an 8% average increase in type 2 diabetes risk and a 2% (at 0–365 g d⁻¹) increase in IHD risk. TFA consumption (at 0.25–2.56% of daily energy intake) was associated with at least a 3% average increase in IHD risk. These associations each received two-star ratings reflecting weak relationships or inconsistent input evidence, highlighting both the need for further research and—given the high burden of these chronic diseases—the merit of continuing to recommend limiting consumption of these foods.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"25 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515596","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":"International partnership for governing generative artificial intelligence models in medicine","authors":"Jasmine Chiat Ling Ong, Yilin Ning, Gary S. Collins, Danielle S. Bitterman, Ashley N. Beecy, Robert T. Chang, Alastair K. Denniston, Oscar Freyer, Stephen Gilbert, Anne de Hond, Artuur M. Leeuwenberg, Liang Zhao, John C. W. Lim, Mingxuan Liu, Xiaoxuan Liu, Christopher A. Longhurst, Yian Ma, Yue Qiu, Rupa Sarkar, Bin Sheng, Kuldev Singh, Iris Siu Kwan Tan, Yih Chung Tham, Arun J. Thirunavukarasu, Daniel Shu Wei Ting, Silke Vogel, Rui Zhang, Jianfei Zhao, Wendy W. Chapman, Nigam H. Shah, Karel G. M. Moons, Tien Yin Wong, Nan Liu","doi":"10.1038/s41591-025-03787-4","DOIUrl":"https://doi.org/10.1038/s41591-025-03787-4","url":null,"abstract":"<p>Generative artificial intelligence (GenAI) models, such as generative adversarial networks (GANs) and transformer-based large language models (LLMs), are developing at an accelerated pace and positioned to be integrated into clinical workflows and healthcare systems across the world. However, this rapid rise of GenAI in medicine and healthcare presents not just unprecedented opportunities, but also systemic risks in the integration of this new technology and critical vulnerabilities in terms of safety, governance and regulatory oversight. GenAI and LLMs are non-deterministic in nature, possess broad generalist functionalities, and display evolving capabilities¹. These characteristics challenge conventional regulatory frameworks designed for deterministic, task-specific artificial intelligence (AI) models, such as those for Software as a Medical Device (SaMD).</p><p>Some of the fundamental risks associated with GenAI and LLMs applications in healthcare are clear but yet to be fully addressed by current regulatory framework (‘known unknowns’), whereas other risks and challenges have not yet even surfaced (‘unknown unknowns’). Known unknowns include a lack of transparency in training data (including the possible use of synthetic data for training²), susceptibility to bias, hallucination of incorrect medical content, and potential misuse in high-stakes clinical settings¹ (Box 1).</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"27 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515850","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":"Exercise therapy and self-management support for individuals with multimorbidity: a randomized and controlled trial","authors":"Søren T. Skou, Mette Nyberg, Mette Dideriksen, Hanne Rasmussen, Jan Arnholtz Overgaard, Christine Bodilsen, Anne Merete B. Soja, Amir Pasha Attarzadeh, Manuel J. Bieder, Nadia P. Dridi, Andreas Heltberg, Peter H. Gæde, Johan L. Reventlow, Sidse Arnfred, Uffe Bodtger, Jan C. Brønd, Lau C. Thygesen, Sanne P. Møller, Madalina Jäger, Alessio Bricca","doi":"10.1038/s41591-025-03779-4","DOIUrl":"https://doi.org/10.1038/s41591-025-03779-4","url":null,"abstract":"<p>Despite increasing individual and societal burden, evidence for effective management strategies of multimorbidity is missing. Exercise therapy and self-management support are promising interventions, but their effect has not been evaluated. We hypothesized that exercise therapy and self-management support were superior to usual care alone in improving health-related quality of life (HRQoL) in individuals with multimorbidity. In this pragmatic multicenter, assessor-blinded randomized controlled trial (MOBILIZE), we enrolled 228 adult patients with two or more selected long-term conditions that limited their daily activities, but who were able to walk at least 3 meters without assistance, and who did not have unstable health conditions, life expectancy less than 12 months, or selected psychiatric conditions. Patients were randomized (1:1) to a 12 week personalized exercise therapy and self-management support program in addition to usual care or usual care alone. The primary outcome was HRQoL (using the EQ-5D-5L (European Quality of Life 5-dimensions 5-level version), ranging from −0.758 to 1, with higher scores being better) at 12 months, while secondary outcomes included functional performance (6 minute walk test and the 30 second chair-stand test), serious adverse events (SAEs), physical activity level (steps per day and minutes per day of at least light intensity measured with accelerometers), disease burden (Bayliss burden of illness measure), depression (Personal Health Questionnaire Depression Scale-8), anxiety (General Anxiety Disorder-7), self-efficacy (Self-Efficacy for Managing Chronic Disease scale), disability (12 item WHO Disability Assessment Schedule) and self-rated health (EQ-VAS (EuroQoL Visual Analog Scale)). In total, 197 of 228 participants (86%) completed the 12 month follow-up. On intention-to-treat analysis the exercise therapy and self-management support program had a statistically significantly greater effect on HRQoL than usual care alone (0.050 versus −0.014; adjusted mean difference, 0.064 points; 95% CI: 0.014–0.115). There were 36 and 48 SAEs in the exercise therapy and self-management group and usual care group, respectively (<i>P</i> = 0.388). Among the other secondary outcomes, only self-rated health was statistically significantly different between the groups (adjusted mean difference, 6.9 points; 95% CI: 1.8–12.1), in favor of the intervention group. In conclusion, this trial suggests that personalized exercise therapy and self-management support are more effective than usual care alone in improving health-related quality of life at 12 months in adults with multimorbidity, without compromising safety. The clinical relevance of the results remains unclear. ClinicalTrials.gov registration: NCT04645732.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"47 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515851","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":"Updating the evidence on ultra-processed foods and health","authors":"Wanglong Gou, Ju-Sheng Zheng","doi":"10.1038/s41591-025-03782-9","DOIUrl":"https://doi.org/10.1038/s41591-025-03782-9","url":null,"abstract":"A new analysis supports dietary guidelines to reduce the consumption of processed meat, sugar-sweetened beverages and trans-fatty acids — highlighting the need for a collaborative, meticulous health assessment framework for ultra-processed foods.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"40 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515826","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":"AAV mini-dystrophin gene therapy for Duchenne muscular dystrophy: a phase 1b trial","authors":"Russell J. Butterfield, Perry B. Shieh, Huihua Li, Michael Binks, Tara G. McDonnell, Kelly A. Ryan, Marielle Delnomdedieu, Beth A. Belluscio, Srividya Neelakantan, Daniel I. Levy, Pamela F. Schwartz, Edward C. Smith","doi":"10.1038/s41591-025-03750-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03750-3","url":null,"abstract":"<p>Gene therapy represents a promising approach for Duchenne muscular dystrophy (DMD), a rare X-linked genetic muscle disease. Fordadistrogene movaparvovec (PF-06939926) is an adeno-associated virus serotype 9 gene therapy containing a miniaturized dystrophin being developed for DMD, which aims to restore functional protein to muscle. We present 1-year data from ambulatory and nonambulatory participants in a phase 1b, multicenter, single-arm, open-label trial. Pediatric ambulatory male participants with a genetic DMD diagnosis and receiving stable glucocorticoids received a single intravenous low-dose (<i>n</i> = 3) or high-dose (<i>n</i> = 16) fordadistrogene movaparvovec. The primary endpoint was safety and tolerability at 1 year after dosing. In the ambulatory group, mean ± s.d. age at dosing was 8.6 ± 1.6 years. The most common treatment-emergent adverse events in the ambulatory group were vomiting (<i>n</i> = 15), nausea (<i>n</i> = 10), thrombocytopenia (<i>n</i> = 9), pyrexia (<i>n</i> = 9), decreased appetite (<i>n</i> = 8), fatigue (<i>n</i> = 7) and headache (<i>n</i> = 7). Three treatment-related serious adverse events occurred after dosing (dehydration, acute kidney injury, thrombocytopenia; all resolved within 15 days). In a small nonambulatory group (<i>n</i> = 3), mean ± s.d. age at dosing was 15.1 ± 1.0 years. The most common treatment-emergent adverse events were nausea (<i>n</i> = 3), vomiting (<i>n</i> = 3) and headache (<i>n</i> = 3); two severe treatment-related adverse events (hemolytic uremic syndrome and fatal cardiogenic shock) were observed. In the high-dose ambulatory group, the secondary endpoint of mini-dystrophin quantification showed robust expression. Mean (95% confidence interval) percent of mini-dystrophin-positive fibers for baseline, 2 months and 1 year were 0.1% (0.1–0.2), 20.3% (12.2–29.3) and 34.8% (21.1–49.8), respectively. At the 1-year time point of primary completion, fordadistrogene movaparvovec demonstrated an acceptable safety profile in the ambulatory population. Larger trials are needed to assess the efficacy of the gene therapy in DMD. ClinicalTrials.gov registration no. NCT03362502.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"246 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500424","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":"Stem cell therapies for diabetes","authors":"Juin Ting Chen, Nidheesh Dadheech, Eddie Han Pin Tan, Natasha Hui Jin Ng, Mickey Boon Chai Koh, James Shapiro, Adrian Kee Keong Teo","doi":"10.1038/s41591-025-03767-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03767-8","url":null,"abstract":"<p>Diabetes has long-term, potentially severe implications for healthspan and lifespan and imposes an immense burden on global healthcare, the economy and society. Although a repertoire of medications is available to treat diabetes, these do not properly address the eventual lack of functional pancreatic beta cells that are needed to secrete insulin and maintain glucose homeostasis. Human islet cell transplantation from deceased donors is an established treatment for insulin-requiring type 1 diabetes, but demand outstrips supply. Substantial scientific and clinical progress has occurred in the last decade toward deriving pancreatic islet-like cells from human pluripotent stem cells, suggesting a potentially limitless solution to the supply issue and a new era in cell therapy for diabetes. Here, we critically review the scientific advances, the clinical trials and the various regulatory considerations that will need to be overcome for human stem cell-derived pancreatic islet-like cells to become the next cell therapy breakthrough for diabetes treatment.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"22 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500425","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}