Nature MedicinePub Date : 2026-09-25DOI: 10.1038/s41591-026-04659-1
Elisa Dal Canto, Ernest Diez Benavente, Tim van de Hoef, Nabila Bouatia-Naji, Karen Reue, Mete Civelek, Hester den Ruijter
{"title":"Redesigning cardiovascular medicine around sex differences","authors":"Elisa Dal Canto, Ernest Diez Benavente, Tim van de Hoef, Nabila Bouatia-Naji, Karen Reue, Mete Civelek, Hester den Ruijter","doi":"10.1038/s41591-026-04659-1","DOIUrl":"10.1038/s41591-026-04659-1","url":null,"abstract":"Cardiovascular disease remains the leading cause of death in women and a major contributor to disability, yet the evidence guiding diagnosis and treatment is still largely derived from studies in which men and male-pattern disease phenotypes have predominated. Women exhibit distinct cardiovascular physiology that contributes to sex differences in cardiovascular health and disease across the life course. However, these biological differences rarely inform clinical decision-making and remain incompletely understood, owing to a research ecosystem that inadequately addresses sex-specific biology. Conditions such as spontaneous coronary artery dissection, Takotsubo syndrome and coronary vasomotor disorders disproportionately affect women but were historically under-recognized as distinct clinical entities. Consequently, they remain understudied, with limited mechanistic insight and few evidence-based therapeutic strategies. In this Perspective, we advocate strengthening the translational understanding of sex-biased mechanisms and integrating these insights into diagnostics and therapeutics, with a focus on female-predominant conditions. We outline a roadmap for translational research that embeds sex as a biological variable and illustrates how advances in emerging technologies can accelerate the development of an evidence base that improves cardiovascular care for women. Connecting evidence across preclinical and clinical domains, this Perspective calls for a greater understanding of sex-biased mechanisms and integration of these insights into diagnostics and therapeutics—with a focus on female-predominant cardiovascular conditions.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 10","pages":"3551-3563"},"PeriodicalIF":52.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049621","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}
Nature MedicinePub Date : 2026-09-24DOI: 10.1038/s41591-026-04700-3
Kohei Shitara, Zev Wainberg, Josep Tabernero, Eric Van Cutsem, Clélia Coutzac, Christelle De La Fouchardière, Jeeyun Lee, Sun Young Rha, Yoon-Koo Kang, Philip Fanning, Alison Forgie, Cherry Mao, Daniel Brickman, Jaume Pons, Athanasios C Tsiatis, Sophia Randolph, Keun-Wook Lee
{"title":"Evorpacept plus trastuzumab, ramucirumab and paclitaxel in HER2-positive gastric cancer: a randomized phase 2 trial.","authors":"Kohei Shitara, Zev Wainberg, Josep Tabernero, Eric Van Cutsem, Clélia Coutzac, Christelle De La Fouchardière, Jeeyun Lee, Sun Young Rha, Yoon-Koo Kang, Philip Fanning, Alison Forgie, Cherry Mao, Daniel Brickman, Jaume Pons, Athanasios C Tsiatis, Sophia Randolph, Keun-Wook Lee","doi":"10.1038/s41591-026-04700-3","DOIUrl":"https://doi.org/10.1038/s41591-026-04700-3","url":null,"abstract":"<p><p>Evorpacept blocks the CD47-signal regulatory protein α interaction, enhancing antibody-dependent cellular phagocytosis. In the phase 2 portion of ASPEN-06 (a multicenter, open-label, randomized phase 2/3 study), 127 patients with pretreated, human epidermal growth factor receptor 2 (HER2)-overexpressing, advanced gastric/gastroesophageal junction cancer were randomized to evorpacept plus trastuzumab, ramucirumab and paclitaxel (evo + TRP; n = 63; fresh HER2<sup>+</sup> biopsy, n = 22) or TRP alone (n = 64; fresh HER2<sup>+</sup> biopsy, n = 26). The primary end point was investigator-assessed objective response rate (ORR). The primary analysis of ORR was designed to evaluate an ORR exceeding the historical 30% benchmark (ramucirumab/paclitaxel) (80% power for intent to treat (ITT) and 50% power for the ITT subpopulation (HER2 overexpression based on a post-trastuzumab 'fresh' biopsy)) and an improvement of ≥8.0% and ≥9.7% versus TRP in the ITT and ITT subpopulations, respectively. Key secondary end points included ORR by blinded independent central review, duration of response and progression-free survival by investigator or blinded independent central review, overall survival and safety. Post hoc biomarker analyses, including the assessment of the association of treatment efficacy with retained HER2 status (defined by HER2 positivity on fresh tumor biopsy or amplification in circulating tumor DNA analysis) and CD47 expression in tumor samples, were conducted. The investigator-assessed ORRs were 40.3% (evo + TRP) versus 26.6% (TRP) in the ITT population and 54.8% versus 23.1% in the fresh biopsy HER2<sup>+</sup> subgroup. ORR differences (13.7% and 31.7%) exceeded the prespecified thresholds in both the ITT population and fresh biopsy HER2<sup>+</sup> subgroup, meeting one of the two primary objectives; however, compared to the historical benchmark (30%), ORRs in the ITT population (40.3%; P = 0.0949, one-sided) and fresh biopsy HER2<sup>+</sup> subgroup (54.8%; P = 0.030, one-sided) did not meet the prespecified statistical criterion (one-sided α = 0.025). While hematologic toxicities were more common with evo + TRP, overall safety was similar. In summary, evo + TRP showed encouraging efficacy with manageable safety in advanced gastric/gastroesophageal junction cancer. ClinicalTrials.gov identifier: NCT05002127 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040048","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}
Nature MedicinePub Date : 2026-09-24DOI: 10.1038/s41591-026-04653-7
Saleh A Alessy, Laure-Anne Teuwen, Eva Segelov, Saleh A Alqahtani
{"title":"Developing cancer-control policies to address the cancer burden among young adults.","authors":"Saleh A Alessy, Laure-Anne Teuwen, Eva Segelov, Saleh A Alqahtani","doi":"10.1038/s41591-026-04653-7","DOIUrl":"https://doi.org/10.1038/s41591-026-04653-7","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040112","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}
Nature MedicinePub Date : 2026-09-23DOI: 10.1038/s41591-026-04672-4
Alexandra Kautzky-Willer
{"title":"Sex and gender differences belong in treatment guidelines","authors":"Alexandra Kautzky-Willer","doi":"10.1038/s41591-026-04672-4","DOIUrl":"10.1038/s41591-026-04672-4","url":null,"abstract":"Clinical guidelines should state what is already known, where evidence is missing and what future trials must report.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 10","pages":"3511-3511"},"PeriodicalIF":52.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022195","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}
Nature MedicinePub Date : 2026-09-23DOI: 10.1038/s41591-026-04643-9
Richa Tiwari, Rajroshan Sawhney, Kasumi Widner, Kim Ramasamy, Ravindran Padmanabhan, Paisan Ruamviboonsuk, Angus Turner, Jay Nayar, Jessica Williams, Naama Hammel, Xiang Yin, Theo Guidroz, Dave Watson, Jonathan Krause, Quang Duong, Yun Liu, Yossi Matias, Ronit Levavi Morad, Avinatan Hassidim, Dale Webster, Sunny Virmani
{"title":"Practical lessons in the global scaling of clinical AI: from one hospital to over a million patients screened","authors":"Richa Tiwari, Rajroshan Sawhney, Kasumi Widner, Kim Ramasamy, Ravindran Padmanabhan, Paisan Ruamviboonsuk, Angus Turner, Jay Nayar, Jessica Williams, Naama Hammel, Xiang Yin, Theo Guidroz, Dave Watson, Jonathan Krause, Quang Duong, Yun Liu, Yossi Matias, Ronit Levavi Morad, Avinatan Hassidim, Dale Webster, Sunny Virmani","doi":"10.1038/s41591-026-04643-9","DOIUrl":"10.1038/s41591-026-04643-9","url":null,"abstract":"Scaling a successful deep learning tool across three highly distinct settings – in India, Thailand and Australia — offers cross-cutting insights that may inform the expansion of healthcare artificial intelligence globally.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 10","pages":"3525-3527"},"PeriodicalIF":52.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022193","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}
Nature MedicinePub Date : 2026-09-23DOI: 10.1038/s41591-025-04128-1
Chenfeng He, Athan Z. Li, Kalpana Hanthanan Arachchilage, Chirag Gupta, Xiang Huang, Xinyu Zhao, Carissa L. Sirois, PsychAD Consortium, Kiran Girdhar, Georgios Voloudakis, Gabriel E. Hoffman, Jaroslav Bendl, John F. Fullard, Donghoon Lee, Panos Roussos, Daifeng Wang
{"title":"AI-based characterization of Alzheimer’s disease phenotypes from population-scale single-cell data","authors":"Chenfeng He, Athan Z. Li, Kalpana Hanthanan Arachchilage, Chirag Gupta, Xiang Huang, Xinyu Zhao, Carissa L. Sirois, PsychAD Consortium, Kiran Girdhar, Georgios Voloudakis, Gabriel E. Hoffman, Jaroslav Bendl, John F. Fullard, Donghoon Lee, Panos Roussos, Daifeng Wang","doi":"10.1038/s41591-025-04128-1","DOIUrl":"10.1038/s41591-025-04128-1","url":null,"abstract":"The complexity of Alzheimer’s disease (AD) manifests in diverse clinical phenotypes, including cognitive impairment and neuropsychiatric symptoms. However, the etiology of these phenotypes remains elusive. To address this, the PsychAD project generated a population-level single-nucleus RNA sequencing dataset comprising over 6 million nuclei from the prefrontal cortex of >1,000 individual brains, covering a variety of disease phenotypes. Here, leveraging this dataset, we developed a computational framework, called Phenotype Associated Single Cell encoder (PASCode), to score single-cell phenotype associations, and identified ∼1.5 million phenotype-associated cells (PACs) from 584 donors with AD-related phenotypes. PASCode ensembles multiple statistical methods into a graph neural model for robust scoring. Comparing PACs within 27 brain cell subclasses, we prioritized cell subpopulations and their expressed genes for various AD phenotypes. For instance, we identified microglia subpopulations implicated in AD pathology; reactive astrocyte subtypes with altered neuroprotective and neurotoxic gene expression that likely confer cognitive resilience; and enhanced excitatory/inhibitory imbalance and mitochondrial dysfunction in cognitively impaired AD donors. We also identified many PACs for multiple phenotypes, including the astrocytes between AD and depression showing specific gene expression patterns such as inflammation and endoplasmic reticulum stress pathways. These prioritized subpopulations, genes and pathways potentially offer valuable insights for precision diagnostic and therapeutic development. We also validated our findings in external population-scale datasets including AD and major depressive disorder, compiled an AD-phenotypic single-cell atlas and delivered the framework as an open-source tool with pre-trained models and a web application for community use. Based on single-cell data from a cohort of 584 brain donors including patients with Alzheimer’s disease (AD) and controls, a graph neural network is used to investigate differential patterns between disease and control, to identify those related to cognitive resilience and to insurgence of depression in patients with AD.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 10","pages":"3682-3694"},"PeriodicalIF":52.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41591-025-04128-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022192","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}
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