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Nature Medicine · Dec 01, 2025

Liraglutide in mild to moderate Alzheimer’s disease: a phase 2b clinical trial

Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer’s disease syndrome. ‘Evaluating liraglutide in Alzheimer’s disease’ (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer’s disease syndrome with no diabetes. Participants received daily injections of liraglutide or placebo for 52 weeks. They underwent fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and detailed neuropsychometric evaluations. The primary outcome was a change in cerebral glucose metabolic rate. Secondary outcomes were safety and tolerability and cognitive changes. The primary outcome showed no significant differences in cerebral glucose metabolism (difference = −0.17; 95% confidence interval: −0.39 to 0.06; P = 0.14) between the two groups. The secondary outcome—score on the Alzheimer’s Disease Assessment Scale-Executive domain (ADAS-Exec)—performed better in liraglutide-treated patients compared to placebo (0.15; 95% confidence interval: 0.03−0.28; unadjusted P = 0.01). No significant differences were observed in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) (−0.58; 95% confidence interval: −3.13 to 1.97; unadjusted P = 0.65) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) (−0.06; 95% confidence interval: −0.57 to 0.44; unadjusted P = 0.81) scores. Liraglutide was generally safe and well tolerated in non-diabetic patients with Alzheimer’s disease. ClinicalTrials.gov identifier: NCT01843075 . Results from the phase ELAD 2 trial reveal that liraglutide is safe and well tolerated in people with mild to moderate Alzheimer’s disease but does not significantly slow brain metabolism decline.

Alzheimer's disease Cell death in the nervous system biology
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Nature Medicine · Nov 28, 2025

Targeting of HIF2-driven cachexia in kidney cancer

Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC), is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show thatPTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increasedPTHLHexpression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in patients with ccRCC, including in some who did not exhibit objective tumor shrinkage. Our findings support prospective clinical studies to determine whether HIF2 inhibitors can be leveraged not only for tumor control, but also for the treatment of cancer-associated cachexia in renal cell carcinoma.

Cancer metabolism Renal cancer Targeted therapies biology mouse experiments
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Nature Medicine · Nov 24, 2025

A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial

Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer affecting children and young adults that is driven by a chimeric protein, DNAJ-PKAc. The development of molecular inhibitors of DNAJ-PKAc has been hampered by unacceptable on-target toxicity, but the chimera results in a tumor-specific antigen (neoantigen) that may be targeted immunologically. Here we conducted a phase 1 clinical trial of a therapeutic peptide vaccine targeting DNAJ-PKAc (FLC-Vac), in combination with nivolumab and ipilimumab, in children and adults with advanced FLC, who had not previously received immune checkpoint therapy. The primary objectives were safety and T cell responses after week 10 (priming phase). Of the 16 patients enrolled, 12 completed the vaccine priming phase and were evaluable for both immunological and clinical endpoints. The median age was 24 years (range 12–47 years). Grade 3 treatment-related adverse events were reported by six patients (37.5%). DNAJ-PKAc-specific T cell responses were detected in 9 of 12 patients after treatment. In the subset of patients who completed the initial priming phase the disease control rate was 75% (9/12), with three partial responses (25%). All patients with clinical responses also had DNAJ-PKAc-specific T cell responses, from which we identified multiple class-II-restricted T cell receptors with specificity for DNAJ-PKAc. Correlates of response included both functional neoantigen reactivity and changes in T cell receptor repertoire features over time. Immune escape in two patients corresponded with immune exhaustion rather than neoantigen escape or human leukocyte antigen loss. Our findings demonstrate the potential for therapeutic vaccines targeting ‘undruggable’ oncogenic drivers and suggest a rubric for evaluating effective anti-neoantigen immunity. ClinicalTrials.gov identifier:NCT04248569.

Cancer immunotherapy Immunology biology
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Nature Medicine · Nov 20, 2025

Factor IX-Padua AAV gene therapy in hemophilia B: phases 1/2 and 3 trials

Gene therapy for hemophilia B with adeno-associated virus (AAV) vector has achieved great advances over the last decade. We previously conducted a pilot study demonstrating the safety and efficacy of AAV-factor IX (FIX) Padua gene therapy (BBM-H901) in ten male participants with hemophilia B. Here we report a single-arm dose-escalation phase 1/2 trial in 6 male participants and a multicentre phase 3 trial in 26 participants with hemophilia B in China. The phase 1/2 study tested a dose of 5 × 1012vg kg−1(n= 6), with primary endpoints assessing dose-limiting toxicities (DLT) and adverse events (AEs). The primary endpoint was met with no DLT observed in the 10 weeks postinfusion. The most common drug-related AEs were transaminitis (33.3%), and no grade 3 drug-related AE occurred within 52 weeks postintervention. The phase 3 study tested the 5 × 1012vg kg−1dose, as determined in the phase 1/2 study, in 26 patients. The primary endpoint evaluated the annualized bleeding rate (ABR) after gene therapy and secondary endpoints included vector-derived FIX:C, target joint and percentage of participants with zero bleeds postgene therapy. The study met its primary endpoint as the mean (95% confidence interval (CI)) ABR within 52 weeks after BBM-H901 infusion decreased to 0.60 (0.18–1.99), and the upper limit of the 95% CI (1.99) was lower than the predefined superiority margin of 5.0 (historical ABR assumed for patients receiving prophylactic FIX treatment in China). In the phase 3 trial, the most common drug-related AEs were transaminitis as well, and the vector-derived FIX:C had a mean of 41.9 (28.7) IU dl−1at week 52. None of the participants had a target joint, and 80.8% of participants experienced zero bleeds during the 52-week follow-up. Our study supports the safety and efficacy of AAV-FIX Padua gene therapy in a large Chinese cohort. ClinicalTrials.gov registration:NCT05203679.

Drug development Haematological diseases
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Nature Medicine · Nov 17, 2025

Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide

Obesity and related conditions are associated with distressing food preoccupation that often culminates in dysregulated eating behaviors. Incretin-based therapies can reduce excessive weight in obesity, but their impact on dysregulated eating behaviors remains largely unexamined. Understanding how these pharmacologics engage the brain’s mesolimbic circuitry may inform the expansion of their therapeutic potential. We report a rare, first-in-human exploration of the physiological action of these therapies by examining the electrophysiology directly within the human nucleus accumbens. After a short-term course of tirzepatide, the patient-participant exhibited increased severe food preoccupation episodes, which were preceded by an increased delta–theta frequency (≤7 Hz) power in the nucleus accumbens region. We propose that the effects of an incretin-based therapy (tirzepatide) on food preoccupation may be associated with modulation of aberrant activity within this key hub of human mesolimbic circuitry.

Biomarkers Obesity Psychiatric disorders Reward
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Nature Medicine · Nov 14, 2025

Microbial signals in primary and metastatic brain tumors

Gliomas and brain metastases are associated with poor prognosis, necessitating a deeper understanding of brain tumor biology and the development of effective therapeutic strategies. Although our group and others have demonstrated microbial presence in various tumors, recent controversies regarding cancer-type-specific intratumoral microbiota emphasize the importance of rigorous, orthogonal validation. This prospective, multi-institutional study included a total of 243 samples from 221 patients, comprising 168 glioma and brain metastases samples and 75 non-cancerous or tumor-adjacent tissues. Using stringent fluorescence in situ hybridization, immunohistochemistry and high-resolution spatial imaging, we detected intracellular bacterial 16S rRNA and lipopolysaccharides in both glioma and brain metastases samples, localized to tumor, immune and stromal cells. Custom 16S and metagenomic sequencing workflows identified taxa associated with intratumoral bacterial signals in the tumor microenvironment; however, standard culture methods did not yield readily cultivable microbiota. Spatial analyses revealed significant correlations between bacterial 16S signals and antimicrobial and immunometabolic signatures at regional, neighborhood and cellular levels. Furthermore, intratumoral 16S bacterial signals showed sequence overlap with matched oral and gut microbiota, suggesting a possible connection with distant communities. Together, these findings introduce microbial elements as a component of the brain tumor microenvironment and lay the foundation for future mechanistic and translational studies.

Bacterial host response CNS cancer
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Nature Medicine · Nov 10, 2025

Endotyping-informed therapy for patients with chest pain and no obstructive coronary artery disease: a randomized trial

Patients undergoing invasive coronary angiography for the investigation of chest pain commonly do not have obstructive coronary artery disease. In contemporary practice, most of these individuals do not undergo functional diagnostic tests, leaving the cause of the chest pain uncertain. Stress cardiovascular magnetic resonance imaging (MRI) can be used to measure myocardial blood flow, detect coronary microvascular dysfunction and endotype individual patients, but evidence of clinical utility from randomized trials is lacking. This study was a prospective, multicenter, parallel group, 1:1 randomized, controlled superiority trial of adenosine stress cardiovascular MRI-guided management in 250 patients (mean age, 63.3 years; 50.4% female) with chest pain and unobstructed coronary arteries. The primary outcome of the diagnostic study, defined as the reclassification of the initial diagnosis based on the angiogram, occurred in 131 patients (53.0% (95% confidence interval: 46.6−59.3%);P< 0.001), indicating that the primary outcome for the diagnostic study was met. The primary outcome of the randomized trial was the Seattle Angina Questionnaire (SAQ) summary score at 12 months after randomization. The mean ± s.d. SAQ summary scores at 12 months in the intervention and control groups were 70.9 ± 23.6 (21.7 ± 22.6 change from baseline) and 52.1 ± 24.1 (−0.8 ± 20.4 change from baseline) (adjusted mean difference: 20.9 (95% confidence interval: 15.8–26.0)), respectively, indicating that the primary outcome of the randomized trial was met. Improvements were also observed in the prespecified secondary outcome of the EQ-5D-5L questionnaire at 12 months (adjusted mean difference 0.09 (95% confidence interval: 0.04−0.13)). In this study of patients with chest pain and unobstructed coronary arteries, endotyping-informed therapy revised the diagnosis in more than half of the participants and improved angina and health-related quality of life. ClinicalTrials.gov identifier:NCT04805814.

Chronic pain Ischaemia Randomized controlled trials
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Nature Medicine · Nov 09, 2025

Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice

Cardiovascular outcome trials of the incretin-based medicines tirzepatide and semaglutide have shown benefits in populations with varying levels of cardiovascular risk. However, without direct head-to-head comparisons, treatment decisions rely on indirect evidence from heterogeneous trial populations, leaving optimal treatment choices uncertain. We therefore conducted five cohort studies to assess the effectiveness of tirzepatide and semaglutide in patients with elevated cardiovascular risk, including obesity and type 2 diabetes, enrolled in insurance programs in United States between 2018 and 2025. First, we emulated two cardiovascular outcome trials, SUSTAIN-6 (semaglutide versus sitagliptin as placebo proxy) and SURPASS-CVOT (tirzepatide versus dulaglutide), to benchmark and critically evaluate our design, data, and analytic framework. Second, we assessed each drug in expanded populations reflective of patients routinely seen in clinical practice. Third, we directly compared tirzepatide versus semaglutide. Baseline confounders were balanced using propensity score matching. For the primary composite end point of myocardial infarction, stroke, or all-cause mortality, benchmarking identified high agreement between the reference trials and their emulations for all individual end points except for all-cause mortality in SUSTAIN-6, informing subsequent analyses. In expanded populations, comparing semaglutide versus sitagliptin for the composite outcome of myocardial infarction or stroke yielded a hazard ratio of 0.82 (95% CI, 0.74 to 0.91), and comparing tirzepatide versus dulaglutide for the composite outcome including mortality yielded a hazard ratio of 0.87 (0.75 to 1.01). In the head-to-head comparison of tirzepatide versus semaglutide, the hazard ratio was 1.06 (0.95 to 1.18). These findings support a comparable cardiovascular benefit of tirzepatide and semaglutide in clinical practice and demonstrate how rigorously designed real-world evidence can complement randomized clinical trials.

Cardiovascular diseases Epidemiology Outcomes research Randomized controlled trials
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Nature Medicine · Nov 07, 2025

Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial

Functional cure is a goal for the treatment of chronic hepatitis B virus (HBV) infection; however, it is infrequently achieved with currently approved treatments. Here we provide a randomized evaluation of the small interfering RNA elebsiran, in combination with pegylated interferon alfa (PEG-IFNα), compared with PEG-IFNα monotherapy. In addition, this study evaluates the potential role of the HBV therapeutic vaccine BRII-179 in identifying immunologically responsive patients and improving hepatitis B surface antigen (HBsAg) loss rates. In part I (cohorts 1–3), virally suppressed participants with chronic HBV infection naive to BRII-179 were randomized 1:1:1 to receive 48 weekly doses of PEG-IFNα alone or in combination with 13 doses of elebsiran (200 mg or 100 mg) administered every 4 weeks. In part II (cohort 4), participants who had previously received 9 doses of elebsiran and BRII-179 in a prospective study (BRII-179-835-001) were categorized as BRII-179 anti-HBs responders or nonresponders based on their peak hepatitis B surface antibody (anti-HBs) levels (≥10 IU l−1or <10 IU l−1, respectively) and subsequently received 13 doses of elebsiran 100 mg every 4 weeks plus 48 weekly doses of PEG-IFNα. Primary endpoints were HBsAg loss at the end of treatment (EOT) and 24 weeks post-EOT. In part I, at 24 weeks post-EOT, HBsAg loss was observed in 4 out of 19 (21.1%) participants receiving elebsiran 200 mg plus PEG-IFNα, 6 out of 18 (33.3%) participants receiving elebsiran 100 mg plus PEG-IFNα and 1 out of 18 (5.6%) participants receiving PEG-IFNα monotherapy. In part II, HBsAg loss was observed in 9 out of 31 (29.0%) participants at 24 weeks post-EOT, with a higher response among BRII-179 anti-HBs responders (8 out of 19 participants, 42.1%) compared with nonresponders (1 out of 12 participants, 8.3%). Elebsiran and PEG-IFNα combination therapy was generally safe and well tolerated. These results demonstrate an additive benefit of elebsiran when combined with PEG-IFNα in achieving sustained HBsAg loss. Furthermore, the increased HBsAg loss rate in BRII-179 anti-HBs responders suggests that BRII-179 may be a valuable tool for immunological profiling to optimize curative outcomes in patients with HBV infection. ClinicalTrials.gov registration:NCT05970289.

Hepatitis B Phase II trials
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Nature Medicine · Nov 06, 2025

A meta-analysis of albuminuria as a surrogate endpoint for kidney failure

Albuminuria is a central biomarker in chronic kidney disease (CKD), used for the detection and prognosis of the disease. In clinical trials assessing CKD progression, change in the level of albuminuria is a candidate surrogate endpoint for kidney failure. Evaluation of the validity of this surrogate endpoint across a diverse range of interventions and populations is required to support its further acceptance. Here, in an individual participant data analysis of 48 randomized controlled trials (studies) involving 85,681 participants, we assessed the association between treatment effects on 6-month urinary albumin:creatinine ratio (UACR) change and the established clinical endpoint of kidney failure or doubling of serum creatinine concentrations. Across all trials, each 30% reduction in the geometric mean of the UACR in the treatment group relative to the control group was associated with an average of 19% lower hazard for the clinical endpoint (95% Bayesian credible interval (BCI): 5−30%); median coefficient of determination (R2) = 0.66 (95% BCI: 0.06−0.98). There was no clear evidence that this association varied by CKD etiology. These results provide further support for use of albuminuria change as a surrogate endpoint in CKD clinical trials.

Chronic kidney disease Predictive markers
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Nature Medicine · Nov 05, 2025

A multimodal whole-slide foundation model for pathology

The field of computational pathology has been transformed with recent advances in foundation models that encode histopathology region-of-interests (ROIs) into versatile and transferable feature representations via self-supervised learning. However, translating these advancements to address complex clinical challenges at the patient and slide level remains constrained by limited clinical data in disease-specific cohorts, especially for rare clinical conditions. We propose Transformer-based pathology Image and Text Alignment Network (TITAN), a multimodal whole-slide foundation model pretrained using 335,645 whole-slide images via visual self-supervised learning and vision-language alignment with corresponding pathology reports and 423,122 synthetic captions generated from a multimodal generative AI copilot for pathology. Without any fine-tuning or requiring clinical labels, TITAN can extract general-purpose slide representations and generate pathology reports that generalize to resource-limited clinical scenarios such as rare disease retrieval and cancer prognosis. We evaluate TITAN on diverse clinical tasks and find that it outperforms both ROI and slide foundation models across machine learning settings, including linear probing, few-shot and zero-shot classification, rare cancer retrieval, cross-modal retrieval and pathology report generation.

Machine learning Pathology
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Nature Medicine · Nov 04, 2025

Cabotegravir and rilpivirine for treatment of HIV infection in Africa: week 96 results from the phase 3b randomized, open-label, noninferiority CARES trial

Evaluation of the durable efficacy and safety of long-acting injectable therapy for HIV is needed in African populations. In a multicenter, open-label phase 3b trial, 512 African adults with HIV-1, stable on first-line oral therapy, with screening plasma viral load (VL) &lt;50 copies ml−1 and without past virologic failure were randomized (1:1) to continue oral therapy or switch to cabotegravir (600 mg) and rilpivirine (900 mg) intramuscular injections every 8 weeks (optional 4-week oral lead-in). VL was monitored every 24 weeks. Here the primary outcome for our analysis up to 96 weeks was VL &lt;50 copies ml−1, using the Food and Drug Administration snapshot algorithm (noninferiority margin 10%) in the intention-to-treat exposed population. At 96 weeks, 247/255 (97%) in the long-acting group and 250/257 (97%) in the oral therapy group had VL &lt;50 copies ml−1 (difference −0.4%; 95% confidence interval −3.1% to 2.0%), demonstrating noninferiority. Adverse events of severity grade ≥3 occurred in 41/255 (16%) in the long-acting group and in 22/257 (9%) in the oral therapy group, mostly considered unrelated to the study drug; only one treatment-related adverse event in the long-acting group led to a decision to discontinue treatment (injection-site abscess). Cabotegravir and rilpivirine long-acting therapy produced durable virologic suppression, met the prespecified noninferiority endpoint compared with oral therapy and demonstrated an acceptable safety and tolerability profile. Long-acting therapy may be considered for use in African treatment programs. PACTR registration: 202104874490818. In this follow-up study presenting results at 96 weeks, cabotegravir and rilpivirine long-acting therapy remained noninferior to oral therapy, had acceptable safety and tolerability profiles, and resulted in durable virologic suppression, further supporting its consideration for African treatment programs.

Randomized controlled trials Translational research
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Nature Medicine · Nov 03, 2025

Physical activity as a modifiable risk factor in preclinical Alzheimer’s disease

Physical inactivity is a recognized modifiable risk factor for Alzheimer’s disease (AD), yet its relationship with progression of AD pathology in humans remains unclear, limiting the effective translation into prevention trials. Using pedometer-measured step counts in cognitively unimpaired older adults, we demonstrated an association between higher physical activity and slower cognitive and functional decline in individuals with elevated baseline amyloid. Importantly, this beneficial association was not related to lower amyloid burden at baseline or longitudinally. Instead, higher physical activity was associated with slower amyloid-related inferior temporal tau accumulation, which significantly mediated the association with slower cognitive decline. Dose–response analyses further revealed a curvilinear relationship, where the associations with slower tau accumulation and cognitive decline reached a plateau at a moderate level of physical activity (5,001–7,500 steps per day), potentially offering a more approachable goal for older sedentary individuals. Collectively, our findings support targeting physical inactivity as an intervention to modify the trajectory of preclinical AD in future prevention trials, and further suggest that preferentially enrolling sedentary individuals with elevated amyloid may maximize the likelihood of demonstrating a protective effect of physical activity on tau accumulation and cognitive and functional decline in early AD.

Alzheimer's disease Lifestyle modification Risk factors
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Nature Medicine · Oct 29, 2025

Data-driven subtypes of polycystic ovary syndrome and their association with clinical outcomes

Polycystic ovary syndrome (PCOS) is a common and heterogeneous endocrine disorder that affects 11%–13% of women worldwide, with profound implications for fertility and long-term metabolic health. Here we identify four reproducible subtypes—PCOS with hyperandrogen, with obesity, with high-sex hormone-binding globulin and with high-luteinizing hormone–anti-Müllerian hormone—through unsupervised clustering of 9 clinical variables in 11,908 affected women, validated across 5 international cohorts. Prospective 6.5-year follow-up and in vitro fertilization treatment data revealed distinct reproductive and metabolic trajectories: hyperandrogenic PCOS showed the highest risk of second trimester pregnancy loss and dyslipidemia incidence; PCOS with obesity exhibited the most severe metabolic complications, lowest live birth rates and highest PCOS remission rate; PCOS with high-sex hormone-binding globulin demonstrated favorable reproductive outcomes and the lowest incidence of diabetes and hypertension; and PCOS with high-luteinizing hormone–anti-Müllerian hormone had the greatest risk of ovarian hyperstimulation and the lowest PCOS remission rate. These findings advance understanding of PCOS heterogeneity and provide a framework for subtype-based risk stratification and personalized management.

Endocrine reproductive disorders Medical research
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Nature Medicine · Oct 27, 2025

A full life cycle biological clock based on routine clinical data and its impact in health and diseases

Aging research has primarily focused on adult aging clocks, leaving a critical gap in understanding a biological clock across the full life cycle, particularly during infancy and childhood. Here we introduce LifeClock, a biological clock model that predicts biological age across all life stages using routine electronic health records and laboratory test data. To enhance individualized predictions, we integrated virtual patient representations from 24,633,025 heterogeneous longitudinal clinical visits across 9,680,764 individuals and projected them into a latent space. Our approach leverages EHRFormer, a time-series transformer-based model, to analyze developmental and aging dynamics with high precision and develop accurate biological age clocks spanning infancy to old age. Our findings reveal distinct biological clock patterns across different life stages. The pediatric clock is strongly associated with children’s development and accurately predicts current and future risks of major pediatric diseases, including malnutrition, growth and developmental abnormalities. The adult clock is strongly associated with aging and accurately predicts current and future risks of major age-related diseases, such as diabetes, renal failure, stroke and cardiovascular diseases. This work therefore distinguishes pediatric development from adult aging, establishing a novel framework to advance precision health by leveraging routine clinical data across the entire lifespan.

Ageing Data mining Machine learning
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Nature Medicine · Oct 21, 2025

Cardiotropic AAV gene therapy for heart failure: a phase 1 trial

Innovative approaches for the treatment of heart failure are needed beyond conventional medical therapy to reverse ventricular dysfunction and modify the course of the disease. AB-1002, a chimeric cardiotropic adeno-associated viral vector that delivers constitutively active protein phosphatase 1 inhibitor 1 to cardiomyocytes, improves cardiac function in preclinical models of heart failure. Here we carried out a phase 1 study to evaluate the safety and feasibility of a single antegrade coronary artery infusion of AB-1002 in patients with nonischemic cardiomyopathy, New York Heart Association class III heart failure, and a left ventricular ejection fraction of 15–35%. Patients received 3.25 × 1013viral genomes (cohort 1,n= 6) or 1.08 × 1014viral genomes (cohort 2,n= 5). In total, nine men and two women were included in the study. No adverse events (AEs) or serious AEs were attributed by the investigators to the study treatment; most AEs were mild or moderate in severity. One death occurred, which was considered not to be related to the treatment with AB-1002. Self-limiting, mild, asymptomatic elevations in liver enzymes occurred, predominantly in cohort 2. The preliminary assessments of efficacy outcomes showed improvements in the New York Heart Association class and left ventricular ejection fraction in both cohorts and improvements in peak oxygen consumption and 6-min walk test performance in cohort 1. These results support the further assessment of AB-1002 in clinical trials. The ClinicalTrials.gov registration wasNCT04179643.

Cardiovascular diseases Physiology
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Nature Medicine · Oct 21, 2025

Safety and pharmacokinetics of SARS-CoV-2 DNA-encoded monoclonal antibodies in healthy adults: a phase 1 trial

Local intramuscular administration of synthetic plasmid DNA (pDNA) encoding monoclonal antibodies (mAb) offers an alternative to recombinant protein-based mAb delivery. In this phase 1 dose-escalation study, we evaluated the safety, tolerability and pharmacokinetics of a pDNA cocktail encoding AZD5396 and AZD8076, modified versions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing mAb cocktail tixagevimab/cilgavimab in healthy adults. Participants received up to four intramuscular doses of pDNA encoding both DNA-based mAbs (DMAbs), administered using CELLECTRA electroporation. The primary endpoints were safety and pharmacokinetics. All 44 participants received at least one dose; DMAbs were detected in 100% of evaluable participants (n= 39), with serum concentrations reaching a peak of 1.61 µg ml−1. Sustained expression was observed in all participants during the 72 weeks of follow-up. The study product was well tolerated, with no product-related serious adverse events reported. Exploratory analyses demonstrated binding to multiple SARS-CoV-2 Spike protein variants and neutralizing activity in a standard pseudovirus assay. No antidrug antibodies were detected across approximately 1,000 serum samples using validated tiered assays. To our knowledge, these data represent the first-in-human proof-of-concept that synthetic pDNA DMAb technology permits the durable in vivo production of a functional mAb cocktail. This study further underscores the collective importance of synthetic design, formulation and delivery to achieve biologically relevant expression of gene-encoded biologics. DMAb delivery may represent a long-acting, scalable, cold-chain-independent platform against a wide range of diseases that can be targeted with mAbs and their derivatives. ClinicalTrials.gov registration:NCT05293249

Nucleic-acid therapeutics Translational research
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Nature Medicine · Oct 20, 2025

Myelin injury precedes axonal injury and symptomatic onset in multiple sclerosis

The timing of the biological onset of multiple sclerosis (MS) is unclear. We used high-throughput discovery proteomics and samples from presymptomatic patients with MS and matched healthy controls to define the biological neurological onset and characterize the mechanisms involved. Remarkably, evidence of myelin injury was seen ~7 years before the symptomatic onset and preceded evidence of axonal injury by ~1 year. By contrast, astrocyte involvement became evident only at clinical onset. Numerous changes in the serum proteome indicate the involvement of interleukin 3 and nuclear factor kappa B pathways during the presymptomatic stage. Furthermore, people with MS with a previously reported distinct autoantibody signature showed increased immune cell activity compared to those without. We propose a protein biomarker panel that may help distinguish presymptomatic patients with MS from healthy controls, pending validation in future studies. Our findings can help understand the pathophysiology of MS as well as the cascade of central nervous system injury and might facilitate early detection of MS in high-risk people.

Diagnostic markers Multiple sclerosis
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Nature Medicine · Oct 20, 2025

Plasma proteome adaptations during feminizing gender-affirming hormone therapy

Sex differences manifest in various traits, as well as in the risk of cardiovascular, metabolic and immunological conditions. Despite the clear physical changes induced by gender-affirming hormone therapy (GAHT), little is known about how it affects underlying physiological and biochemical processes. Here we examined plasma proteome changes over 6 months of feminizing GAHT in 40 transgender individuals treated with estradiol plus one of two antiandrogens: cyproterone acetate or spironolactone. Testosterone levels dropped markedly in the cyproterone group, but less so in those receiving spironolactone. Among 5,279 total proteins measured, feminizing GAHT changed the levels of 245 and 91, in the cyproterone and spironolactone groups, respectively, with most (>95%) showing a decrease. Proteins associated with male spermatogenesis showed a marked decrease in the cyproterone group, attributable specifically to loss of testosterone. Changes in body fat percentage and breast volume following GAHT were also reflected in the plasma proteome, including an increase in leptin expression. We show that feminizing GAHT remodels the proteome toward a cis-female profile, altering 36 (cyproterone) and 22 (spironolactone) of the top 100 sex-associated proteins in UK Biobank adult data. Moreover, 43% of cyproterone-affected proteins overlapped with those altered by menopausal hormone therapy in cis women, showing the same directional changes, with notable exceptions including CXCL13 and NOS3. Feminizing GAHT skewed the protein profile toward that linked to asthma and autoimmunity, while GAHT with cyproterone specifically skewed it away from an atherosclerosis-associated profile, suggesting a protective effect. These results reveal that feminizing GAHT reshapes the plasma proteome in a hormone-dependent manner, with implications for reproductive capacity, immune regulation and long-term health outcomes.

Biomarkers Cytokines Endocrinology Proteomics
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Nature Medicine · Oct 20, 2025

Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the randomized phase 2/3 DYNAMIC-III trial

Adjuvant chemotherapy in stage III colon cancer provides uncertain benefit at the individual level. Circulating tumor DNA (ctDNA) may help refine risk-adjusted treatment selection. In this multicenter, randomized, phase 2/3 trial, patients with stage III colon cancer underwent ctDNA testing 5–6 weeks after surgery and were assigned (1:1) to ctDNA-guided or standard management. In the ctDNA-guided arm, patients negative for ctDNA received de-escalated therapy, whereas ctDNA-positive patients received escalated therapy. Clinicians prespecified the standard regimen. Primary endpoints were 3-year recurrence-free survival (RFS) for ctDNA-negative patients and 2-year RFS for ctDNA-positive patients. Secondary endpoints included treatment-related hospitalization and ctDNA clearance. Among 968 evaluable patients, 702 (72.5%) were ctDNA negative. With a median follow-up of 47 months, ctDNA-negative patients experienced significantly fewer recurrences than ctDNA-positive patients (3-year RFS 87% versus 49%; P &lt; 0.001). In ctDNA-negative patients, de-escalation reduced oxaliplatin use (34.8% versus 88.6%) and hospitalizations (8.5% versus 13.2%) but yielded slightly lower RFS than standard management (85.3% versus 88.1%), not meeting the non-inferiority margin. In ctDNA-positive patients, higher ctDNA burden correlated with recurrence risk (3-year RFS 77% to 23% across quartiles; P &lt; 0.001). Escalated therapy did not improve outcomes over standard management (2-year RFS 51% versus 61%). There was no unexpected toxicity. Persistent ctDNA after treatment predicted markedly worse prognosis (3-year RFS 14% versus 79%). ctDNA is validated as a strong prognostic classifier. ctDNA-guided de-escalation reduced oxaliplatin exposure and adverse events with outcomes approaching standard of care, whereas exploratory chemotherapy intensification conferred no RFS benefit, suggesting a need for novel strategies in ctDNA-positive disease. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617001566325 . As presented at the ESMO Congress 2025: Results of the phase 2/3 AGITG DYNAMIC-III trial show that de-escalated chemotherapy based on ctDNA-negative status in patients with stage III colon cancer did not meet non-inferiority for 3-year recurrence-free survival when compared to standard of care, although it enables better informed treatment decisions.

Colon cancer Prognostic markers
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Nature Medicine · Oct 19, 2025

YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial

Constitutive YAP activation resulting from dysregulated Hippo signaling drives tumor progression in mesothelioma and other cancers. VT3989, a first-in-class potent oral TEAD palmitoylation inhibitor, disrupts YAP transcriptional activity. Here we report the first-in-human phase 1/2 trial findings evaluating VT3989 in refractory solid tumors with a focus on mesothelioma. This study is ongoing, and we report results from the dose escalation and non-prespecified interim efficacy results of the expansion cohorts for which recruitment is ongoing. Dose escalation (n= 85) and expansion (n= 87) cohorts included 172 patients (135 mesothelioma). VT3989 exhibited a favorable safety profile with mostly grade 1–2 toxicities, including increased urine albumin:creatinine ratio (UACR), proteinuria, peripheral edema and fatigue. Proteinuria was reversible with dose adjustment and did not result in renal impairment. The overall response rate (ORR) was 26% in 47 patients with mesothelioma treated at clinically optimized doses, whereas the ORR was 32% (disease control rate 86%; median progression-free survival 10 months) in 22 patients with mesothelioma when clinically optimized doses and UACR thresholds were incorporated. These data provide the first early clinical proof of concept for effectively drugging the Hippo−YAP−TEAD pathway. VT3989 was recently awarded orphan drug designation and fast-track designation for the treatment of mesothelioma by the US Food and Drug Administration (FDA). ClinicalTrials.gov Identifier:NCT04665206.

Drug development Mesothelioma
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Nature Medicine · Oct 18, 2025

Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial

Dual inhibition of T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) may enhance antitumor immunity in advanced gastroesophageal cancers. Here we report the EDGE-Gastric study, an ongoing, multicenter, international, phase 2 study with three cohorts, one in the first-line setting (cohort A) and two in the second-line or greater setting (cohorts B and C). Cohort A comprises four arms: two nonrandomized (A1 and A2) and two randomized (A3 and A4). In arm A1, presented here, dual blockade of TIGIT and PD-1 with domvanalimab (Fc-silent anti-TIGIT) and zimberelimab (anti-PD-1) plus oxaliplatin, leucovorin, fluorouracil (FOLFOX) was evaluated in patients with previously untreated advancedHER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Among 41 treated patients, the confirmed objective response rate was 59% (90% confidence interval (CI) 44.5–71.6%), median progression-free survival was 12.9 months (90% CI 9.8–14.6 months) and median overall survival was 26.7 months (90% CI 18.4 months to not estimable (NE)). In patients with tumor area positivity ≥1% (PD-L1 positive) and tumor area positivity ≥5% (PD-L1 high), respectively, the objective response rate was 62% (90% CI 45.1–77.1%) and 69% (90% CI 45.2–86.8%), median progression-free survival was 13.2 months (90% CI 11.3–15.2 months) and 14.5 months (90% CI 11.3 months–NE), and median overall survival was 26.7 months (90% CI 19.5 months–NE) and not reached (90% CI 17.4 months–NE). Immune-related adverse events were reported in 27% of patients; the safety profile was consistent with that reported for anti-PD-1 plus platinum-based chemotherapy. Dual TIGIT and PD-1 blockade with domvanalimab and zimberelimab plus chemotherapy demonstrated encouraging efficacy, and the regimen is being evaluated in the phase 3 STAR-221 trial. ClinicalTrials.gov identifier:NCT05329766.

Cancer Cancer therapy Gastrointestinal cancer
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Nature Medicine · Oct 18, 2025

Adjuvant nivolumab and relatlimab in stage III/IV melanoma: the randomized phase 3 RELATIVITY-098 trial

Based on RELATIVITY-047, nivolumab plus relatlimab is approved for advanced melanoma. Here, to address a current unmet need for more efficacious adjuvant regimens for completely resected melanoma, the phase 3, double-blind RELATIVITY-098 trial compared adjuvant nivolumab plus relatlimab to nivolumab after complete resection of stage III/IV melanoma. Patients were randomized 1:1 to receive nivolumab 480 mg plus relatlimab 160 mg (n= 547) or nivolumab 480 mg (n= 546) intravenously every 4 weeks for ≤1 year; safety populations totaled 543 and 545 patients, respectively. The primary endpoint was recurrence-free survival (RFS), and the key secondary was overall survival; translational endpoints were exploratory. There was no difference in RFS for nivolumab plus relatlimab versus nivolumab (hazard ratio = 1.01; 95% confidence interval: 0.83–1.22;P= 0.928); therefore, overall survival was not tested. Translational data across trials showed lower circulating LAG-3+T cells in the adjuvant setting (RELATIVITY-098) versus advanced melanoma (RELATIVITY-047), where LAG-3+T cells were enriched in tumor versus blood. The absence of macroscopic tumor and reduced peripheral LAG-3+T cells may explain the lack of added benefit of nivolumab plus relatlimab over nivolumab in resected versus metastatic melanoma. ClinicalTrials.gov identifier:NCT05002569.

Melanoma Randomized controlled trials Translational research
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Nature Medicine · Oct 18, 2025

Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial

Perioperative treatment strategies for HER2-positive esophagogastric adenocarcinoma remain suboptimal. Here in the open-label, phase 2 IKF/AIO PHERFLOT trial, we evaluated the safety and efficacy of adding pembrolizumab and trastuzumab to FLOT chemotherapy in patients with localized HER2-positive esophagogastric adenocarcinoma. The primary endpoints are the pathological complete response rate and the 2-year disease-free survival rate. Secondary endpoints include the R0 resection rate, feasibility and safety. Exploratory endpoints include clinical efficacy in molecularly defined subgroups. In this prespecified interim analysis, given the limited median follow-up period of 14.8 months, only one of the primary endpoints, the pathological complete response rate, and selected secondary endpoints, including the R0 resection rate, feasibility and safety, are reported here. Among 31 enrolled patients, 30 proceeded to R0 resection, and one patient declined surgery without disease progression. The combination regimen resulted in grade ≥3 treatment-related serious adverse events in 48.4% of patients (15 out of 31) aligning with established toxicity profiles of the respective agents and no treatment-related deaths. After four cycles of therapy, the pathological complete response rate was 48.4% (95% confidence interval 30.2–66.9; 15 out of 31) in the intention-to-treat population, and the subtotal regression rate (TRG1b according to Becker classification) was 19.4% (95% confidence interval 7.5–37.5; 6 out of 31), resulting in a major pathological response rate of 67.7% (95% confidence interval 48.6–83.3; 21 out of 31). Responses tended to be enriched in tumors with strong HER2 expression (immunohistochemistry 3+), high PD-L1 combined positive scores and lower T stage, but were also observed in substantial fractions of HER2 immunohistochemistry 2+/ISH+, T3 or T4 and combined positive scores <10 tumors. These findings support the feasibility and antitumor activity of perioperative chemoimmunotherapy targeting HER2 and PD-1 and warrant further validation in randomized trials. ClinicalTrials.gov registration:NCT05504720.

Cancer immunotherapy Chemotherapy Gastric cancer Oesophageal cancer Targeted therapies
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Nature Medicine · Oct 16, 2025

MRI-based multi-organ clocks for healthy aging and disease assessment

Biological aging clocks across organ systems and tissues have advanced understanding of human aging and disease. In this study, we expand this framework to develop seven magnetic resonance imaging-based multi-organ biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney and pancreas. Using data from 313,645 individuals curated by the MULTI Consortium, we link the seven MRIBAGs to 2,923 plasma proteins, 327 metabolites and 6,477,810 common genetic variants. Genome-wide associations identify 53 MRIBAG−locus pairs (P< 5 × 10−8). Genetic correlation and Mendelian randomization analyses support organ-specific and cross-organ interconnection, including 24 non-MRI biological aging clocks and 525 disease endpoints. Through functional gene mapping and Bayesian co-localization multi-omics evidence, we prioritize nine druggable genes as targets for future anti-aging treatments. Furthermore, the seven MRIBAGs are linked to future risk of systemic disease endpoints (for example, diabetes mellitus) and all-cause mortality. Finally, participants with more youthful versus more aged brain profiles exhibited distinct cognitive decline trajectories over 240 weeks of treatment with the Alzheimer’s disease drug solanezumab, although this heterogeneity cannot be fully attributed to the drug. In summary, we developed seven MRIBAGs that enhance the existing multi-organ biological aging framework, and we demonstrate their clinical potential to advance aging research.

Data mining Genetics research Predictive markers
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Nature Medicine · Oct 16, 2025

Genetic architecture and phenotypic diversity of oocyte and early embryo competence defects in female infertility

Oocyte and early embryo competence defects (OECD) represent a recently recognized cause of female infertility with the application of assisted reproductive technology, characterized by impaired oocyte or early embryo development. To investigate the genetic landscape and subtypes of OECD, we performed whole-exome sequencing on 2,140 patients, classifying them into six distinct subtypes. We identified 183 pathogenic/likely pathogenic variants across 28 established genes. Notably, distinct genetic profiles and diagnostic rates emerged across subtypes, with a rate of 53% in the Empty Follicle subtype. Additionally, we identified and validated two potentially causative genes,MLH3andCENPH. Gene burden analysis, using 2,424 fertile controls, suggested nine potential previously unreported associated genes and offered biological insights into the underlying pathogenic mechanisms of OECD. Collectively, these genetic findings accounted for 12.8–23.1% of OECD cases. This study delineates the genetic architecture of OECD, offering insights that may inform the development of diagnostic genetic screenings and provide a reference for standardized subtyping of patients with OECD.

Disease genetics Infertility
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Nature Medicine · Oct 16, 2025

Macrovascular tumor infiltration and circulating tumor cell cluster dynamics in patients with cancer approaching the end of life

End-of-life events related to carcinoma lethality are poorly characterized. Herein we conducted an observational, prospective, case–control study enrolling 21 patients with solid tumors and 10 patients without known malignancy, complemented by a retrospective validation cohort of 1,250 patients with cancer. In our prospective cohort, we observed spikes in circulating tumor cell (CTC) counts, particularly clusters, immediately before death (P< 0.0001), as well as pathological evidence of macrovascular infiltration and large-vessel occlusion obtained through rapid autopsy. In the validation cohort, radiological evidence of macrovascular infiltration emerged as the strongest predictor of poor survival—independent of metastasis—in treatment-homogeneous patients with colorectal, lung, ovarian, hepatocellular or pancreatic cancer (hazard ratios = 4.0–22.4). Collectively, these findings suggest that macrovascular infiltration and spikes in CTC clusters with consequent vascular failure could be pivotal end-of-life events associated with cancer lethality, providing a rationale for future trials aimed at curbing infiltration into large vessels.

Cancer
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Nature Medicine · Oct 16, 2025

Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk

Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF)MC4Rmutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoFMC4Rvariants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction.

Endocrine system and metabolic diseases Genetic association study Metabolism
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Nature Medicine · Oct 16, 2025

Characterizing the physiology of circulatory arrest in humans

The dying process from circulatory arrest is an underexplored domain in humans and has transdisciplinary pertinence. Here we conducted a prospective, observational cohort study of the dying process in 39 adults, with a multimodal assessment of cerebrovascular and cardiovascular physiology. We found that cerebral blood velocities and brain tissue oxygen tensions ceased before systemic hemodynamics. The brain exhibited diffusion limitation of oxygen extraction during the dying process compared with extracranial tissues. Anterior and posterior brain circulations had differences in timing of cessation of circulation and physiologic responses during the dying process. Blood-based neurologic biomarkers from the brain did not change during the associated ischemia related to the dying process. Heart pathology was associated with the length of the dying process. This study provides proof-of-concept of an in vivo human model to comprehensively investigate severe cerebral ischemia and the human dying process. ClinicalTrials.gov registration:NCT06130033.

Blood flow Brain injuries Diagnostic markers Experimental models of disease Translational research
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Nature Medicine · Oct 15, 2025

Budigalimab, an anti-PD-1 inhibitor, for people living with HIV-1: a randomized, placebo-controlled phase 1b study

Chronic human immunodeficiency virus type 1 (HIV-1) disease results in immune exhaustion and dampened T cell responses, and programmed cell death 1 (PD-1) inhibitors offer a potential approach to enable viral control without antiretroviral therapy (ART) through reversal of these effects. Budigalimab is an investigational humanized anti–PD-1 monoclonal antibody. Multiple intravenous (IV) low doses of budigalimab (Stage 1: 2 mgn= 10, 10 mgn= 10, placebon= 5, two doses every 4 weeks; Stage 2: 10 mgn= 11, placebon= 5, four doses every 2 weeks (Q2W)) were assessed in people living with HIV (PLWH;n= 41) in a randomized, double-blind, multicenter, placebo-controlled phase 1 study with an analytical treatment interruption (ATI) to identify an efficacious regimen with a favorable safety profile in PLWH. The primary endpoints were safety, tolerability and pharmacokinetics. Demographics and baseline characteristics were balanced across treatment groups, except for sex, which was mostly male. All participants identified as cisgender. Budigalimab was well tolerated for up to 44 weeks, with 29 of 41 participants experiencing an adverse event (AE), including 2 participants who each experienced one grade 1 reversible immune-related AE (thyroiditis, hyperthyroidism). Three grade 3 AEs were reported by two participants and one serious AE by one participant; none were deemed related to treatment. IV budigalimab 10 mg Q2W resulted in a slight accumulation of drug in serum, with concentrations remaining above the estimated concentration required for near-complete (>95%) PD-1 receptor saturation on CD8+T cells for ~10 weeks in peripheral blood. In an exploratory efficacy analysis of a 12-week ATI initiated with the first of four 10 mg Q2W doses, 6 of 11 participants experienced a delayed rebound with a relatively low viral peak and/or off-ART viral control (<200 copies ml−1) for ≥6 weeks during ATI, with 2 sustaining ART-free viral control to study end (204−252 days). The study achieved prespecified endpoints, supporting further evaluation of budigalimab in PLWH in a phase 2 study. ClinicalTrials.gov identifier:NCT04223804.

Drug development HIV infections Immunotherapy Outcomes research
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Nature Medicine · Oct 09, 2025

Feasibility, acceptability and clinical outcomes of the BabyScreen+ genomic newborn screening study

Incorporating genomic sequencing into newborn screening will dramatically increase the number of detectable conditions but evidence is needed to guide policy. The prospective BabyScreen+ cohort study screened 1,000 newborns from the state of Victoria, Australia for variants in 605 genes associated with early-onset, severe, treatable conditions using whole-genome sequencing performed on dried blood spot cards. Sixteen infants (1.6%) were identified as having high-chance results. Of these, only one was detected by standard newborn screening. Average time to genomic newborn result was 13 days. Clinical impact ranged from instituting preventative measures or surveillance to active management, including transplantation. Twenty relatives received a diagnosis following cascade testing. Median parental decisional regret was low (median 0, interquartile range 0–10); >99% of participants thought genomic newborn screening should be available to all parents. Our study demonstrates the feasibility of clinically accredited genomic newborn screening, using a scalable model that is highly acceptable to parents. Future research is needed to address issues of scalability and equity.

Paediatrics Population screening
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Nature Medicine · Oct 08, 2025

A combination typhoid and non-typhoidalSalmonellapolysaccharide conjugate vaccine in healthy adults: a randomized, placebo-controlled phase 1 trial

In sub-Saharan Africa, typhoidal and non-typhoidalSalmonella(NTS) are leading causes of invasive disease among young children. TrivalentSalmonellaconjugate vaccine (TSCV) consists of Vi capsule polysaccharide conjugated to tetanus toxoid and core-plus-O-polysaccharides from the two most prevalent invasive NTS serovars conjugated to flagellin subunits. We conducted a first-in-human, randomized, placebo-controlled, phase 1 trial evaluating the safety and immunogenicity of TSCV. A total of 22 healthy adults aged 18−45 years were randomly allocated to 6.25-µg TSCV (n= 8), 12.5-µg TSCV (n= 10) or placebo (n= 4). The primary objective was the assessment of safety. The co-primary immunogenicity objective was the serum IgG response against the three vaccine polysaccharides and two flagellin carrier proteins. Here we show that TSCV was safe and well tolerated, meeting the prespecified safety endpoints, with the most common solicited symptom being short-lived injection site pain. For each of the three polysaccharides, immune responses, as demonstrated by ≥4-fold increases over baseline, were observed among all (100%) vaccinees, and no responses were elicited in the placebo group, meeting the prespecified immunogenicity endpoints. The two flagellin components elicited 88% (7/8) and 100% (8/8) responses among 6.25-µg and 12.5-µg TSCV recipients and no placebo recipients. These data warrant further evaluation of TSCV for protection against invasiveSalmonelladisease. ClinicalTrial.gov identifier:NCT03981952.

Bacterial infection Conjugate vaccines
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Nature Medicine · Oct 08, 2025

Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial

In DESTINY-Breast04 ( NCT03734029 ), trastuzumab deruxtecan (T-DXd) significantly improved overall survival (OS) and progression-free survival compared with treatment of physician’s choice of chemotherapy (TPC) for patients with human epidermal growth factor receptor 2-low (HER2-low) (immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization-negative) metastatic breast cancer. After an extended median follow-up of 32.0 months, median OS in the overall cohort was 22.9 months for T-DXd and 16.8 months for TPC (hazard ratio 0.69; 95% confidence interval 0.55–0.86). For the hormone receptor-positive cohort, median OS was 23.9 and 17.6 months for T-DXd and TPC, respectively (hazard ratio 0.69; 95% confidence interval 0.55–0.87). Median OS also favored T-DXd in exploratory analyses of hormone receptor-negative, estrogen receptor IHC 1%–10% and estrogen receptor IHC &gt;10% cohorts. The overall safety profile of T-DXd was acceptable and generally manageable. Results confirm T-DXd as standard of care after prior chemotherapy in patients with HER2-low metastatic breast cancer. ClinicalTrials.gov identifier: NCT03734029 . This prespecified updated survival and exploratory subgroup efficacy analysis of the phase 3 DESTINY-Breast04 trial shows that trastuzumab deruxtecan treatment in patients with HER2-low metastatic breast cancer leads to continuous survival benefit irrespective of estrogen receptor or hormone receptor status.

Breast cancer Targeted therapies
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Nature Medicine · Oct 08, 2025

H5N1 influenza virus stability and transmission risk in raw milk and cheese

Highly pathogenic avian influenza H5N1 viruses have recently spread to dairy cattle, with high levels of virus detected in milk from affected animals, raising concern about the risk posed by unpasteurized dairy products consumed by humans. Here we evaluated H5N1 virus persistence in raw-milk cheeses (n= 3 per condition) made with milk acidified to pH 6.6, 5.8 and 5.0 before cheese making and validated our findings in raw-milk cheeses (n= 4) inadvertently produced with naturally contaminated raw milk. The pH values tested (6.6, 5.8 and 5.0) reflect the pH range encountered in raw-milk cheeses at the marketplace. We observed pH-dependent virus survival, with infectious virus persisting through the cheese-making process and up to 120 days of aging in cheeses made with raw milk at pH levels of 6.6 and 5.8, whereas at pH 5.0, the virus did not survive the cheese-making process. Notably, while ferrets (Mustela furo) fed H5N1 virus-contaminated raw milk (n= 4) became infected, those fed raw-milk cheese (n= 4) or cheese suspension (n= 4) did not. These results demonstrate that the H5N1 virus can remain infectious for extended periods in raw-milk cheeses under specific conditions, underscoring the potential public health risks associated with consuming raw-milk cheese produced from contaminated milk and highlighting the need for additional mitigation measures in cheese production to prevent human exposure to the virus.

Influenza virus Policy and public health in microbiology
N
Nature Medicine · Oct 08, 2025

Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial

Patients with cutaneous squamous cell carcinoma (CSCC) frequently require mutilating surgery and adjuvant radiotherapy (RT). CSCC has been demonstrated to be highly responsive to neoadjuvant anti-PD-1 immune-checkpoint blockade (ICB). However, efficacy and safety of neoadjuvant anti-PD-1 combined with anti-CTLA-4 are lacking. In the MATISSE trial, the primary objective was met to investigate the pathological response rate on neoadjuvant nivolumab (NIVO) and nivolumab plus ipilimumab (NIVO + IPI) at the time of standard of care (SOC: surgery ± RT), defined as the proportion of remaining viable tumor cells in the surgical specimen. Fifty patients with stage I–IVa resectable CSCC were treated with NIVO (weeks 0 and 2) or NIVO (weeks 0 and 2) plus low-dose IPI (week 0) before SOC in week 4. The median follow-up was 31 months. Forty patients underwent SOC; 9 of 20 (45%) patients who received NIVO and 10 of 20 (50%) patients who received NIVO + IPI reached a major pathological response (MPR) and 2 of 20 (10%) patients with NIVO and 6 of 20 (30%) with NIVO + IPI reached a partial pathological response (PPR), resulting in pathological response rates of 55% and 80%, respectively. MPR or PPR was accompanied by 2-year disease-specific survival (DSS) of 100%. ICB was safe with 12% (NIVO) and 8% (NIVO + IPI), grade 3, immune-related toxicity without surgical delays. Ten patients opted to decline surgery and RT, of whom nine reached durable organ preservation and a clinical complete remission on two ICB infusions alone, accompanied by a 2-year DSS of 100% and favorable health-related quality of life. Early changes in [18F]fluorodeoxyglucose positron emission tomography/computed tomography’s total lesion glycolysis can safely select patients for response-guided treatment de-escalation in future trials. The ClinicalTrials.gov identifier is: NCT04620200 . Results from the randomized, noncomparative, phase 2 MATISSE trial show that ultra-short neoadjuvant therapy with ipilimumab and nivolumab can prevent surgery and radiotherapy in patients with resectable cutaneous squamous cell carcinoma, with an early decrease in total lesion glycolysis by [18F]FDG-PET/CT associated with response.

Immunotherapy Predictive markers Squamous cell carcinoma
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Nature Medicine · Oct 07, 2025

Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial

Inhibition of poly(ADP-ribose) polymerase (PARP) after relapse on hormone therapy is well established for patients with prostate cancer with homologous recombination repair (HRR) gene alterations, but resistance often develops. We hypothesized that PARP inhibition within 6 months of starting androgen deprivation therapy for metastatic castration-sensitive prostate cancer (mCSPC) could be effective and improve radiographic progression-free survival when added to standard-of-care treatments. The double-blind AMPLITUDE trial evaluated combining niraparib, a potent and specific PARP inhibitor, with abiraterone acetate and prednisone (AAP) versus placebo and AAP in mCSPC with HRR gene alterations. Patients (n= 696) were randomized in a 1:1 ratio (348 per group). Median age was 68 years; 56% hadBRCA1orBRCA2alterations; 78% had high-volume metastases; and 16% had received docetaxel. The primary endpoint was met, with a significant improvement in radiographic progression-free survival observed first in the BRCA subgroup (median not reached at the time of analysis for the niraparib and AAP group versus 26 months for the AAP group; hazard ratio = 0.52; 95% confidence interval: 0.37–0.72;P< 0.0001) and then in the intention-to-treat population (hazard ratio = 0.63; 95% confidence interval: 0.49–0.80;P= 0.0001). The data for overall survival, a key secondary endpoint, are immature (193/389 events) but favor niraparib (hazard ratio = 0.79 (95% confidence interval: 0.59–1.04); BRCA subgroup: hazard ratio = 0.75 (95% confidence interval: 0.51–1.11)). Incidence of grade 3 or 4 adverse events was 75% in the niraparib and AAP group and 59% in the AAP group; most frequent in the niraparib and AAP group were anemia (29%), with 25% of patients requiring a blood transfusion, and hypertension (27%). There were 14 treatment-emergent adverse events leading to deaths in the niraparib group and seven in the placebo group. Combining niraparib with AAP significantly improved radiographic progression-free survival in patients with mCSPC harboringBRCA1/BRCA2or other HRR gene alterations, suggesting clinical benefit with this combination for these patients. ClinicalTrials.gov identifier:NCT04497844.

Drug development Prostate cancer
N
Nature Medicine · Oct 07, 2025

Impact of the indigenous rotavirus vaccine Rotavac in the Universal Immunization Program in India during 2016–2020

In 2016, India introduced Rotavac (G9P[11]), an indigenous oral rotavirus vaccine administered at 6, 10 and 14 weeks of age through the Universal Immunization Program. Evaluating its effectiveness under routine programmatic conditions is critical, given the variable performance of rotavirus vaccines in low- and middle-income countries. Here we assessed Rotavac’s real-world effectiveness and impact across 31 hospitals in 9 states between 2016 and 2020 using a test-negative case–control design. Overall, 24,624 children were enrolled in surveillance (62% male and 38% female). Of 8,372 children aged 6–59 months eligible for effectiveness analysis (1,790 rotavirus-positive cases and 5,437 rotavirus-negative controls), 6,646 received 3 doses and 581 were unvaccinated. The adjusted vaccine effectiveness of 3 doses against severe rotavirus gastroenteritis was 54% (95% confidence interval (CI) 45% to 62%), with 1,574 vaccinated cases versus 5,072 vaccinated controls. Among children aged 6–23 months (1,486 vaccinated cases and 4,595 vaccinated controls), genotype-specific adjusted vaccine effectiveness was 51% (95% CI 36% to 62%) for G3P[8], 81% (95% CI 73% to 87%) for G1P[8] and 64% (95% CI 21% to 83%) for G1P[6]. Following vaccine introduction, rotavirus positivity among hospitalized children declined from 40% to 20%. These findings confirm that Rotavac provides substantial protection against severe rotavirus disease, including nonvaccine strains, and performs comparably to internationally licensed vaccines in similar settings.

Gastroenteritis Research data
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Nature Medicine · Oct 06, 2025

Varicella-zoster virus reactivation and the risk of dementia

Varicella-zoster virus (VZV) is a neurotropic virus that establishes lifelong latency in humans. VZV reactivation is associated with a wide range of symptoms, including herpes zoster (HZ; also known as shingles), and has been implicated in the development of dementia, although to an unknown extent. Here we present a large-scale longitudinal analysis of health records from more than 100 million individuals in the United States that demonstrates a consistent relationship of VZV reactivation with dementia after controlling for nearly 400 measured characteristics (covering demographics, socioeconomic factors, comorbidities, medications, proxies for healthcare-seeking behavior, shifts in clinical guidelines and completeness of records). We found that recurrent HZ was associated with an increased risk of dementia compared to a single HZ episode. Additionally, exposure to HZ vaccines was associated with a reduced risk of dementia compared to the control 23-valent pneumococcal polysaccharide vaccine. Furthermore, the reduced risk of dementia after administration of the live-attenuated zoster vaccine waned over time and was highly correlated with a waning of the vaccine-mediated protection against HZ. The dementia risk reduction at 3 and 5 years postexposure was also stronger in individuals who received multiple as opposed to only one dose of the recombinant HZ vaccine and those at greater risk of HZ. Our findings strongly implicate VZV reactivation as a modifiable risk factor for dementia.

Neurological disorders Risk factors
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Nature Medicine · Oct 06, 2025

Global risk of selection and spread ofPlasmodium falciparumhistidine-rich protein 2 and 3 gene deletions

Since their first detection in 2010, Plasmodium falciparum malaria parasites lacking the P. falciparum histidine-rich protein 2 gene (pfhrp2) have been observed in 40 of 47 surveyed countries, as documented by the World Health Organization. These genetic deletions reduce detection by the most widely used rapid diagnostic tests, prompting three countries to switch to alternative diagnostics. However, manufacturing of alternative rapid diagnostic tests has not been scaled up and there are no World Health Organization-prequalified combination tests that use P. falciparum Plasmodium lactate dehydrogenase. The continuing spread of pfhrp2 and/or pfhrp3 (pfhrp2/3) deletions threatens malaria control, creating an emerging public health crisis. Here we use mathematical modeling informed by current pfhrp2/3 deletion prevalence and a literature review to assess the global risk of pfhrp2/3 deletions. We identify ten priority countries for surveillance and predict that the primary spread in Africa will move southward from the Horn of Africa through East Africa within 20 years. Despite variation in modeled timelines due to uncertainty in model parameters, four countries yet to switch rapid diagnostic tests are consistently classified as high risk under a range of model assumptions. This updated model offers refined predictions to guide pfhrp2/3 policy and prioritize future surveillance efforts and innovation. A modeling approach to assess the global risk of Plasmodium falciparum histidine-rich protein 2 and 3 gene deletions identifies ten priority African countries for surveillance and could inform malaria control policies.

Developing world Malaria
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Nature Medicine · Oct 06, 2025

Lifetime Benefits of Comprehensive Medical Therapy in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

Sodium glucose co-transporter-2 inhibitors (SGLT2i) and the non-steroidal mineralocorticoid receptor antagonist (nsMRA) finerenone have each been shown to individually improve heart failure events among patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Moreover, the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan has been shown to improve outcomes in patients with HFmrEF/HFpEF with a left ventricular ejection fraction (LVEF) below normal (<60%). However, the expected benefits of the combined use of these agents with long-term administration are not well defined. In this cross-trial analysis of DELIVER, FINEARTS-HF, and PARAGON-HF, combined use of SGLT2i and nsMRA therapies was estimated to reduce the risk of cardiovascular death or first worsening HF event by 31% in the overall population (HR 0.69; 95% CI 0.59 to 0.81), while combined use of SGLT2i, nsMRA, and ARNI therapies was estimated to reduce risk by 39% in patients with HFmrEF/HFpEF and an LVEF<60% (HR 0.61; 95% CI 0.48 to 0.77). With long-term use, combined SGLT2i and nsMRA therapies in a 65-year-old patient with HFmrEF/HFpEF, or combined SGLT2i, nsMRA, and ARNI therapies in a 65-year-old patient with an LVEF<60%, were projected to afford 3.6 (2.0 to 5.2) or 4.9 (2.6 to 7.3) additional years free from cardiovascular death or a HF event, respectively. Combined therapy was estimated to result in meaningful gains in event-free survival across a broad age range from 55 to 85 years. Among patients with HFmrEF and HFpEF, the potential aggregated long-term treatment effects of early combination medical therapy with SGLT2i and nsMRA (and ARNI in selected individuals) are projected to be substantial.

Heart failure Randomized controlled trials
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Nature Medicine · Oct 06, 2025

Sonelokimab, an IL-17A/IL-17F-inhibiting nanobody for active psoriatic arthritis: a randomized, placebo-controlled phase 2 trial

Psoriatic arthritis (PsA) is a progressive, multidomain and interleukin-17 (IL-17)-linked disease that results in substantial quality-of-life deficits. Thereby, we conducted a phase 2 randomized, double-blind, placebo (PBO)-controlled trial of sonelokimab (SLK), a nanobody that binds with a similarly high affinity to IL-17A and IL-17F, inhibiting all dimers. Overall, 207 patients with active PsA were randomized to SLK 120-mg or 60-mg every 4 weeks (Q4W; both with induction (WI)), or to 60-mg Q4W with no induction, PBO or adalimumab (reference arm). The primary endpoint of American College of Rheumatology (ACR) 50 at week 12 was met for SLK 60-mg and 120-mg WI (60-mg WI = 46.3% (19/41; odds ratio (OR) = 3.6; 95% confidence interval (CI) = 1.3–9.9;P< 0.05); 120-mg WI = 46.5% (20/43; OR = 4.0; 95% CI = 1.4–11.3;P< 0.01) versus PBO = 20.0% (8/40)). SLK resulted in significant benefits across the key secondary endpoints of ACR20 (60-mg WI = 78.0% (32/41;P< 0.001) and 120-mg WI = 72.1% (31/43;P= 0.002) versus PBO = 37.5% (15/40)) and Psoriasis Area and Severity Index (PASI) 90 at week 12 (60-mg WI = 76.9% (20/26;P< 0.001) and 120-mg WI = 59.3% (16/27;P= 0.003) versus PBO = 15.4% (4/26)). Robust responses were observed among patients randomized to SLK at week 24 for the high-threshold composite endpoints of ACR70 + PASI 100 (exploratory) and minimal disease activity (secondary), achieved by up to 48% (13/27; 120-mg WI) and 61% (25/41; 60-mg WI), respectively. SLK was well-tolerated; the most common treatment-emergent adverse events were nasopharyngitis (60 mg = 6.1%; 120 mg = 5.2%), upper respiratory tract infection (60 mg = 6.1%; 120 mg = 4.1%), injection-site erythema (60 mg = 3.7%; 120 mg = 3.1%) and headache (60 mg = 2.4%; 120 mg = 4.1%). Four cases of mild to moderate oral candidiasis occurred (60 mg = 2.4%; 120 mg = 2.1%). Overall, SLK delivered substantial improvements in the signs and symptoms of PsA across various outcomes and domains. ClinicalTrials.gov registration:NCT05640245.

Inflammatory diseases Rheumatic diseases
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Nature Medicine · Oct 02, 2025

A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults

This systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and impact on obesity-related complications. Here a Medline and Embase search was performed up to 31 January 2025 for randomized controlled trials comparing OMMs versus placebo/active comparators in adults. Primary endpoint was percentage of total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and ≥3 years, lipid profile, blood pressure, hemoglobin A1c, fasting plasma glucose, mental health, serious adverse events, quality of life, cardiovascular morbidity and mortality, remission of obesity-related complications and all-cause mortality. Fifty-six clinical trials were identified—orlistat (22), semaglutide (14), liraglutide (11), tirzepatide (6), naltrexone/bupropion (5) and phentermine/topiramate (2)—enrolling 60,307 patients (32,598 OMM and 27,709 placebo). All OMMs showed a significantly greater TBWL% versus placebo (P< 0.0001), more than 10% for semaglutide and tirzepatide. Both tirzepatide and semaglutide showed normoglycemia restoration, remission of type 2 diabetes and reduction in hospitalization due to heart failure. Semaglutide was effective in reducing major adverse cardiovascular events and reducing pain in knee osteoarthritis. Tirzepatide was effective in remission of obstructive sleep apnea syndrome and metabolic dysfunction-associated steatohepatitis. These results support the need to individualize the selection of OMMs.

Obesity Pharmaceutics
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Nature Medicine · Sep 30, 2025

A consensus immune dysregulation framework for sepsis and critical illnesses

Critical care syndromes such as sepsis, acute respiratory distress syndrome (ARDS) and trauma continue to have unacceptably high morbidity and mortality, with progress limited by the inherent heterogeneity within syndromic illnesses. Although numerous immune endotypes have been proposed for sepsis and critical care, the similarities and differences between these endotypes remain unclear, hindering clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine in critical care through the sharing of transcriptomic data. Here, evaluating the overlap of existing immune endotypes in sepsis across >7,074 samples from 37 independent cohorts, we developed cell-type-specific gene expression signatures to quantify dysregulation within immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. Importantly, this dysregulation was also observed in patients with ARDS, trauma and burns, suggesting a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation are associated with differential mortality in patients treated with anakinra in the SAVE-MORE trial (n= 452) and corticosteroids in the VICTAS (n= 89) and VANISH (n= 117) trials, underscoring their prognostic and therapeutic implications. In conclusion, our proposed immunology-based framework for quantifying cellular compartment dysregulation offers a potentially valuable tool for understanding immune dysregulation in critical illness with prognostic and therapeutic significance.

Computational biology and bioinformatics Infection Predictive markers Sepsis Translational immunology
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Nature Medicine · Sep 30, 2025

Clinical validation of an AI-based blood testing device for diagnosis and prognosis of acute infection and sepsis

Lack of reliable diagnostics for the presence, type and severity of infection in patients presenting to emergency departments with non-specific symptoms poses considerable challenges. We developed TriVerity, which uses isothermal amplification of 29 mRNAs and machine learning algorithms on the Myrna instrument to determine likelihoods of bacterial infection, viral infection and need for critical care interventions within 7 days. To validate TriVerity, the SEPSIS-SHIELD study enrolled 1,222 patients with clinically adjudicated infection status and need for critical care intervention within 7 days as endpoints. The TriVerity Bacterial and Viral scores had higher accuracy than C-reactive protein, procalcitonin or white blood cell count for the diagnosis of bacterial infection with area under the receiver operating characteristic (AUROC) of 0.83, and viral infection (AUROC = 0.91). The TriVerity Severity score had an AUROC of 0.78 for predicting illness severity and allowed reclassification of risk for critical care interventions compared to clinical assessment (quick Sequential Organ Failure Assessment) alone. Each of the three scores had rule-in specificity >92% and rule-out sensitivity >95%. Comparison of antibiotics administration at presentation with post-follow-up adjudication found that TriVerity could potentially reduce false positives and false negatives for inappropriate antibiotics use by 60–70%. Further clinical testing in an interventional setting is needed to prove actionability and clinical benefit of TriVerity.

Bacterial infection Viral infection
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Nature Medicine · Sep 30, 2025

A consensus blood transcriptomic framework for sepsis

Sepsis is a life-threatening condition driven by a maladaptive host response to infection. To establish a standardized blood transcriptomic subtype model, we aggregated blood transcriptomics data from two major sepsis cohorts: the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) project (n= 678 sampled on intensive care unit admission; ClinicalTrials.gov registration no.NCT01905033) and the Genomic Advances in Sepsis (GAinS) study (n= 444 sampled on intensive care unit admission andn= 817 follow-up samples; ClinicalTrials.gov registration no.NCT00131196). We demonstrate a strong interconnection across three separate classification methods, resulting in the proposed groupings of three consensus transcriptomic subtypes (CTSs). The distinguishing characteristics of CTS1 included gene activation of typical inflammatory pathways, more pronounced endothelial activation and an overall immature neutrophil theme. CTS2 was characterized by gene activation of a heme metabolism pathway, fibrinolytic disturbances and platelet and eosinophil signatures. CTS3 was associated with genes involved in the activation of allograft rejection, interferon signaling and anticoagulation functions, together with lymphocyte and nonclassical monocyte features. Evaluating CTS classification in independent patient cohorts, specifically the vasopressin vs noradrenaline as initial therapy in septic shock (VANISH) randomized controlled trial (n= 176; ISRCTN registration no.ISRCTN20769191) and patients hospitalized with suspected sepsis at a district hospital in Uganda (n= 128), ascertained the robustness of our approach. Notably, post hoc analysis of a pseudo-randomized cohort, along with a reanalysis of the VANISH trial data, unmasked a harmful signal in CTS2-assigned patients treated with corticosteroids. The CTS classification method aligns diverse sepsis transcriptomic subgroupings into a robust, reproducible framework, thereby enabling biological interpretation and potentially assisting aspects of clinical trial design to advance precision medicine in sepsis.

Diagnostic markers RNA sequencing Sepsis Translational immunology
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Nature Medicine · Sep 30, 2025

Dietary profiles and associated metabolic risk factors in India from the ICMR–INDIAB survey-21

Rapid dietary transitions in India have been associated with an alarming rise in cardiometabolic diseases. Using data from the national Indian Council of Medical Research–India Diabetes survey (18,090 adults), we examined India’s dietary profile and the effect of isocaloric substitution of carbohydrates with other macronutrients on metabolic risk. Indian diets are characterized by high intakes of low-quality carbohydrates (white rice, milled whole grains and added sugar), high levels of saturated fat and low intakes of protein. Compared to those with the least carbohydrate intakes, those with the highest intakes had higher risk of newly diagnosed type 2 diabetes (T2D; odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.14,1.47), prediabetes (OR = 1.20, 95% CI = 1.06,1.33), generalized obesity (OR = 1.22, 95% CI = 1.07,1.37) and abdominal obesity (OR = 1.15, 95% CI = 1.01, 1.30). Replacing refined cereals with whole wheat or millet flour without decreasing overall carbohydrate quantity was not associated with lower risk for T2D (OR = 0.94, 95% CI = 0.57, 1.56) or abdominal obesity (OR = 1.08, 95% CI = 0.66, 1.76). Modeled isocaloric substitution of carbohydrates for plant, dairy, egg or fish protein was associated with lower likelihood of T2D (ranging from OR = 0.89, 95% CI = 0.83, 0.95—for dairy to OR = 0.91, 95% CI = 0.82, 0.99—egg) and prediabetes (ranging from OR = 0.82, 95% CI = 0.72, 0.92—for dairy to OR = 0.94, 95% CI = 0.89, 0.99—for fish). Public health strategies that reduce overall carbohydrates and saturated fat while increasing intake of plant and dairy proteins could mitigate the risk of metabolic diseases in India.

Risk factors Type 2 diabetes
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Nature Medicine · Sep 29, 2025

Genomically matched therapy in advanced solid tumors: the randomized phase 2 ROME trial

Despite recent advancements demonstrating the potential of tumor-agnostic biomarkers to guide effective therapies, randomized evidence supporting the clinical superiority of precision oncology approaches compared to standard therapies remains limited. The ROME trial was a multicenter, randomized, open-label phase 2 study comparing tailored treatment (TT) to standard of care (SoC) in patients with advanced solid tumors progressing after one or two lines of therapy. Comprehensive genomic profiling on tissue and blood was performed to identify actionable alterations. Overall response rate (ORR) was the primary endpoint, and progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), time to next treatment (TTNT) and safety were the secondary endpoints. Between November 2020 and August 2023, 1,794 patients were screened, 897 were evaluated by the molecular tumor board (MTB) and 400 were randomized to TT or SoC. TT achieved a significantly higher ORR (17.5% versus 10%;P= 0.0294) and improved median PFS (3.5 months versus 2.8 months; hazard ratio = 0.66 (0.53–0.82),P= 0.0002). TT also showed superior 12-month PFS rates (22.0% versus 8.3%). Median OS was similar, with a 52% crossover rate. Grade 3/4 adverse events were also similar (40% TT versus 52% SoC). These results highlight the potential of TT to improve outcomes for patients with diverse actionable genomic alterations. These results also provide relevant evidence supporting a tumor-agnostic precision oncology strategy and highlight the potential of TTs, guided by genomic profiling and MTB recommendations, to significantly improve outcomes for patients with diverse actionable genomic alterations. ClinicalTrials.gov identifier:NCT04591431.

Cancer genomics Cancer immunotherapy Cancer models Drug development Targeted therapies
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Nature Medicine · Sep 29, 2025

Prevention of type 2 diabetes through prediabetes remission without weight loss

Clinical practice guidelines recommend defined weight loss goals for the prevention of type 2 diabetes (T2D) in those individuals with increased risk, such as prediabetes. However, achieving prediabetes remission, that is, reaching normal glucose regulation according to American Diabetes Association criteria, is more efficient in preventing T2D than solely reaching weight loss goals. Here we present a post hoc analysis of the large, multicenter, randomized, controlled Prediabetes Lifestyle Intervention Study (PLIS), demonstrating that prediabetes remission is achievable without weight loss or even weight gain, and that it also protects against incident T2D. The underlying mechanisms include improved insulin sensitivity, β-cell function and increments in β-cell-GLP-1 sensitivity. Weight gain was similar in those achieving prediabetes remission (responders) compared with nonresponders; however, adipose tissue was differentially redistributed in responders and nonresponders when compared against each other—while nonresponders increased visceral adipose tissue mass, responders increased adipose tissue in subcutaneous depots. The findings were reproduced in the US Diabetes Prevention Program. These data uncover essential pathways for prediabetes remission without weight loss and emphasize the need to include glycemic targets in current clinical practice guidelines to improve T2D prevention.

Lifestyle modification Metabolic syndrome Obesity Preventive medicine Type 2 diabetes
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Nature Medicine · Sep 29, 2025

Full-spectrum extract fromCannabis sativaDKJ127 for chronic low back pain: a phase 3 randomized placebo-controlled trial

Chronic low back pain (CLBP) affects over half a billion people worldwide. Current pharmacologic treatments offer limited efficacy and carry substantial risks, warranting the development of safe and effective alternatives. This multicenter, randomized, placebo-controlled phase 3 trial evaluated the efficacy and safety of VER-01 in CLBP. It enrolled 820 adults with CLBP (VER-01,n= 394; placebo,n= 426) and included a double-blind 12-week treatment phase (phase A), a 6-month open-label extension (phase B), followed by either a 6-month continuation (phase C) or randomized withdrawal (phase D). The primary endpoint of phase A was a change in mean numeric rating scale (NRS) pain intensity, with a change in total neuropathic pain symptom inventory (NPSI) score as a key secondary endpoint in participants with a neuropathic pain component (PainDETECT > 18). The primary endpoint for phase D was time to treatment failure. The study met its primary endpoint in phase A, with a mean pain reduction of −1.9 NRS points in the VER-01 group (mean difference (MD) versus placebo = −0.6, 95% confidence interval (CI) = −0.9 to −0.3;P< 0.001). Pain further decreased to −2.9 NRS points in phase B, with effects sustained through phase C. The study also met its key secondary endpoint of phase A, with a mean NPSI decrease of −14.4 (standard error, 3.3) points from baseline in the VER-01 arm (MD versus placebo = −7.3, 95% CI = −13.2 to −1.3;P= 0.017). Although phase D did not meet its primary endpoint (hazard ratio = 0.75, 95% CI = 0.44–1.27;P= 0.288), pain increased significantly more with placebo upon withdrawal (MD = 0.5, 95% CI = 0.0–1.0;P= 0.034). In phase A, the incidence of adverse events—mostly mild to moderate and transient—was higher with VER-01 than with placebo (83.3% versus 67.3%;P< 0.001). VER-01 was well-tolerated, with no signs of dependence or withdrawal. VER-01 shows potential as a new, safe and effective treatment for CLBP. ClinicalTrials.gov registration:NCT04940741.

Diseases Randomized controlled trials Translational research
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Nature Medicine · Sep 25, 2025

Antibody-mediated LOX-1 inhibition in patients with residual inflammation after myocardial infarction: a randomized phase 2 trial

The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is a key scavenger receptor for oxidized low-density lipoprotein cholesterol (oxLDL), which promotes inflammation and atherosclerosis. Here we evaluated MEDI6570, an antibody that acts as a LOX-1 antagonist, in a randomized, double-blind, dose-finding study in patients with myocardial infarction (MI) and residual inflammation (high-sensitivity C-reactive protein ≥ 1 mg l−1). At 30–365 days after MI, 423 patients (75 women, 348 men) were randomly allocated to 50 mg, 150 mg or 400 mg MEDI6570 or placebo treatment subcutaneously every 4 weeks for 32 weeks. The primary endpoint, the change in the noncalcified plaque volume in the most diseased coronary segment (NCPVMD) by computed tomography angiography, was not significantly different between placebo and MEDI6570 at any dose. The secondary endpoints, global NCPV and low-attenuation plaque volume, were also not different between placebo and MEDI6570 at any dose (all placebo-adjusted comparisons,P> 0.05). With regard to exploratory endpoints, there were reductions in free soluble LOX-1 (sLOX-1) from baseline by 44.8%, 85.8%, 94.0% and 96.4% in the placebo, 50 mg, 150 mg and 400 mg dose arms, respectively (all placebo-adjusted comparisonsP< 0.001). Interleukin-6 (IL-6) levels decreased by 2.9%, −3.0%, 18.9% and 21.5% in the placebo, 50 mg, 150 mg and 400 mg arms, respectively, with substantial placebo-adjusted reductions observed only at 150 mg and 400 mg (P< 0.05). MEDI6570 was well tolerated and rates of serious adverse events were similar in the MEDI6570 and placebo groups. In summary, despite favorable effects on sLOX-1 and IL-6, a LOX-1 inhibitor did not reduce noncalcified coronary plaque volume in patients with residual inflammation after acute MI. EudraCT registration:2020-000840-75.

Myocardial infarction Outcomes research
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Nature Medicine · Sep 24, 2025

Co-infusion of CD19-targeting and BCMA-targeting CAR-T cells for treatment-refractory systemic lupus erythematosus: a phase 1 trial

Systemic lupus erythematosus (SLE) remains refractory to conventional immunosuppression in a subset of patients. In treatment-refractory SLE, we show that peripheral CD19⁺B cells and bone marrow CD19⁻BCMA⁺ long-lived plasma cells are dominant autoantibody sources, motivating dual CD19 and BCMA targeting. Here we report results from a cohort of patients (14 female, one male) in an ongoing phase 1 dose-escalation trial of co-infused autologous anti-CD19 and anti-BCMA chimeric antigen receptor (CAR) T cells after fludarabine/cyclophosphamide lymphodepletion. Primary endpoints were dose-limiting toxicities (DLTs) within 28 days and adverse events within 12 weeks; key secondary endpoints comprised attainment of Lupus Low Disease Activity State (LLDAS) and DORIS remission within 12 weeks and in vivo CAR-T persistence within 24 weeks. Exploratory endpoints were the duration of post-infusion B cell depletion and time to recovery, the kinetics of immune reconstitution and longitudinal changes in autoantibody titers and serum immunoglobulin concentrations after CAR-T therapy. Over a median 712-day follow-up (range, 613–1,134), no DLTs occurred. Grade 1 cytokine release syndrome developed in 86.7% of patients, with no neurotoxicity or treatment-related deaths. The most common grade 3 or higher adverse events were neutropenia (100%), thrombocytopenia (40%) and anemia (13.3%), all of which were reversible with supportive care. By week 12, 12 of 15 patients (80%) fulfilled both the LLDAS and DORIS remission criteria. Multiomic analyses confirmed elimination of autoreactive CD19⁺BCMA⁺ clones, reconstitution of naive IgM/IgD B cells and durable downregulation of interferon-stimulated and BAFF-dependent signatures, indicating improved immune homeostasis. Longitudinal monitoring of three patients for 1 year demonstrated sustained eradication of pathogenic clones, suggesting potential cure. Dual anti-CD19/anti-BCMA CAR-T cell therapy demonstrates good safety and promising clinical efficacy in treatment-refractory SLE. This study supports the further development of this treatment approach for patients with rSLE. ClinicalTrials.gov identifier:NCT05030779.

Autoimmunity Immunotherapy Systemic lupus erythematosus
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Nature Medicine · Sep 24, 2025

Neoadjuvant PD-1 and LAG-3-targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 Morpheus-Melanoma trial

Patients with stage III melanoma are at high risk of relapse. The NADINA trial evaluating neoadjuvant nivolumab plus ipilimumab and the SWOG-1801 trial evaluating neoadjuvant pembrolizumab have demonstrated superior clinical outcomes with neoadjuvant versus adjuvant checkpoint inhibition. Morpheus-Melanoma was a phase 1b/2, randomized umbrella trial evaluating tobemstomig (anti-PD-1/anti-LAG-3 bispecific antibody;n= 40), tobemstomig plus tiragolumab (anti-TIGIT monoclonal antibody;n= 20) and atezolizumab (PD-L1-targeting monoclonal antibody) plus tiragolumab (n= 20) versus nivolumab (anti-PD-1 monoclonal antibody) plus ipilimumab (anti-CTLA-4 monoclonal antibody;n= 22) in stage III melanoma. The primary endpoint was pathological response by independent pathological review. Additional endpoints included safety and exploratory biomarkers. Here tobemstomig showed a similar pathological response rate (pRR) versus nivolumab plus ipilimumab (80.0% (32/40) versus 77.3% (17/22)); major pathological responses were less frequent with tobemstomig versus nivolumab plus ipilimumab treatment (62.5% (25/40) versus 72.7% (16/22)). Tobemstomig plus tiragolumab and atezolizumab plus tiragolumab showed a lower pRR versus nivolumab plus ipilimumab (60.0% (12/20) and 45.0% (9/20) versus 77.3% (17/22), respectively). Tobemstomig demonstrated improved safety versus nivolumab plus ipilimumab, with 2.5% (1/40) and 22.7% (5/22) of patients experiencing grade 3 or higher treatment-related adverse events (TRAEs), respectively, and 0% (0/40) and 13.6% (3/22) of patients discontinuing treatment due to TRAEs, respectively. Grade 3 or higher TRAEs were reported by 15% (3/20) of patients in the tobemstomig plus tiragolumab arm and by no patients in the atezolizumab plus tiragolumab arm. Baseline CD8+and CD3+tumor-infiltrating T cell density, IFNγ pathway and effector T cell gene expression, tumor mutational burden and pre-surgery circulating tumor DNA correlated with pathological response across treatments. In conclusion, in the Morpheus-Melanoma study, tobemstomig demonstrated a similar pathological response and improved safety profile versus nivolumab plus ipilimumab in patients with resectable stage III melanoma. ClinicalTrials.gov identifier:NCT05116202.

Cancer immunotherapy Melanoma Translational research Tumour biomarkers
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Nature Medicine · Sep 22, 2025

Heat-related mortality in Europe during 2024 and health emergency forecasting to reduce preventable deaths

Successive record-breaking summer temperatures, both globally and in Europe, raise the urgent question of how to better protect vulnerable populations. Here we quantified the heat-related mortality burden during the summers of 2022–2024, and assessed the forecast skill of a new generation of continental-wide, impact-based early warning systems during health emergencies. We fitted epidemiological models with the newly created, format-homogeneous daily mortality database of the EARLY-ADAPT project, covering 654 contiguous regions across 32 European countries, which represents the entire urban and rural population of 539 million people. We estimated 62,775 (95% confidence interval = 36,765–84,379) heat-related deaths in 2024, largely exceeding the burden in 2023 (50,798; 29,442–68,610), but somewhat smaller than that of 2022 (67,873; 38,465–92,455). We demonstrated that health emergencies can be forecast with high confidence at least 1 week in advance, even for highly vulnerable regions and population subgroups. These findings have implications for public health agencies and end users, given that the adoption of the system would enable reliable heat-health emergency alerts within the time window that is relevant for stakeholders to take effective actions to reduce preventable deaths.

Epidemiology Health policy Risk factors
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Nature Medicine · Sep 18, 2025

Clinical implementation of an AI-based prediction model for decision support for patients undergoing colorectal cancer surgery

Adverse outcomes after elective cancer surgery are a main contributor to decreased survival, poorer oncological outcomes and increased healthcare costs. Identifying high-risk patients and selecting interventions according to individual risk profiles in the perioperative period in cancer surgery is a challenge. Using real-world data on 18,403 patients with colorectal cancer from Danish national registries and consecutive patients from a single center, we developed, validated and implemented an artificial-intelligence-based risk prediction model in clinical practice as a decision support tool for personalized perioperative treatment. Personalized treatment pathways were designed according to the predicted risk of 1-year mortality with the intensity of interventions increasing with the predicted risk. The developed model had an area under the receiver operating characteristic curve of 0.79 in the validation set. Results from the nonrandomized before/after cohort study showed an incidence proportion of the comprehensive complication index >20 of 19.1% in the personalized treatment group versus 28.0% in the standard-of-care group, adjusted odds ratio of 0.63 (95% confidence interval, 0.42–0.92;P= 0.02). The incidence of any medical complication was 23.7% in the personalized treatment group and 37.3% in the standard-of-care group; odds ratio of 0.53 (95% confidence interval, 0.36–0.76;P< 0.001). According to the short-term health economic modeling, personalized perioperative treatment was cost effective. The study demonstrates a fully scalable registry-based approach for using readily available data in an artificial-intelligence-based decision support pipeline in clinical practice. Our results indicate that this specific approach can be a cost-effective strategy to improve key surgical clinical outcomes.

Colorectal cancer Colorectal surgery
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Nature Medicine · Sep 18, 2025

The arts for disease prevention and health promotion: a systematic review

Differences in risk factor exposure and access to prevention resources have led to unequal health outcomes for noncommunicable diseases (NCDs) globally. Recent studies elucidate the health benefits of arts participation, but no systematic reviews have focused on NCD prevention and health promotion. Here we share results of a mixed-methods systematic review that included 95 studies of arts programs, practices and activities, addressing NCD risk factors across 27 countries. We found that most reported outcomes were related to physical inactivity, unhealthy diets, mental health, and systemic, structural and social drivers of health. Our findings suggest that the arts may support NCDs prevention and health promotion by generating cultural relevance, providing opportunities for increased physical activity and social connectedness and by helping to identify and address systemic, structural and social forces contributing to health disparities and inequities.

Diseases Risk factors
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Nature Medicine · Sep 17, 2025

An implantable system to restore hemodynamic stability after spinal cord injury

A spinal cord injury (SCI) causes immediate and sustained hemodynamic instability that threatens neurological recovery and impacts quality of life. Here we establish the clinical burden of chronic hypotensive complications due to SCI in 1,479 participants and expose the ineffective treatment of these complications with conservative measures. To address this clinical burden, we developed a purpose-built implantable system based on biomimetic epidural electrical stimulation (EES) of the spinal cord that immediately triggered robust pressor responses. The system durably reduced the severity of hypotensive complications in people with SCI, removed the necessity for conservative treatments, improved quality of life and enabled superior engagement in activities of daily living. Central to the development of this therapy was the head-to-head demonstration in the same participants that EES must target the last three thoracic segments, and not the lumbosacral segments, to achieve the safe and effective regulation of blood pressure in people with SCI. These findings in 14 participants establish the path to designing a pivotal device trial that will evaluate the safety and efficacy of EES to treat the underappreciated, treatment-resistant hypotensive complications due to SCI.

Clinical trials Spinal cord injury
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Nature Medicine · Sep 16, 2025

Oligodendrocyte-targeted adeno-associated virus gene therapy for Canavan disease in children: a phase 1/2 trial

This open-label phase 1/2 clinical study uses a novel recombinant vector, rAAV-Olig001, with selective tropism for oligodendrocytes, to deliver gene therapy for Canavan disease (CD), a rare leukodystrophy characterized by defective aspartoacylase and elevatedN-acetyl-aspartic acid (NAA) concentrations. A total of 8 participants received intracranial doses of 3.7 × 1013vector genomes (vg) of rAAV-Olig001-ASPA (MYR-101), with an interim analysis at 12 months. The primary objective was to assess the safety of intracranial dosing of MYR-101 in children with typical CD. Efficacy measures included Mullen Scales of Early Learning (MSEL), Gross Motor Function Measure (GMFM) and analysis of NAA, myelination, white matter and extracellular water content in the brain. The participants were White; 5 (62.5%) were male. Of the participants, 7 (87.5%) experienced ≥1 serious adverse event, none of which were considered MYR-101 related. All participants experienced ≥1 adverse event. All adverse events and serious adverse events resolved fully. Treatment reduced NAA concentrations in cerebrospinal fluid (P= 0.0008), increased myelination (P= 0.0137) and improved MSEL developmental outcomes (P= 0.0171). Thus, interim results suggest that gene therapy with MYR-101 is well tolerated and shows early effects in CD. While these findings are preliminary, reductions in NAA concentrations indicateASPAexpression and increases in myelination and imply successful targeting of oligodendrocytes. These results may support the development of similar gene therapy strategies for other demyelinating and metabolic brain disorders. ClinicalTrials.gov registration:NCT04833907.

Drug development Translational research
N
Nature Medicine · Sep 16, 2025

Macrovascular and microvascular outcomes of metabolic surgery versus GLP-1 receptor agonists in patients with diabetes and obesity

Both metabolic surgery and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) improve cardiometabolic outcomes, but their long-term outcomes have not been directly compared. Here, we compared macrovascular and microvascular outcomes in 1,657 patients (65.7% female) with type 2 diabetes and obesity who underwent metabolic surgery with 2,275 similar patients (53.5% female) who received treatment with GLP-1 RAs. Using a doubly robust estimation method to balance baseline characteristics between groups, we examined the time to all-cause mortality, incident major adverse cardiovascular events (MACE), nephropathy and retinopathy over a median follow-up of 5.9 years. The 10-year cumulative incidence of all-cause mortality was 9.0% (95% confidence interval (CI) 6.8–10.8%) in the metabolic surgery group and 12.4% (95% CI 9.9–15.2%) in the GLP-1 RA group (adjusted hazard ratio (HR) 0.68 (95% CI 0.48–0.96),P= 0.028). Compared with the GLP-1 RA group, metabolic surgery was also associated with a lower risk of MACE (adjusted HR 0.65; 95% CI 0.51–0.82;P< 0.001), nephropathy (adjusted HR 0.53; 95% CI 0.43–0.67;P< 0.001) and retinopathy (adjusted HR 0.46; 95% CI 0.29–0.75;P= 0.002). These findings indicate that even with the availability of GLP-1 RAs, metabolic surgery remains superior to medical treatment. Future studies should compare the cardiometabolic outcomes of metabolic surgery with newer GLP-1 RAs that are more effective for weight reduction.

Diabetes complications Obesity Outcomes research
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Nature Medicine · Sep 15, 2025

Primary care detection of Alzheimer’s disease using a self-administered digital cognitive test and blood biomarkers

After the clinical implementation of amyloid-β-targeting therapies for people with cognitive impairment due to Alzheimer’s disease (AD), there is an urgent need to efficiently identify this patient population in primary care. Therefore, we created a brief and self-administered digital cognitive test battery (BioCog). Based on its sub-scores, a logistic regression model was developed in a secondary care cohort (n= 223) and then evaluated in an independent primary care cohort comprising 19 primary care centers (n= 403). In primary care, BioCog had an accuracy of 85% when using a single cutoff to define cognitive impairment, which was significantly better than the assessment of primary care physicians (accuracy 73%). The accuracy increased to 90% when using a two-cutoff approach. BioCog had significantly higher accuracy than standard paper-and-pencil tests (that is, Mini-Mental State Examination, Montreal Cognitive Assessment, Mini-Cog) and another digital cognitive test. Furthermore, BioCog combined with a blood test could detect clinical, biomarker-verified AD with an accuracy of 90% (one cutoff), significantly better than standard-of-care (accuracy 70%) or when using the blood test alone (accuracy 80%). In conclusion, this proof-of-concept study shows that a brief, self-administered digital cognitive test battery can detect cognitive impairment and, when combined with a blood test, accurately identify clinical AD in primary care.

Alzheimer's disease Psychology
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Nature Medicine · Sep 12, 2025

Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities

Obesity is a heterogeneous condition not adequately captured by a single adiposity trait. We conducted a multi-trait genome-wide association analysis using individual-level data from 452,768 UK Biobank participants to study obesity in relation to cardiometabolic health. We defined continuous ‘uncoupling phenotypes’, ranging from high adiposity with healthy cardiometabolic profiles to low adiposity with unhealthy ones. We identified 266 variants across 205 genomic loci where adiposity-increasing alleles were simultaneously associated with lower cardiometabolic risk. A genetic risk score (GRSuncoupling) aggregating these variants was associated with a lower risk of cardiometabolic disorders, including dyslipidemia and ischemic heart disease, despite higher obesity risk; unlike an adiposity score based on body fat percentage-associated variants (GRSBFP). The 266 variants formed eight genetic subtypes of obesity, each with distinct risk profiles and pathway signatures. Proteomic analyses revealed signatures separating adiposity- and health-driven effects. Our findings reveal new mechanisms that uncouple obesity from cardiometabolic comorbidities and lay a foundation for genetically informed subtyping of obesity to support precision medicine.

Genome-wide association studies Obesity Personalized medicine
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Nature Medicine · Sep 10, 2025

Association between the English National Health Service Diabetes Prevention Programme and incident multiple long-term conditions

Existing evaluations of the National Health Service Diabetes Prevention Programme (NHS DPP) in England have demonstrated associated reductions in body weight, hemoglobin A1c and incident type 2 diabetes (T2D). In this study, we examined associations between completion of the NHS DPP and incidence of T2D and 30 other long-term conditions (LTCs), including LTCs considered linked to the programʼs interventional goals of body weight reduction, increased physical activity and improved diet quality (LTC-L) and LTCs considered to be possibly linked to those goals (LTC-PL). We found that completers of the NHS DPP had lower incidences of T2D, LTC-L and LTC-PL compared to non-attenders. Although these associations attenuated over time, they remained significant for all outcomes at 24 months with an odds ratio of 0.53 (95% confidence interval: 0.48–0.59) for T2D and rate ratios of 0.79 (0.74–0.84) and 0.80 (0.74–0.88) for LTC-L and LTC-PL, respectively. However, we were not able to directly conclude whether lower incidence rates were a direct result of completing the NHS DPP or due to residual bias stemming from unmeasured confounding and imprecision in the estimation of diagnosis.

Lifestyle modification Type 2 diabetes
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Nature Medicine · Sep 08, 2025

Heterologous two-dose Ebola vaccine regimen in pregnant women in Rwanda: a randomized controlled phase 3 trial

Risk of death for both mother and fetus following Ebola virus infection is extremely high. In this study, healthy women in Rwanda aged ≥18 years were randomized to two-dose Ebola vaccination (Ad26.ZEBOV, MVA-BN-Filo) during pregnancy (group A) or postpartum (group B). Unvaccinated pregnant group B women served as control. This was a parallel, randomized, controlled, open-label, single-center trial to evaluate the safety (primary endpoint—outcomes of interest and serious adverse events (SAEs)) and immunogenicity (secondary endpoint) of the two-dose Ebola vaccination. Among 3,484 women screened, 2,013 were randomized, and 2,012 women and 1,945 infants born alive were descriptively analyzed. Adverse outcomes of interest occurred in women (5.2% in group A and 7.3% in group B) and infants (26.0% in group A and 25.6% in group B). The most common maternal outcome of interest was pathways to preterm birth (3.2% in group A and 3.4% in group B), and the most common infant outcome of interest was small for gestational age (14.3% in group A and 11.8% in group B). Maternal/fetal and neonatal/infant SAE frequencies were comparable between groups (9.8% in group A, 9.0% in group B and 21.9% in group A, 15.9% in group B, respectively). Anti-Ebola virus glycoprotein-specific binding antibody response (secondary endpoint) was sustained in ≥90% of women at 1 year postdose 1. In group A, binding antibodies were detected in cord blood (99%) and infant serum (95%) samples 14 weeks postbirth. The trial met all primary and secondary objectives. Ad26.ZEBOV, MVA-BN-Filo did not raise concerns regarding adverse maternal/fetal or neonatal/infant outcomes, had no unexpected safety issues, and induced binding antibody responses in women and offspring through passive transfer. ClinicalTrials.gov registration:NCT04556526.

Randomized controlled trials Viral infection
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Nature Medicine · Sep 08, 2025

Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses

Immune checkpoint blockade (ICB) is standard of care in advanced diffuse pleural mesothelioma (DPM), but its role in the perioperative management of DPM is unclear. In tandem, circulating tumor DNA (ctDNA) ultra-sensitive residual disease detection has shown promise in providing a molecular readout of ICB efficacy across resectable cancers. This phase 2 trial investigated neoadjuvant nivolumab and nivolumab/ipilimumab in resectable DPM along with tumor-informed liquid biopsy residual disease assessments. Patients with resectable epithelioid/biphasic DPM enrolled sequentially to nivolumab 240 mg every 2 weeks (q2w) for three cycles (Arm A,n= 16) or nivolumab 3 mg kg−1q2w for three cycles plus ipilimumab 1 mg kg−1on cycle 1 (Arm B,n= 14), followed by surgery, optional chemotherapy and/or radiotherapy, and nivolumab 480 mg q4w for 1 year. Co-primary endpoints included safety and feasibility; key exploratory endpoints included progression-free survival (PFS), overall survival (OS) and ctDNA analyses. The trial met its primary endpoints, and, in Arms A and B, 81.3% and 85.7% of patients proceeded to surgery, respectively. Treatment was safe, with a single dose-limiting toxicity in each arm. In Arm A, median PFS and OS were 9.6 months (95% confidence interval (CI): 2.5–27.7) and 19.3 months (95% CI: 14.9–34.7), respectively. In Arm B, median PFS and OS were 19.8 months (7.1–not reached) and 28.6 months (20.4–not reached), respectively. Persistent ctDNA was detected during neoadjuvant therapy in patients who did not undergo complete surgical resection due to disease progression (Fisher’s exact test,P= 0.00013). Patients with detectable ctDNA on cycle 3 and pre-surgery had shorter PFS (log-rank test,P= 0.027 andP= 0.0059, respectively); this association was more pronounced when quantitative ctDNA changes were considered (log-rank test,P= 1.8 × 10−6). Our findings support the feasibility of neoadjuvant ICB and the clinical utility of ctDNA analyses to capture residual disease in resectable DPM. ClinicalTrials.gov identifier:NCT03918252.

Cancer genomics Mesothelioma Tumour biomarkers
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Nature Medicine · Sep 05, 2025

Molecularly matched targeted therapies plus radiotherapy in glioblastoma: the phase 1/2a N2M2umbrella trial

Advances in molecular understanding and diagnostic precision of glioblastoma enable the identification of key genetic alterations in a timely manner and, in principle, allow treatments with targeted compounds based on molecular markers. Here we report the results of the phase 1/2 umbrella trial NCT Neuro Master Match (N2M2), which evaluated targeted treatments in 228 patients with newly diagnosed glioblastoma without O6-methylguanine DNA-methyltransferase promoter hypermethylation. Stratification for treatment was conducted by a trial-specific molecular tumor board across five subtrials, each evaluating a targeted therapy—alectinib, idasanutlin, palbociclib, vismodegib or temsirolimus—selected according to the best-matching molecular alteration. Patients without matching alterations were randomized between subtrials without strong biomarkers using atezolizumab and asunercept, and the standard of care (SOC), temozolomide. All received radiotherapy. The primary endpoints were dose-limiting toxicities (phase 1) and progression-free survival at 6 months (PFS-6; phase 2). Secondary endpoints included safety and tolerability, as well as overall survival (OS). The subtrials for alectinib and vismodegib did not open as they did not have matching patients. The idasanutlin subtrial (n= 9) was terminated early at the discretion of the manufacturing company. The temsirolimus subtrial (n= 46) demonstrated a PFS-6 of 39.1% and median OS of 15.4 months in patients with activated mammalian target of rapamycin (mTOR) signaling compared to a PFS-6 at 18.5% in the SOC group (n= 54), meeting the primary endpoint. The atezolizumab (n= 42), asunercept (n= 26) and palbociclib (n= 41) subtrials did not meet the primary endpoint for efficacy. The safety signals of N2M2match prior experiences with the drugs in quality and quantity; no relevant negative interaction with the parallel radiotherapy was noted. The results of the N2M2trial support further investigation of temsirolimus in addition to radiotherapy in patients with newly diagnosed glioblastoma with activated mTOR signaling. ClinicalTrials.gov registration:NCT03158389.

Drug development Predictive markers
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Nature Medicine · Sep 05, 2025

Pridopidine in early-stage manifest Huntington’s disease: a phase 3 trial

Huntington’s disease (HD) is a rare, neurodegenerative disorder for which only symptomatic treatments are available. The PROOF-HD study was a randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of pridopidine, a selective Sigma-1 receptor agonist, in HD. The primary and key secondary endpoints, change in total functional capacity (TFC) and composite Unified Huntington’s Disease Rating Scale (cUHDRS) score at week 65, were not met in the overall population. The TFC least-squares mean difference between pridopidine and placebo was −0.18 (95% confidence interval −0.49 to 0.14;P= 0.26). The cUHDRS least-squares mean difference between pridopidine and placebo was −0.11 (95% confidence interval −0.40 to 0.18;P= 0.45). Sensitivity analysis in a subgroup of participants not treated with antidopaminergic medications at any time demonstrated a consistent pattern favoring pridopidine across multiple measures, including TFC and cUHDRS. Notably, pridopidine 45 mg twice daily demonstrated a favorable safety and tolerability profile. Taken together, pridopidine has the potential to address a critical unmet need in HD. ClinicalTrials.gov identifier:NCT04556656.

Drug development Huntington's disease
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Nature Medicine · Sep 05, 2025

Feasibility and clinical utility of expanded genomic newborn screening in the Early Check program

Although genomic sequencing presents groundbreaking newborn screening (NBS) opportunities, critical feasibility and utility questions remain. Here we present initial results from the Early Check program—an observational study assessing the feasibility and clinical utility of genomic NBS in North Carolina. Recruitment was statewide through mailed letters with electronic consent. Genome sequencing with analysis of 169 high actionability genes (plus 29 optional lower actionability genes) was performed using residual NBS dried blood spots. In 8 months, 1,979 newborns were screened, with 50 (2.5%) screen positives. Negative results were returned electronically, positive results by genetic counselors. Twenty-eight results (55%) were true positives, all received anticipatory guidance, surveillance and management recommendations, and referral to specialists as appropriate. We report technical feasibility and preliminary clinical utility finding, along with interpretation and follow-up challenges that hinder public health implementation. We propose standardized terminology to facilitate cross-study comparisons and accurate characterization of genomic NBS outcomes.

Genetics research Population screening
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Nature Medicine · Sep 04, 2025

Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer: circulating tumor DNA analysis of a randomized phase 3 trial

CDK4/6 inhibitors (CDK4/6i) improve outcome in patients with advanced estrogen receptor-positive, HER2−breast cancer. The phase 3 SONIA trial compared the addition of CDK4/6i to first- versus second-line endocrine therapy for time to disease progression after second-line treatment (progression-free survival after two lines of treatment (PFS2)), as well as for secondary outcomes overall survival, PFS after one line of treatment (PFS1), health-related quality of life (HRQOL), toxicity and cost-effectiveness. No significant difference in PFS2 was observed; however, on an individual patient level this may be different. Using prespecified circulating tumor DNA analyses, we performed an exploratory study to evaluate whether pretreatment circulating tumor DNA (ctDNA) levels in plasma can identify patients that benefit from CDK4/6i during their first-line treatment. Cell free DNA before start of first-line treatment from 409 female patients participating in SONIA was analyzed with the modified fast aneuploidy screening test-sequencing system. This assay yields a genome-wide aneuploidy score, indicative of ctDNA levels. Cox proportional hazard analyses for PFS1 and PFS2 were performed separately for the ctDNA high group (aneuploidy score ≥ 5) and the ctDNA low group (aneuploidy score < 5). In total, 141 of the 409 included patients had a high genome-wide aneuploidy score at baseline. PFS2 in the first- compared to the second-line CDK4/6i strategy showed hazard ratios of 0.58 (95% confidence interval 0.38–0.88) and 1.36 (95% confidence interval 0.95–1.96) in the high and low aneuploidy group, respectively. A significant interaction was demonstrated between treatment strategy and aneuploidy score for PFS2 (P= 0.004). In conclusion, this study demonstrated that pretreatment ctDNA levels can be used to identify patients that benefit from first-line CDK4/6i treatment. ClinicalTrials.gov registration:NCT03425838.

Breast cancer Predictive markers
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Nature Medicine · Sep 04, 2025

Patritumab deruxtecan in HR+HER2−advanced breast cancer: a phase 2 trial

Antibody–drug conjugates have shown impressive clinical outcomes, particularly in metastatic breast cancer, but biomarkers to predict response and resistance remain unidentified. Here we report the results of ICARUS-BREAST01, a phase 2 study evaluating efficacy, safety and biomarkers of response and resistance to patritumab deruxtecan (HER3-DXd), in patients with HR+HER2−metastatic breast cancer, who previously progressed on CDK4/6 inhibitors and one line of chemotherapy. From May 2021 to June 2023, 99 patients were enrolled to receive HER3-DXd 5.6 mg kg−1intravenously every 3 weeks. The study met its primary endpoint, showing an overall response rate of 53.5% (90% confidence interval [44.8–62.1%]). The most frequent adverse events were fatigue (83%), nausea (75%), diarrhea (53%) and alopecia (40%). Exploratory biomarker analysis of baseline tumor samples suggested preliminary associations between overall response rate and both HER3 spatial distribution and absence of estrogen receptor 1 (ESR1) mutations, as well as between progression-free survival and HER3 expression, pending further validation. Analysis of on-treatment tumor samples showed that treatment efficacy seems to be associated with antibody–drug conjugate intratumoral distribution and interferon response. Overall, HER3-DXd showed promising activity and manageable tolerability in patients with HR+HER2−metastatic breast cancer who progressed on CDK4/6 inhibitors. These findings highlight the need for larger trials to define HER3-DXd efficacy relative to other drugs, including antibody–drug conjugates (ClinicalTrials.gov Identifier:NCT04965766).

Breast cancer Drug development
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Nature Medicine · Aug 31, 2025

Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial

Relaxin is a peptide hormone that may decrease circulatory congestion and improve kidney function. In this study, we conducted a double-blind, international, multicenter trial to test whether volenrelaxin, a long-acting form of human relaxin, can improve left atrial (LA) function, reduce congestion and improve kidney function in patients with heart failure and preserved ejection fraction (HFpEF). We randomly assigned patients with New York Heart Association (NYHA) class II–IV HFpEF and recent heart failure (HF) decompensation to 25-mg, 50-mg or 100-mg volenrelaxin or placebo administered subcutaneously once weekly. The primary outcome was the change in LA reservoir strain at 26 weeks, with key secondary endpoints including changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR) and safety. The trial was stopped early by the sponsor because of evidence for worsening congestion after 332 participants had been enrolled (mean age 74 years, 49% women, mean body mass index 30.6 kg m−2, 31.9% NYHA class III–IV). Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6,P= 0.006) but did not have effects on this outcome at 50-mg (+1.3%, 95% CI: −1.3 to 3.9,P= 0.332) or 100-mg (+0.9%, 95% CI: −1.8 to 3.6,P= 0.521) doses. At 26 weeks, volenrelaxin (pooling all dosages) increased NT-proBNP levels (+24.5%, 95% CI: 2.0–51.8) and had no significant effect on eGFR (+2.2 ml min−11.73 m−2, 95% CI: −1.8 to 6.3). Volenrelaxin was also associated with a non-significant increase in risk for HF hospitalization compared to placebo (hazard ratio = 2.64, 95% CI: 0.93–7.56,P= 0.070), along with signals for an increased number of cardiovascular and renal serious adverse events (odds ratio = 2.52, 95% CI: 0.95–6.68,P= 0.056). In conclusion, despite some evidence for improvement in LA function at a low dose, treatment with this long-acting form of human relaxin was associated with worsening congestion in patients with recently decompensated HFpEF. ClinicalTrials.gov identifier:NCT05592275.

Medical research Outcomes research
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Nature Medicine · Aug 28, 2025

Influenza vaccine strain selection with an AI-based evolutionary and antigenicity model

Current vaccines provide limited protection against rapidly evolving viruses. For example, Centers for Disease Control and Prevention estimates show that the overall influenza vaccine effectiveness against outpatient illness in the United States averaged below 40% between 2012 and 2021. Moreover, the clinical outcomes of a vaccine can be assessed only retrospectively. Here we propose an in silico method named VaxSeer that predicts the antigenic match of vaccine candidates with circulating viruses, in the context of the viruses’ relative dominance in the future influenza season. Based on 10 years of retrospective evaluation using sequencing and antigenicity data, our approach consistently selects strains with better empirical antigenic matches to circulating viruses than annual recommendations. Finally, our predicted estimate of antigenic match exhibits a strong correlation with influenza vaccine effectiveness and reduction in disease burden, highlighting the promise of this framework to drive the vaccine selection process.

Epidemiology Machine learning Vaccines
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Nature Medicine · Aug 28, 2025

An eyecare foundation model for clinical assistance: a randomized controlled trial

In the context of an increasing need for clinical assessments of foundation models, we developed EyeFM, a multimodal vision–language eyecare copilot, and conducted a multifaceted evaluation, including retrospective validations, multicountry efficacy validation as a clinical copilot and a double-masked randomized controlled trial (RCT). EyeFM was pretrained on 14.5 million ocular images from five imaging modalities paired with clinical texts from global, multiethnic datasets. Efficacy validation invited 44 ophthalmologists across North America, Europe, Asia and Africa in primary and specialty care settings, highlighting its utility as a clinical copilot. The RCT—a parallel, single-center, double-masked study—assessed EyeFM as a clinical copilot in retinal disease screening among a high-risk population in China. A total of 668 participants (mean age 57.5 years, 79.5% male) were randomized to 16 ophthalmologists, equally allocated into intervention (with EyeFM copilot) and control (standard care) groups. The primary endpoint indicated that ophthalmologists with EyeFM copilot achieved higher correct diagnostic rate (92.2% versus 75.4%,P< 0.001) and referral rate (92.2% versus 80.5%,P< 0.001). Secondary outcome indicated improved standardization score of clinical reports (median 33 versus 37,P< 0.001). Participant satisfaction with the screening was similar between groups, whereas the intervention group demonstrated higher compliance with self-management (70.1% versus 49.1%,P< 0.001) and referral suggestions (33.7% versus 20.2%,P< 0.001) at follow-up. Post-deployment evaluations indicated strong user acceptance. Our study provided evidence that implementing EyeFM copilot can improve the performance of ophthalmologists and the outcome of patients. Chinese Clinical Trial Registry registration:ChiCTR2500095518.

Diabetes complications Eye manifestations
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Nature Medicine · Aug 26, 2025

Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency

The magnitude of weight reduction in the SURMOUNT-1 trial of the dual GLP-1 and GIP receptor agonist tirzepatide suggests that this treatment may be particularly effective in addressing the treatment needs of people with severe obesity (body mass index >40 kg m−2), some of whom may carry rare penetrant genetic variants. Here we investigated the clinical response of men and women in the SURMOUNT-1 trial who carried pathogenic mutations in the melanocortin 4 receptor (MC4R) gene, the most common genetic cause of obesity. We found that 32 of 2,291 people (1.4%) for whom data were available carried pathogenicMC4Rmutations. At baseline,MC4Rmutation carriers exhibited a higher body mass index compared with noncarriers (40 kg m−2versus 38 kg m−2;P= 0.036). In the treatment arm, the weight loss trajectory over 72 weeks was comparable in both groups: 18.3% weight reduction inMC4Rmutation carriers versus 19.9% in noncarriers. We conclude that tirzepatide is an effective treatment for the most common genetic subtype of obesity, MC4R deficiency.

Endocrine system and metabolic diseases Metabolism
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Nature Medicine · Aug 21, 2025

GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/phase 2 trial

Antidisialoganglioside (GD2), third-generation chimeric antigen receptor (CAR) T cells (GD2–CART01) have shown encouraging efficacy in children with high-risk metastatic, relapsed, or refractory neuroblastoma in the interim analysis of a phase 1/phase 2 clinical trial. We now present the final results obtained in all 35 patients enrolled and in 19 additional children selected with the same criteria of the trial and treated in a hospital exemption setting. Primary endpoints for the trial were safety, maximum tolerated dose, overall response rate (ORR) and complete remission rate at various timepoints. Secondary endpoints included 5-year overall survival (OS) and persistence of GD2–CART01. No new safety signals were observed. Grade 3 immune effector cell-associated neurotoxicity syndrome was diagnosed in four children and rapidly controlled with the activation of the inducible caspase-9 suicide gene by rimiducid. The maximum tolerated dose was 10 × 106CAR+cells per kg. The ORR of the patients enrolled in the clinical trial was 66% (21/32—excluding the three patients treated in nonevidence of disease). The complete remission rate at 6 weeks, 3 months and 6 months reached 37%, 34% and 40%, respectively. GD2–CART01 persisted ≥12 months in 64% of the patients enrolled in the clinical trial. With a median follow-up of 4.2 years, the 5-year OS for the trial cohort was 42.67%. In total, 38 of 54 children were treated with low disease burden at 10 × 106GD2–CART01 cells per kg (defined as the target population), including eight patients consolidated in nonevidence of disease after the first line. The ORR in the target population was 77%, the 5-year OS and event-free survivals were 78% and 53%, respectively. Substantially superior 5-year OS and event-free survivals were observed in patients treated after one or two lines of therapy versus those treated after ≥3 lines of therapy. Better results were observed in patients whose lymphocyte collection was performed at the time of diagnosis. These results confirm that GD2–CART01 can induce durable remissions in children with high-risk metastatic, relapsed, or refractory neuroblastoma. ClinicalTrials.gov identifier:NCT03373097.

Cancer immunotherapy Paediatric cancer
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Nature Medicine · Aug 21, 2025

Perioperative IDH inhibition in treatment-naive IDH-mutant glioma: a pilot trial

Mutant isocitrate dehydrogenase (mIDH) inhibition significantly improves progression-free survival in patients with mIDH WHO grade 2 glioma; however, a large proportion of patients will progress, and mechanisms of adaptation to mIDH inhibition remain poorly understood. Perioperative studies with evaluation of paired pre- and post-treatment samples enable detailed understanding of drug response, facilitating biomarker development, but are rare in glioma owing to safety and cost concerns. Here we conducted a single-arm, open-label feasibility perioperative trial in patients with mIDH1 low-grade glioma, treatment naive to radiation and chemotherapy, with safusidenib (AB-218/DS-1001b), an orally available small-molecule inhibitor of mIDH1. As of 8 November 2024, 10 patients were enrolled and have completed the perioperative component, with a median follow-up of 14 months. Patients continue postoperative safusidenib with ongoing follow-up for safety and efficacy. The primary endpoint showed the feasibility and acceptability of conducting a two-stage perioperative trial. One patient experienced a serious surgery-related adverse event, and ten reported safusidenib-related adverse events; most were grade 1, and one experienced grade 3 elevation of transaminases. Tumor 2-hydroxyglutarate quantification revealed on-target activity, associated with alterations in differentiation programs and neural excitability, functionally validated in post hoc analysis by patch-clamp electrophysiology. Taken together, these results provide a detailed investigation of observations associated with mIDH inhibition in glioma. The study shows the safety and feasibility of this perioperative approach, which can be applied broadly in clinical trial design, serving as proof of concept for advancing drug development in glioma. ClinicalTrials.gov registration:NCT05577416.

Cancer metabolism CNS cancer Transcriptomics Translational research
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Nature Medicine · Aug 20, 2025

AI-driven reclassification of multiple sclerosis progression

Multiple sclerosis (MS) affects 2.9 million people. Traditional classification of MS into distinct subtypes poorly reflects its pathobiology and has limited value for prognosticating disease evolution and treatment response, thereby hampering drug discovery. Here we report a data-driven classification of MS disease evolution by analyzing a large clinical trial database (approximately 8,000 patients, 118,000 patient visits and more than 35,000 magnetic resonance imaging scans) using probabilistic machine learning. Four dimensions define MS disease states: physical disability, brain damage, relapse and subclinical disease activity. Early/mild/evolving (EME) MS and advanced MS represent two poles of a disease severity spectrum. Patients with EME MS show limited clinical impairment and minor brain damage. Transitions to advanced MS occur via brain damage accumulation through inflammatory states, with or without accompanying symptoms. Advanced MS is characterized by moderate to high disability levels, radiological disease burden and risk of disease progression independent of relapses, with little probability of returning to earlier MS states. We validated these results in an independent clinical trial database and a real-world cohort, totaling more than 4,000 patients with MS. Our findings support viewing MS as a disease continuum. We propose a streamlined disease classification to offer a unifying understanding of the disease, improve patient management and enhance drug discovery efficiency and precision.

Multiple sclerosis
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Nature Medicine · Aug 20, 2025

AI-based diagnosis of acute aortic syndrome from noncontrast CT

The accurate and timely diagnosis of acute aortic syndrome (AAS) in patients presenting with acute chest pain remains a clinical challenge. Aortic computed tomography (CT) angiography is the imaging protocol of choice in patients with suspected AAS. However, due to economic and workflow constraints in China, the majority of suspected patients initially undergo noncontrast CT as the initial imaging testing, and CT angiography is reserved for those at higher risk. Although noncontrast CT can reveal specific signs indicative of AAS, its diagnostic efficacy when used alone has not been well characterized. Here we present an artificial intelligence-based warning system, iAorta, using noncontrast CT for AAS identification in China, which demonstrates remarkably high accuracy and provides clinicians with interpretable warnings. iAorta was evaluated through a comprehensive step-wise study. In the multicenter retrospective study (n= 20,750), iAorta achieved a mean area under the receiver operating curve of 0.958 (95% confidence interval 0.950–0.967). In the large-scale real-world study (n= 137,525), iAorta demonstrated consistently high performance across various noncontrast CT protocols, achieving a sensitivity of 0.913–0.942 and a specificity of 0.991–0.993. In the prospective comparative study (n= 13,846), iAorta demonstrated the capability to significantly shorten the time to correct diagnostic pathway for patients with initial false suspicion from an average of 219.7 (115–325) min to 61.6 (43–89) min. Furthermore, for the prospective pilot deployment that we conducted, iAorta correctly identified 21 out of 22 patients with AAS among 15,584 consecutive patients presenting with acute chest pain and under noncontrast CT protocol in the emergency department. For these 21 AAS-positive patients, the average time to diagnosis was 102.1 (75–133) min. Finally, iAorta may help prevent delayed or missed diagnoses of AAS in settings where noncontrast CT remains the only feasible initial imaging modality—such as in resource-limited regions or in patients who cannot receive, or did not receive, intravenous contrast.

Aortic diseases Computed tomography Machine learning
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Nature Medicine · Aug 20, 2025

Genetic and molecular landscape of comorbidities in people living with HIV

People living with HIV (PLHIV) have an increased susceptibility to non-AIDS comorbidities. In this study, we systematically profiled 1,342 PLHIV across five omics layers and immune function. We found latent factors, resulting from integrating epigenomics, transcriptomics, proteomics, metabolomics and immune responses, linked to cardiovascular diseases, the presence of carotid plaque and chronic obstructive pulmonary disease in PLHIV. Mapping four omics layers to genetic variation identified 5,962 molecular quantitative trait loci, illustrating a common genetic regulation in PLHIV compared to healthy individuals. By performing Mendelian randomization, we uncovered host genetic-driven changes in baseline molecules causally related to immune responses upon stimulation with inactivated pathogens. Lastly, we uncovered that the inflammasome, genetically regulated by theNLRP12locus, contributes to systemic inflammation across multiple molecular layers. This study offers a unique catalog of genetic and molecular determinants of immune function in PLHIV and elucidates molecular pathways driving inter-individual variation in immune response and comorbidities.

Epidemiology HIV infections
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Nature Medicine · Aug 19, 2025

A plasma proteomics-based candidate biomarker panel predictive of amyotrophic lateral sclerosis

Identifying a reliable biomarker for amyotrophic lateral sclerosis (ALS) is crucial for clinical practice. Here, in this cross-sectional study, we used the Olink Explore 3072 platform to investigate plasma proteomics as a biomarker tool for this neurodegenerative condition. Thirty-three proteins were differentially abundant in the plasma of patients with ALS (n= 183) versus controls (n= 309). We replicated our findings in an independent cohort (n= 48 patients with ALS andn= 75 controls). We then applied machine learning to create a model that diagnosed ALS with high accuracy (area under the curve, 98.3%). By analyzing plasma samples from individuals before ALS symptoms emerged, we estimated the age of clinical onset and showed that the disease process—impacting skeletal muscle, nerves and energy metabolism—occurs years before symptoms appear. Our research suggests that plasma proteins can be a biomarker for this fatal disease and offers molecular insights into its prodromal phase.

Diagnostic markers Predictive markers
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Nature Medicine · Aug 19, 2025

First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial

Sacituzumab tirumotecan (sac-TMT, also known as MK-2870 or SKB264) is an antibody–drug conjugate targeting trophoblast cell surface antigen 2. We report the initial findings from the ongoing phase 2 OptiTROP-Lung01 study, evaluating the combination of sac-TMT and tagitanlimab (KL-A167), an anti-PD-L1 antibody, as first-line therapy in patients with advanced or metastatic non-small-cell lung cancer who lack actionable genomic alterations (cohorts 1A and 1B). Cohort 1A received sac-TMT (5 mg kg−1, every 3 weeks) plus tagitanlimab (1,200 mg, every 3 weeks) in each 3-week cycle, whereas cohort 1B was treated with sac-TMT (5 mg kg−1, every 2 weeks) plus tagitanlimab (900 mg, every 2 weeks) in each 4-week cycle, in a nonrandomized manner until disease progression or unacceptable toxicity. The primary endpoints included safety and objective response rate. This study was not powered for formal hypothesis testing. A total of 40 and 63 patients were enrolled in cohorts 1A and 1B, respectively. The median age was 63 years in both cohorts. An Eastern Cooperative Oncology Group performance status of 1 was observed in 97.5% and 85.7% of patients in cohorts 1A and 1B, respectively. In cohorts 1A and 1B, the most common grade ≥3 treatment-related adverse events were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%) and anemia (5.0% and 19.0%). No treatment-related deaths were observed. After median follow-ups of 19.3 months for cohort 1A and 13.0 months for cohort 1B, the confirmed objective response rate in the full analysis set was 40.0% (16 of 40) and 66.7% (42 of 63), the disease control rate was 85.0% and 92.1% and median progression-free survival was 15.4 months (95% confidence interval 6.7–17.9) and not reached for cohorts 1A and 1B, respectively. sac-TMT plus tagitanlimab showed promising efficacy as a first-line treatment for advanced or metastatic non-small-cell lung cancer, with a manageable safety profile. ClinicalTrials.gov registration:NCT05351788.

Cancer immunotherapy Non-small-cell lung cancer
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Nature Medicine · Aug 15, 2025

Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial

The dual rAAVrh8-HEXAand rAAVrh8-HEXBvector can restore central nervous system hexosaminidase (Hex) enzyme activity, decrease GM2 levels in cerebrospinal fluid and rescue phenotypic consequences of GM2 gangliosidosis, Tay–Sachs and Sandhoff diseases in animal models following simultaneous bi-thalamic (BiT) injections. Following up on ann= 2 expanded access trial, we initiated a phase 1/2, single-dose, dose-escalation of combined BiT, intra-cisterna magna and intrathecal infusion in children with Tay–Sachs and Sandhoff diseases (six infantile, three juvenile). The BiT injection volume and vector dose were doubled between four cohorts, with the lowest dose matching the earlier expanded access trial. Cerebrospinal fluid HexA enzyme activity, serum total Hex activity and GM2 levels showed a dose-dependent biochemical correction of the disease. Serum Hex activity surpassed 40 nmol h−1ml−1, two times the lower limit of normal, and neuroimaging demonstrated increased fiber tracts. Correction was greatest at 12 weeks, but in decline by 24 weeks postdosing. Infantile patients experienced global clinical stabilization and prolonged oral feeding without aspiration until 3–3.5 years. Seizures had a later onset, were less frequent, less severe and more responsive to anti-convulsant medication. Adverse events were rare in infantile patients, but worsening dystonia was observed in juvenile patients, who were excluded from ongoing enrollment. ClinicalTrials.gov registration:NCT04669535andNCT06614569.

Drug development Paediatric neurological disorders