Nature Medicine最新文献

{"title":"Personalized inhaled bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa in cystic fibrosis","authors":"Benjamin K. Chan, Gail L. Stanley, Kaitlyn E. Kortright, Albert C. Vill, Mrinalini Modak, Isabel M. Ott, Ying Sun, Silvia Würstle, Casey N. Grun, Barbara I. Kazmierczak, Govindarajan Rajagopalan, Zachary M. Harris, Clemente J. Britto, Jill Stewart, Jaideep S. Talwalkar, Casey R. Appell, Nauman Chaudary, Sugeet K. Jagpal, Raksha Jain, Adaobi Kanu, Bradley S. Quon, John M. Reynolds, Charlotte C. Teneback, Quynh-Anh Mai, Veronika Shabanova, Paul E. Turner, Jonathan L. Koff","doi":"10.1038/s41591-025-03678-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03678-8","url":null,"abstract":"<p>Bacteriophage (phage) therapy, which uses lytic viruses as antimicrobials, is a potential strategy to address the antimicrobial resistance crisis. Cystic fibrosis, a disease complicated by recurrent <i>Pseudomonas aeruginosa</i> pulmonary infections, is an example of the clinical impact of antimicrobial resistance. Here, using a personalized phage therapy strategy that selects phages for a predicted evolutionary trade-off, nine adults with cystic fibrosis (eight women and one man) of median age 32 (range 22–46) years were treated with phages on a compassionate basis because their clinical course was complicated by multidrug-resistant or pan-drug-resistant <i>Pseudomonas</i> that was refractory to prior courses of standard antibiotics. The individuals received a nebulized cocktail or single-phage therapy without adverse events. Five to 18 days after phage therapy, sputum <i>Pseudomonas</i> decreased by a median of 10⁴ CFU ml⁻¹, or a mean difference of 10² CFU ml⁻¹ (<i>P</i> = 0.006, two-way analysis of variance with Dunnett’s multiple-comparisons test), without altering sputum microbiome, and an analysis of sputum <i>Pseudomonas</i> showed evidence of trade-offs that decreased antibiotic resistance or bacterial virulence. In addition, an improvement of 6% (median) and 8% (mean) predicted FEV₁ was observed 21–35 days after phage therapy (<i>P</i> = 0.004, Wilcoxon signed-rank <i>t</i>-test), which may reflect the combined effects of decreased bacterial sputum density and phage-driven trade-offs. These results show that a personalized, nebulized phage therapy trade-off strategy may affect clinical and microbiologic endpoints, which must be evaluated in larger clinical trials.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"13 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884919","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":"Cerebrospinal fluid biomarker predicts dementia onset and progression in Alzheimer’s disease","authors":"","doi":"10.1038/s41591-025-03700-z","DOIUrl":"https://doi.org/10.1038/s41591-025-03700-z","url":null,"abstract":"Proteomics analyses of thousands of proteins in human cerebrospinal fluid reveal that the ratio of two proteins can be used to predict future dementia or cognitive resilience among people with Alzheimer’s disease brain pathology.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"80 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880485","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":"Changing climate and socioeconomic factors contribute to global antimicrobial resistance","authors":"Weibin Li, Tingting Huang, Chaojie Liu, Haishaerjiang Wushouer, Xinyi Yang, Ruonan Wang, Haohai Xia, Xiying Li, Shengyue Qiu, Shanquan Chen, Hung Chak Ho, Cunrui Huang, Luwen Shi, Xiaodong Guan, Guobao Tian, Gordon Liu, Kristie L. Ebi, Lianping Yang","doi":"10.1038/s41591-025-03629-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03629-3","url":null,"abstract":"<p>Climate change poses substantial challenges in containing antimicrobial resistance (AMR) from a One Health perspective. Using 4,502 AMR surveillance records involving 32 million tested isolates from 101 countries (1999–2022), we analyzed the impact of socioeconomic and environmental factors on AMR. We also established forecast models based on several scenarios, considering antimicrobial consumption reduction, sustainable development initiatives and different shared socioeconomic pathways under climate change. Our findings reveal growing AMR disparities between high-income countries and low- and middle-income countries under different shared socioeconomic pathway scenarios. By 2050, compared with the baseline, sustainable development efforts showed the most prominent effect by reducing AMR prevalence by 5.1% (95% confidence interval (CI): 0.0–26.6%), surpassing the effect of antimicrobial consumption reduction. Key contributors include reducing out-of-pocket health expenses (3.6% (95% CI: −0.5 to 21.4%)); comprehensive immunization coverage (1.2% (95% CI: −0.1% to 8.2%)); adequate health investments (0.2% (95% CI: 0.0–2.4%)) and universal access to water, sanitation and hygiene services (0.1% (95% CI: 0.0–0.4%)). These findings highlight the importance of sustainable development strategies as the most effective approach to help low- and middle-income countries address the dual challenges of climate change and AMR.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"24 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880445","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":"Polygenic risk score boosts prostate cancer detection","authors":"","doi":"10.1038/d41591-025-00027-7","DOIUrl":"https://doi.org/10.1038/d41591-025-00027-7","url":null,"abstract":"The polygenic score, based on analysis of DNA from a saliva sample, led to the detection of more cancers than would have been found with standard screening pathways.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880483","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":"Author Correction: T cell malignancies after CAR T cell therapy in the DESCAR-T registry","authors":"Remy Dulery, Vincent Guiraud, Sylvain Choquet, Catherine Thieblemont, Emmanuel Bachy, Stéphane Barete, Ève Todesco, Bertrand Arnulf, Nicolas Boissel, André Baruchel, Jacques-Olivier Bay, Steven Le Gouill, Roch Houot","doi":"10.1038/s41591-025-03717-4","DOIUrl":"https://doi.org/10.1038/s41591-025-03717-4","url":null,"abstract":"<p>Correction to: <i>Nature Medicine</i> https://doi.org/10.1038/s41591-024-03458-w, published online 8 January 2025.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"9 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876312","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":"Author Correction: Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers","authors":"Conan G. Kinsey, Soledad A. Camolotto, Amelie M. Boespflug, Katrin P. Guillen, Mona Foth, Amanda Truong, Sophia S. Schuman, Jill E. Shea, Michael T. Seipp, Jeffrey T. Yap, Lance D. Burrell, David H. Lum, Jonathan R. Whisenant, G. Weldon Gilcrease, Courtney C. Cavalieri, Kaitrin M. Rehbein, Stephanie L. Cutler, Kajsa E. Affolter, Alana L. Welm, Bryan E. Welm, Courtney L. Scaife, Eric L. Snyder, Martin McMahon","doi":"10.1038/s41591-025-03713-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03713-8","url":null,"abstract":"<p>Correction to: <i>Nature Medicine</i> https://doi.org/10.1038/s41591-019-0367-9, published online 4 March 2019.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"45 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872500","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":"CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade","authors":"Gusztav Milotay, Martin Little, Robert A. Watson, Dylan Muldoon, Sophie MacKay, Ayako Kurioka, Orion Tong, Chelsea A. Taylor, Isar Nassiri, Louisa M. Webb, Oluwafemi Akin-Adigun, Julia Bremke, Weiyu Ye, Bo Sun, Piyush Kumar Sharma, Ros Cooper, Sara Danielli, Flavia Matos Santo, Alba Verge de Los Aires, Guangyi Niu, Lea Cohen, Esther Ng, James J. Gilchrist, Amanda Y. Chong, Alex Mentzer, Victoria Woodcock, Nicholas Coupe, Miranda J. Payne, Michael Youdell, Mark R. Middleton, Paul Klenerman, Benjamin P. Fairfax","doi":"10.1038/s41591-025-03647-1","DOIUrl":"https://doi.org/10.1038/s41591-025-03647-1","url":null,"abstract":"<p>Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV⁺ patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8⁺ T cell gene expression. Combination anti-CTLA-4/anti-PD-1 ICB, but not single-agent anti-PD-1 ICB, induces cytotoxicity and CMV-associated gene expression in CD8⁺ T cells from CMV⁻ patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV⁺ hazard ratio for death: 1.02, <i>P</i> = 0.92), whereas CMV⁺ single-agent anti-PD-1 ICB recipients had improved overall survival (CMV⁺ hazard ratio for death: 0.37, <i>P</i> &lt; 0.01), a finding also seen in CMV⁺ adjuvant single-agent anti-PD-1 ICB recipients (CMV⁺ hazard ratio for recurrence: 0.19, <i>P</i> = 0.03). We identify <i>TBX21</i>, encoding T-bet, as a transcriptional driver of CMV-associated CD8⁺ T cell gene expression, finding that <i>TBX21</i> expression is predictive of overall survival (hazard ratio: 0.62, <i>P</i> = 0.026). CMV⁺ patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, <i>P</i> = 2.2 × 10⁻⁵), with lower incidence of colitis (<i>P</i> = 7.8 × 10⁻⁴) and pneumonitis (<i>P</i> = 0.028), an effect replicated in non-melanoma ICB recipients (<i>n</i> = 58, <i>P</i> = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, <i>P</i> = 1.8 × 10⁻⁴), indicating CMV seropositivity may protect against MM. Specifically, patients with <i>BRAF</i>-mutated MM are less likely to be CMV⁺ (odds ratio = 2.2, <i>P</i> = 0.0054), while CMV⁻ patients present 9 yr earlier with <i>BRAF</i> wild-type MM (<i>P</i> = 1.3 × 10⁻⁴). This work reveals an interaction between CMV infection, MM development according to <i>BRAF</i> status and response to ICB, while demonstrating CMV infection is protective against severe ICB immune-related adverse events, highlighting the potential importance of previous infection history and chronic immune activation in MM development and immunotherapy outcomes.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"7 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862721","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":"Benchmark evaluation of DeepSeek large language models in clinical decision-making","authors":"Sarah Sandmann, Stefan Hegselmann, Michael Fujarski, Lucas Bickmann, Benjamin Wild, Roland Eils, Julian Varghese","doi":"10.1038/s41591-025-03727-2","DOIUrl":"https://doi.org/10.1038/s41591-025-03727-2","url":null,"abstract":"<p>Large Language Models (LLMs) are increasingly transforming medical applications. However, proprietary models such as GPT-4o face significant barriers to clinical adoption because they cannot be deployed on site within healthcare institutions, making them non-compliant with stringent privacy regulations. Recent advancements in open-source LLMs such as DeepSeek models offer a promising alternative since they allow efficient fine-tuning on local data in hospitals with advanced IT infrastructure. To demonstrate the clinical utility of DeepSeek-V3 and DeepSeek-R1, we benchmarked their performance on clinical decision support tasks against proprietary LLMs, including GPT-4o and Gemini-2.0 Flash Thinking Experimental. Using 125 patient cases with sufficient statistical power, covering a broad range of frequent and rare diseases, we found that DeepSeek models perform equally well and in some cases better than proprietary LLMs. Our study demonstrates that open-source LLMs can provide a scalable pathway for secure model training enabling real-world medical applications in accordance with data privacy and healthcare regulations.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"34 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862719","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":"Comparative benchmarking of the DeepSeek large language model on medical tasks and clinical reasoning","authors":"Mickael Tordjman, Zelong Liu, Murat Yuce, Valentin Fauveau, Yunhao Mei, Jerome Hadjadj, Ian Bolger, Haidara Almansour, Carolyn Horst, Ashwin Singh Parihar, Amine Geahchan, Anis Meribout, Nader Yatim, Nicole Ng, Phillip Robson, Alexander Zhou, Sara Lewis, Mingqian Huang, Timothy Deyer, Bachir Taouli, Hao-Chih Lee, Zahi A. Fayad, Xueyan Mei","doi":"10.1038/s41591-025-03726-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03726-3","url":null,"abstract":"<p>DeepSeek is a newly introduced large language model (LLM) designed for enhanced reasoning, but its medical-domain capabilities have not yet been evaluated. This study assessed the capabilities of three LLMs— DeepSeek-R1, ChatGPT-o1, and Llama 3.1-405B—in performing four different medical tasks: answering questions from the United States Medical Licensing Examination (USMLE), interpreting and reasoning based on text-based diagnostic and management cases, providing tumor classification according to RECIST 1.1 criteria, and providing summaries of diagnostic imaging reports across multiple modalities. In the USMLE test, the performance of DeepSeek-R1(accuracy=0.92) was slightly inferior to that of ChatGPT-o1(accuracy=0.95; p = 0.04) but better than that of Llama 3.1-405B (accuracy=0.83; p &lt; 10^-3). For text-based case challenges, DeepSeek-R1 performed similarly to ChatGPT-o1 (accuracy of 0.57 vs 0.55; p = 0.76 and 0.74 vs 0.76; p = 0.06, using New England Journal of Medicine and Medicilline databases, respectively). For RECIST classifications, DeepSeek-R1 also performed similarly to ChatGPT-o1 (0.73 vs 0.81; p = 0.10). Diagnostic reasoning steps provided by DeepSeek were deemed more accurate than those provided by ChatGPT and Llama 3.1-405B (average Likert score of 3.61, 3.22, and 3.13, respectively, p = 0.005 and p &lt; 10⁻³). However, summarized imaging reports provided by DeepSeek-R1 exhibited lower global quality than those provided by ChatGPT-o1 (5-point Likert score: 4.5 vs 4.8; p &lt; 10⁻³). This study highlights the potential of DeepSeek-R1 LLM for medical applications but also underlines areas needing improvements.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"54 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862720","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":"Cognitive behavioral therapy skills via a smartphone app for subthreshold depression among adults in the community: the RESiLIENT randomized controlled trial","authors":"Toshi A. Furukawa, Aran Tajika, Rie Toyomoto, Masatsugu Sakata, Yan Luo, Masaru Horikoshi, Tatsuo Akechi, Norito Kawakami, Takeo Nakayama, Naoki Kondo, Shingo Fukuma, Ronald C. Kessler, Helen Christensen, Alexis Whitton, Inbal Nahum-Shani, Wolfgang Lutz, Pim Cuijpers, James M. S. Wason, Hisashi Noma","doi":"10.1038/s41591-025-03639-1","DOIUrl":"https://doi.org/10.1038/s41591-025-03639-1","url":null,"abstract":"<p>Subthreshold depression, defined as a depressive status falling short of the diagnostic threshold for major depression, is common, disabling and constitutes a risk factor for future depressive episodes. Cognitive behavioral therapies (CBT) have been shown to be effective but are usually provided as packages of various skills. Little research has been done to investigate whether all their components are beneficial and contributory to mental health promotion. We addressed this issue by developing a smartphone CBT app that implements five representative CBT skills (behavioral activation, cognitive restructuring, problem solving, assertion training and behavior therapy for insomnia), and conducting a master randomized study that included four 2 × 2 factorial trials to enable precise estimation of skill-specific efficacies. Between September 2022 and February 2024, we recruited 3,936 adult participants with subthreshold depression. Among those randomized, the follow-up rate was 97% at week 6 and adherence to the app was 84%. The study showed that all included CBT skills and their combinations differentially beat all three control conditions of delayed treatment, health information or self-check, with effect sizes ranging between −0.67 (95% confidence interval: −0.81 to −0.53) and −0.16 (−0.30 to −0.02) for changes in depressive symptom severity from baseline to week 6, as measured with the Patient Health Questionnaire-9 scores. Knowledge of the active ingredients of CBT can better inform the design of more effective and scalable psychotherapies in the future. (UMIN Clinical Trials Registry UMIN000047124).</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"4 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862722","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}