Nature Medicine最新文献

Correction to: Nature Medicine https://doi.org/10.1038/s41591-024-03458-w, published online 8 January 2025.

Correction to: Nature Medicine https://doi.org/10.1038/s41591-019-0367-9, published online 4 March 2019.

Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV⁺ patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8⁺ T cell gene expression. Combination anti-CTLA-4/anti-PD-1 ICB, but not single-agent anti-PD-1 ICB, induces cytotoxicity and CMV-associated gene expression in CD8⁺ T cells from CMV⁻ patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV⁺ hazard ratio for death: 1.02, P = 0.92), whereas CMV⁺ single-agent anti-PD-1 ICB recipients had improved overall survival (CMV⁺ hazard ratio for death: 0.37, P < 0.01), a finding also seen in CMV⁺ adjuvant single-agent anti-PD-1 ICB recipients (CMV⁺ hazard ratio for recurrence: 0.19, P = 0.03). We identify TBX21, encoding T-bet, as a transcriptional driver of CMV-associated CD8⁺ T cell gene expression, finding that TBX21 expression is predictive of overall survival (hazard ratio: 0.62, P = 0.026). CMV⁺ patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, P = 2.2 × 10⁻⁵), with lower incidence of colitis (P = 7.8 × 10⁻⁴) and pneumonitis (P = 0.028), an effect replicated in non-melanoma ICB recipients (n = 58, P = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, P = 1.8 × 10⁻⁴), indicating CMV seropositivity may protect against MM. Specifically, patients with BRAF-mutated MM are less likely to be CMV⁺ (odds ratio = 2.2, P = 0.0054), while CMV⁻ patients present 9 yr earlier with BRAF wild-type MM (P = 1.3 × 10⁻⁴). This work reveals an interaction between CMV infection, MM development according to BRAF status and response to ICB, while demonstrating CMV infection is protective against severe ICB immune-related adverse events, highlighting the potential importance of previous infection history and chronic immune activation in MM development and immunotherapy outcomes.

Large Language Models (LLMs) are increasingly transforming medical applications. However, proprietary models such as GPT-4o face significant barriers to clinical adoption because they cannot be deployed on site within healthcare institutions, making them non-compliant with stringent privacy regulations. Recent advancements in open-source LLMs such as DeepSeek models offer a promising alternative since they allow efficient fine-tuning on local data in hospitals with advanced IT infrastructure. To demonstrate the clinical utility of DeepSeek-V3 and DeepSeek-R1, we benchmarked their performance on clinical decision support tasks against proprietary LLMs, including GPT-4o and Gemini-2.0 Flash Thinking Experimental. Using 125 patient cases with sufficient statistical power, covering a broad range of frequent and rare diseases, we found that DeepSeek models perform equally well and in some cases better than proprietary LLMs. Our study demonstrates that open-source LLMs can provide a scalable pathway for secure model training enabling real-world medical applications in accordance with data privacy and healthcare regulations.

DeepSeek is a newly introduced large language model (LLM) designed for enhanced reasoning, but its medical-domain capabilities have not yet been evaluated. This study assessed the capabilities of three LLMs— DeepSeek-R1, ChatGPT-o1, and Llama 3.1-405B—in performing four different medical tasks: answering questions from the United States Medical Licensing Examination (USMLE), interpreting and reasoning based on text-based diagnostic and management cases, providing tumor classification according to RECIST 1.1 criteria, and providing summaries of diagnostic imaging reports across multiple modalities. In the USMLE test, the performance of DeepSeek-R1(accuracy=0.92) was slightly inferior to that of ChatGPT-o1(accuracy=0.95; p = 0.04) but better than that of Llama 3.1-405B (accuracy=0.83; p < 10^-3). For text-based case challenges, DeepSeek-R1 performed similarly to ChatGPT-o1 (accuracy of 0.57 vs 0.55; p = 0.76 and 0.74 vs 0.76; p = 0.06, using New England Journal of Medicine and Medicilline databases, respectively). For RECIST classifications, DeepSeek-R1 also performed similarly to ChatGPT-o1 (0.73 vs 0.81; p = 0.10). Diagnostic reasoning steps provided by DeepSeek were deemed more accurate than those provided by ChatGPT and Llama 3.1-405B (average Likert score of 3.61, 3.22, and 3.13, respectively, p = 0.005 and p < 10⁻³). However, summarized imaging reports provided by DeepSeek-R1 exhibited lower global quality than those provided by ChatGPT-o1 (5-point Likert score: 4.5 vs 4.8; p < 10⁻³). This study highlights the potential of DeepSeek-R1 LLM for medical applications but also underlines areas needing improvements.

Subthreshold depression, defined as a depressive status falling short of the diagnostic threshold for major depression, is common, disabling and constitutes a risk factor for future depressive episodes. Cognitive behavioral therapies (CBT) have been shown to be effective but are usually provided as packages of various skills. Little research has been done to investigate whether all their components are beneficial and contributory to mental health promotion. We addressed this issue by developing a smartphone CBT app that implements five representative CBT skills (behavioral activation, cognitive restructuring, problem solving, assertion training and behavior therapy for insomnia), and conducting a master randomized study that included four 2 × 2 factorial trials to enable precise estimation of skill-specific efficacies. Between September 2022 and February 2024, we recruited 3,936 adult participants with subthreshold depression. Among those randomized, the follow-up rate was 97% at week 6 and adherence to the app was 84%. The study showed that all included CBT skills and their combinations differentially beat all three control conditions of delayed treatment, health information or self-check, with effect sizes ranging between −0.67 (95% confidence interval: −0.81 to −0.53) and −0.16 (−0.30 to −0.02) for changes in depressive symptom severity from baseline to week 6, as measured with the Patient Health Questionnaire-9 scores. Knowledge of the active ingredients of CBT can better inform the design of more effective and scalable psychotherapies in the future. (UMIN Clinical Trials Registry UMIN000047124).

Early-onset SCN2A developmental and epileptic encephalopathy is caused by SCN2A gain-of-function variants. Here we describe the clinical experience with intrathecally administered elsunersen, a gapmer antisense oligonucleotide targeting SCN2A, in a female preterm infant with early-onset SCN2A developmental and epileptic encephalopathy, in an expanded access program. Before elsunersen treatement, the patient was in status epilepticus for 7 weeks with a seizure frequency of 20–25 per hour. Voltage-clamp experiments confirmed impaired channel inactivation and increased persistent current consistent with a gain-of-function mechanism. Elsunersen treatment demonstrated a favorable safety profile with no severe or serious adverse events reported after 19 intrathecal administrations over 20 months. After administration in combination with sodium channel blockers, status epilepticus was interrupted intermittently and ultimately ceased after continued dosing. A >60% reduction in seizure frequency corresponding to five to seven seizures per hour was observed, which has been sustained during follow-up until the age of 22 months. These data provide preliminary insights on the safety and efficacy of elsunersen in a preterm infant. Additional investigation on the benefits of elsunersen in clinical trials is warranted.

Although iron deficiency is well documented, less is known about dietary involvement in symptomatic iron deficiency manifesting in medical conditions. In this study, we quantified the global burden of dietary iron deficiency, focusing on where inadequate dietary iron intake leads to clinical manifestations such as anemia. We analyzed data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 to estimate dietary iron deficiency prevalence and disability-adjusted life years (DALYs), stratified by age, sex, geography and socio-demographic index (SDI) across 204 countries. In 2021, global age-standardized prevalence and DALY rates were 16,434.4 (95% uncertainty interval (UI), 16,186.2–16,689.0) and 423.7 (285.3–610.8) per 100,000 population, with rates decreasing by 9.8% (8.1–11.3) and 18.2% (15.4–21.1) from 1990 to 2021. A higher burden was observed in female individual (age-standardized prevalence, 21,334.8 (95% UI, 20,984.8–21,697.4); DALYs, 598.0 (402.6–854.4)) than in male individual ((age-standardized prevalence, 11,684.7 (11,374.6–12,008.8); DALYs, 253.0 (167.3–371.0)). High-SDI countries presented greater improvement, with a 25.7% reduction compared to 11.5% in low-SDI countries. Despite global improvements, dietary iron deficiency remains a major health concern with a global prevalence of 16.7%, particularly affecting female individuals, children and residents in low-SDI countries. Urgent interventions through supplementation, food security measures and fortification initiatives are essential.

Dementia is a leading cause of death and disability worldwide. Here we tested the effectiveness of blood pressure (BP) reduction on the risk of all-cause dementia among 33,995 individuals aged ≥40 years with uncontrolled hypertension in rural China. We randomly assigned 163 villages to a non-physician community healthcare provider-led intervention and 163 villages to usual care. In the intervention group, trained non-physician community healthcare providers initiated and titrated antihypertensive medications according to a simple stepped-care protocol to achieve a systolic BP goal of <130 mm Hg and a diastolic BP goal of <80 mm Hg, with supervision from primary care physicians. Over 48 months, the net reduction in systolic BP was 22.0 mm Hg (95% confidence interval (CI) 20.6 to 23.4; P < 0.0001) and that in diastolic BP was 9.3 mm Hg (95% CI 8.7 to 10.0; P < 0.0001) in the intervention group compared to usual care. The primary outcome of all-cause dementia was significantly lower in the intervention group than in the usual care group (risk ratio: 0.85; 95% CI 0.76 to 0.95; P = 0.0035). Additionally, serious adverse events occurred less frequently in the intervention group (risk ratio: 0.94; 95% CI 0.91 to 0.98; P = 0.0006). This cluster-randomized trial indicates that intensive BP reduction is effective in lowering the risk of all-cause dementia in patients with hypertension. ClinicalTrials.gov: NCT03527719.