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Tuberculosis screening faces challenges of under-detection, costly approaches, and inequitable access. AI-enabled digital stethoscopes have demonstrated promising accuracy and feasibility for detecting lung and cardiovascular abnormalities, with promising results in early TB studies. Training and validation in diverse, high-burden settings are essential to explore the potential of this tool further.

Over the past decade, endovascular therapy (EVT) has transformed the management of acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Building on the pivotal randomized controlled trials (RCTs) of 2015, subsequent evidence has refined indications, extended time windows, and advanced technical approaches. Yet, overall outcomes remain modest, with only half of patients achieving functional independence at 90 days. This has spurred efforts to expand EVT to new subgroups, including patients with medium-distal occlusions and mild deficits while optimizing workflows such as direct-to-angiosuite triage and tailored technical strategies. Recent RCTs have also revisited intra-arterial thrombolysis. Beyond revascularization, emerging research explores peri- and post-reperfusion targets, particularly anti-inflammatory and thromboinflammatory pathways. Collectively, these efforts reflect a paradigm shift, from reperfusion alone toward a broader, physiology-informed strategy aimed at improving functional recovery. Ten years on, EVT continues to evolve, promising greater precision, safety, and impact across AIS care.

Background: Evidence suggests that glucagon-like peptide 1 receptor agonists (GLP-1RAs) might have pro-cognitive effects. No prior study has evaluated the efficacy and safety of a GLP-1RA for the treatment of cognitive dysfunction in adults with major depressive disorder (MDD) in a randomized clinical trial.

Methods: This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345). Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese. Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide. The primary outcome was an executive function composite score comprising the digit symbol substitution test, the Stroop test, and the n-back test. Secondary outcomes included a global cognition composite score, measures of functioning, depressive symptom severity, suicidality, and body weight.

Findings: 72 participants were randomized to oral semaglutide (n = 35) or placebo (n = 37). Semaglutide did not improve executive function (adjusted Z score difference [semaglutide - placebo]: 0.32, 95% confidence interval [CI]: -0.92 to 1.58, p = 0.60). Preplanned secondary analysis showed treatment effects for global cognition (2.39, 95% CI: 0.19 to 4.60, p = 0.03) and body weight (kg) (adjusted mean difference -6.03, 95% CI: -8.76 to -3.29, p < 0.001). Treatment did not affect depressive symptom severity or the frequency of suicidal ideation. Gastrointestinal side effects were common in the semaglutide group, with no serious adverse events.

Conclusion: Semaglutide did not improve executive function; results from secondary analyses suggested effects on specific domains of cognition. Semaglutide was safe for patients with MDD.

Funding: This work was supported by the Physicians' Services Incorporated Foundation.

Pregnancy triggers profound physiological changes, yet postpartum recovery remains under-recognized despite its predictive significance for lifelong health. The fourth trimester offers a critical window to detect cardiometabolic, immunological, and mental-health vulnerabilities. We propose a precision postpartum medicine framework integrating human-relevant models, longitudinal multi-omics, and AI-enabled risk stratification to transform postpartum care.

Emerging therapies for progressive multiple sclerosis (PMS) increasingly target CNS-compartmentalized inflammation driving progression independent of relapse activity. Six pivotal trials are evaluating Bruton's tyrosine kinase inhibitors, CD40-CD40L blockade, and CD19-directed CAR-T cells. Together, these studies may establish mechanism-based strategies to modulate microglia and B cell pathology, redefining treatment of progression and addressing a major unmet clinical need.

The DEBBRAH study showed promising results for patients with HER2-expressing (including HER2-low) metastatic breast cancer who received the antibody-drug conjugate (ADC) trastuzumab deruxtecan for leptomeningeal disease. ADCs represent a novel tool in the precision biomarker-based armamentarium, including in the tumor-agnostic setting, for targeting highly cytotoxic chemotherapy into cancer cells.

Translation of foundation models from benchmarks to clinical impact has been slow, revealing a fundamental limitation: correlation-based predictions from models trained on observational data miss causal pathways that determine disease course and treatment response. Hybrid models combining deep learning with representations of biological mechanisms will enable causal reasoning and provide mechanistic understanding required for disease intervention.

Background: Hereditary hearing loss is one of the most common disabling disorders in children and lacks effective pharmacological treatments. Recent breakthroughs in OTOF gene therapy clinical trials necessitate standardized frameworks to guide emerging therapies. This study aims to establish the first international consensus on the clinical application of gene therapy for hereditary hearing loss.

Methods: A modified Delphi process was conducted from March 2024 to March 2025, involving 46 multidisciplinary experts from several countries across otology, genetics, audiology, gene therapy, and hearing rehabilitation. After a systematic literature review, as well as integration of research and clinical expertise and experience, three iterative voting rounds (two anonymous surveys and one online consensus meeting) were performed. Statements required ≥75% agreement for inclusion.

Findings: From 9,093 publications, 69 were used to draft and support the consensus statements. A total of 30 statements relevant to six domains achieved consensus on gene therapy for hereditary hearing loss, including ethical review (1 statement), patient selection criteria (12 statements), diagnosis and preoperative evaluation (9 statements), gene therapy drug delivery (4 statements), follow-up (3 statements), and post-treatment auditory and speech rehabilitation (1 statement).

Conclusions: This consensus provides the first globally endorsed framework for gene therapy in hereditary hearing loss. It standardizes clinical trial design and patient management, accelerating translation from research to practice while ensuring safety. The guidelines are immediately applicable to OTOF-related hearing loss and adaptable to other genetic forms.

Funding: This work was supported by the National Natural Science Foundation of China, the German Research Foundation (DFG) via the Cluster of Excellence, and others.

IgA nephropathy is in a transformative era, with disease-targeted therapies advancing beyond supportive care. This Trial Watch summarizes recent clinical progress in complement inhibition, endothelin receptor antagonism, and B cell and plasma-cell-directed strategies, highlighting promising reductions in proteinuria, preservation of renal function, and the emerging framework for precision, biomarker-guided treatment.

Background: The dynamic, heterogeneous nature of atrial fibrillation (AF) episodes and poor symptom-rhythm correlation make early AF detection challenging. The optimal screening strategy for early AF detection and its role in stroke prevention are unknown.

Methods: To analyze the impact of screening-mediated AF detection on stroke risk, a Markov-like computer model was created that captured seven clinical states. AF-related atrial remodeling was incorporated, which influenced the age-/sex-dependent transition probabilities between states. Model calibration/validation was performed by replicating clinical studies. The effect of screening strategies on early AF diagnosis and subsequent modulation of stroke rate by simulated oral anticoagulation were assessed.

Findings: The model simulates the entire lifetime of virtual patients with 30-min resolution and provides precise information on the occurrence of AF episodes and clinical outcomes. It replicates numerous age/sex-specific episode- and population-level AF metrics and clinical outcomes. The benefits of intermittent AF screening were frequency and duration dependent, with systematic thrice-daily single electrocardiogram providing the highest detection rates. Screening groups had comparable 5-year and lower 25-year stroke rates than the control group. These differences were increased by more effective anticoagulation therapy, in patients with higher baseline stroke risk, or with delayed clinical AF diagnosis.

Conclusions: We present a novel computational patient-level AF model consistent with a large body of real-world data, enabling for the first time the systematic assessment of AF-management strategies. More frequent and longer screening has higher AF-detection rates, but stroke reduction is highly dependent on patients' and healthcare-systems' characteristics.

Funding: Funding information is shown in the acknowledgments section.