Nature Medicine最新文献

Classic psychedelics typically act at the serotonin 5-HT_2A receptor to profoundly alter brain function and consciousness. Research on these compounds has accelerated. Major strides have been made in understanding their unique mechanisms of action and clinical potential. This Review outlines the state of psychedelic science, spanning cellular mechanisms, systems neuroscience and clinical investigation. We show that preclinical and human research findings converge on two complementary processes: acute neural desynchronization, which destabilizes entrenched network patterns, and subacute neuroplasticity, which opens a window for psychological and behavioral change. We review evidence of therapeutic response across neuropsychiatric indications and consider how this integrates with mechanistic findings. We also explore challenges and opportunities, including discrepancies between preclinical evidence that non-hallucinogenic psychedelic analogs engage putative therapeutic mechanisms, and clinical evidence linking the subjective experience to therapeutic response; the risks inherent to enhanced neuroplasticity; and questions surrounding trial design, scalability and regulatory approval. The growth of psychedelic science and medicine may compel a fundamental rethinking of the relationship between subjective experience and biological change in psychiatry.

The scarcity of subspecialist medical expertise poses a considerable challenge for healthcare delivery. This issue is particularly acute in cardiology, where timely, accurate management determines outcomes. We explored the potential of Articulate Medical Intelligence Explorer (AMIE), a large language model-based experimental medical artificial intelligence system, to augment clinical decision-making in this challenging context. We conducted a randomized controlled trial comparing large language model-assisted care with the usual care of complex patients suspected of having a genetic cardiomyopathy, and we curated a real-world dataset of complex cases from a subspecialist cardiology practice. Nine participating general cardiologists were provided with access to both clinical text reports and raw diagnostic data-including electrocardiograms, echocardiograms, cardiac magnetic resonance imaging scans and cardiopulmonary exercise testing-and were randomized to manage these cases, either with or without assistance from AMIE. We developed a ten-domain evaluation rubric used by three blinded subspecialists to evaluate the quality of triage, diagnosis and management. In our randomized controlled trial with retrospective patient data, subspecialists favored large language model-assisted responses overall, and for the management plan and diagnostic testing domains, with the remaining domains considered a tie. Overall, subspecialists preferred AMIE-assisted cardiology assessments 46.7% of the time, compared with 32.7% for cardiologists alone (P = 0.02), with 20.6% rated as a tie. Subspecialists also quantified errors, extra and missing content, reasoning and potential bias. Cardiologists alone had more clinically significant errors (24.3% versus 13.1%, P = 0.033) and more missing content (37.4% versus 17.8%, P = 0.0021) than cardiologists assisted by AMIE. Lastly, cardiologists who used AMIE reported that AMIE helped their assessment more than half the time (57.0%) and saved time in 50.5% of cases.

Chimeric antigen receptor (CAR) T cell therapy was recently proposed as a treatment for adults with B-cell-mediated autoimmune diseases (ADs) refractory to conventional immunomodulatory therapy. We present a case series of eight children with severe/refractory AD (four systemic lupus erythematosus, three dermatomyositis, one systemic sclerosis) treated at Ospedale Pediatrico Bambino Gesù, Rome, and University Hospital Erlangen with a single infusion of 1 × 10⁶ kg^-1 point-of-care manufactured autologous CD19 CAR T cells (zorpocabtagene autoleucel), in a hospital exemption (HE) program. In Europe, the HE pathway offers the opportunity to treat patients with life-threatening or seriously debilitating disorders who lack valid therapeutic options, using an advanced therapy medicinal product (ATMP) authorized on a nonroutine, single-patient basis. In contrast to the 'compassionate use' pathway, the ATMP does not necessarily need to have undergone clinical trials or marketing authorization applications. Manufacturing was successful in all patients, yielding several drug product bags. Once infused after lymphodepletion, zorpocabtagene autoleucel cells expanded in vivo, promoting prompt B cell clearance. Grade 1 cytokine release syndrome was reported in six patients, and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in one patient. Late-hematotoxicity was limited to grade 1 in two patients. All these adverse events were manageable and no severe infections occurred. With a median follow-up of 16.5 months (range = 9-24 months), all patients experienced a clinically substantial improvement/resolution of AD, as evidenced by reduction in disease activity scores and signs of reversal of organ damage. This improvement enabled sustained discontinuation of immunomodulators, even after B cell reconstitution. The activation of formal clinical trials enrolling children and adolescents is urgently needed to confirm these preliminary results and to assess the long-term safety of this approach.