Infusion-related reactions (IRRs) can occur with AAV gene therapy. IRRs were observed in two participants who received AAV8 gene therapy and in one who received AAV9 gene therapy. AAV gene therapy IRRs may be rate-related, possibly driven by complement activation. In our studies, a slow, staged infusion mitigated additional IRRs.

Kis and colleagues report an integrated sequential-batch IVT–oligo-dT process that links RNA synthesis and affinity capture through a shared buffer, enabling direct crude-IVT loading and flowthrough recycling. The workflow improves cap-analog utilization and raw-material efficiency while preserving functional mRNA expression across five cycles.

Immunization with a nucleoside-modified mRNA-LNP vaccine encoding the conserved malaria antigen E140 induced durable humoral immunity in mice and generated invasion-blocking antibodies against Plasmodium vivax. The results highlight E140 as a promising candidate for next-generation malaria vaccines.

TTN truncating variants cause dilated cardiomyopathy and may be amenable to therapeutic upregulation. Disrupting TTN upstream open reading frames (uORFs) increased luciferase reporter expression, however disrupting endogenous uORFs in hiPSC-derived cardiomyocytes did not increase titin protein. This highlights the importance of validating regulatory mechanisms in disease-relevant cellular contexts.

Ionizable lipid components of LNP vaccine formulations play an integral role in providing the necessary immune stimulatory signals required for effective anti-tumor T cell responses. This study finds that inclusion of a novel ionizable lipid confers effective tumor control in part through the generation of type I interferons.

Lu and colleagues identify BRD4 as a central epigenetic driver of vesicant-induced corneal injury. Using reproducible mouse and rabbit models, they show that short-term topical BRD4 inhibition suppresses acute inflammation and provides durable protection of corneal clarity, stromal organization, endothelial integrity, and neovascularization, supporting translational therapy for chemical eye injuries.

Blancafort and colleagues describe a non-viral polymeric system for the delivery of dCas9-KRAB silencers as ribonucleoprotein (RNP) payloads for EWSR1-FLI1 repression. They demonstrate highly efficient RNP delivery and robust silencing of EWSR1-FLI1 in both cell line and patient-derived xenografts of Ewing sarcoma, accompanied by potent anti-tumor effects.

Tuberculosis (TB) remains a leading cause of infection-related mortality worldwide, with an estimated 10.7 million incident cases and 1.23 million deaths recorded in 2024.1 The Bacillus Calmette-Guérin vaccine (BCG), despite over a century of use, provides unreliable protection against pulmonary disease in adolescents and adults, and the identification of antigens capable of inducing durable protective immunity in these populations remains an unsolved challenge. Against this backdrop, the emergence of plasmid DNA as a vaccine platform in the mid-1990s generated considerable scientific optimism.

In preclinical studies, UB-VV400, an off-the-shelf, investigational lentiviral drug product, generates fully human anti-CD22 CAR T cells in vivo without the need for lymphodepletion. Activation of the synthetic rapamycin-activated cytokine receptor drives selective CAR T cell expansion and enrichment, resulting in complete tumor clearance and B cell depletion.

Cellular antiviral defenses limit lentivector gene delivery. The authors describe lentivector transduction enhancement via inhibition of antiviral IFITM3 by novel inhibitor BG147. BG147 has activity ex vivo in human stem cells and in vivo in mouse subretinal cells, driving IFITM3 degradation via lysosomes. BG147 can expand lentivector utility and reduce treatment costs.

Song and colleagues report an enterovirus-derived capless self-amplifying mRNA vaccine platform that uses internal ribosome entry site-mediated translation to eliminate 5′ capping. When encoding H5 hemagglutinin, CLsamRNA induces robust humoral and cellular immunity and dose-sparing protection against lethal H5N8 challenge in mice, supporting a distinct RNA vaccine architecture.

Injectable methylcellulose microfoam enables rapid bedside/in vivo generation of CAR-T cells by colocalizing patient PBMCs, gene therapy vectors, and stimulatory cues. The platform enhances gene transfer, minimizes systemic vector exposure, and produces therapeutically effective CAR-T cells without conventional ex vivo manufacturing, potentially expanding patient access to cellular immunotherapy.

This article demonstrates the use of adenine base editor nickase activity for precise transgene cargo integration while simultaneously carrying out multiplex gene knockout. This single-step platform achieves efficient knockin and >90% quadplex gene knockout without detectable translocations and low levels of off-target editing, producing highly functional, customizable chimeric antigen receptor T cells.

Multivalent DNA plasmids, each encoding a diverse set of Mtb antigens, elicited robust polyfunctional T cell responses in naive and BCG-primed mice. Boosting with the lead construct, pESX, resulted in superior immunogenicity that correlated with prolonged pulmonary bacterial control in BCG-primed mice.

arXiv:2609.09388v1 Announce Type: cross Abstract: Brain-age prediction models are commonly evaluated by predictive accuracy, yet accurate predictions alone do not establish that a model relies on reproducible or neurobiologically supported mechanisms. Post-hoc explanation methods can expose these mechanisms, but existing workflows typically stop at diagnosis or require correction targets to be specified before model analysis. We propose XAI-Refine, an automated explanation-knowledge loop for brain-age prediction from resting-state functional connectivity. At each iteration, XAI-Refine consolidates complementary post-hoc analyses across repeated training runs into reliable, structured model explanations. It converts each reliable explanation into a neutral neurobiological question, retrieves and verifies relevant literature, and compiles the verified evidence into an admissible set in the same typed explanation space. The target for refinement is defined as the minimal projection of the current model explanation onto the admissible set induced by applicable verified knowledge. This revised explanation is then translated into a differentiable constraint while preserving the originating model variable, measurement operator, and applicable scope. Candidate updates are promoted only when multi-seed validation confirms target-directed explanatory movement, predictive performance remains within a prespecified guardrail, and non-target explanatory drift remains bounded. Experiments on functional-connectivity-based brain-age prediction evaluate predictive performance, explanation reliability, literature alignment, and target-specific model revision, illustrating a structured route from post-hoc analysis to evidence-guided model refinement.

arXiv:2609.09595v1 Announce Type: cross Abstract: Teacher-student systems, in which a teacher neural network generates training labels so that a student neural network can learn to implement the same function, are widely used as an abstract setting to study learning. However, the structure of the teachers is often overlooked by assuming randomly-generated, normally-distributed parameters. This hides substantial variation in how learnable different teachers are. We formalize learnability as the success rate of converging to the global minimum, as a function of overparameterization, learning algorithm, student initialization distribution, and teacher geometry. We both identify an easy distribution that maximizes node dissimilarity and a hard distribution that minimizes it, and show that these two distributions induce markedly different success rates across a large range of settings and for different activation functions. To explain the gap, we study the loss landscape of small neural networks that contain two distinct kinds of suboptimal local minima, out-of-bounds (OOB) minima at the edge of the data distribution and interior minima within. Assuming infinite data and a fast readout layer, we analytically reduce the loss landscape of small networks to two dimensions, showing that the region of attraction of interior minima changes as a function of teacher structure. In larger networks, maximally dissimilar teachers induce more interior minima, while minimally dissimilar teachers induce more OOB minima. Motivated by these analyses, we show that differentially increasing the learning rate of the readout layer and decreasing the learning rate of the inner biases increases success rates. These findings provide an important step in narrowing the gap between the study of teacher-student networks and more structured functions that arise in practice.

arXiv:2609.10421v1 Announce Type: cross Abstract: Background: Emergency Department (ED) return visits are commonly reviewed for quality assurance, but are often limited (e.g., to revisits within 48-72 hours) to increase actionable finding yield while minimizing chart review burden. Those limitations may lead to missed quality improvement opportunities. Methods: We conducted an exploratory, retrospective study of randomly selected ED visits to a multihospital health system having an ED revisit within 1-14 days to the same health system. Given only each visit's primary diagnosis, raters (2-3 clinicians and GPT-4 large language model [LLM]) assessed characteristics of the diagnosis pairs, including the "target": whether a pair warranted further assessment. Informed by rater response analyses, an algorithm leveraging an LLM-populated knowledge graph ("KGA") was created to automatically screen for potentially concerning pairs, then preliminarily assessed. Results: 99 diagnosis pairs were included. GPT-4 responses poorly correlated to clinician raters, rating nearly all (94%) pairs as warranting follow-up (4.4-13.3 times more than clinicians). However, prompt engineering was minimal. Among clinician raters, revisit medical gravity was consistently significantly associated with the target, while a differential diagnosis/complication composite was significantly associated on unadjusted, but not adjusted (though less powered) analysis. The KGA achieved 83-100% positive predictive value for at least one clinician rater determining further assessment was warranted based on the diagnosis pair. Conclusion: These results can inform next steps for improving screening with LLMs like ChatGPT. Further research is warranted to validate this preliminary work's finding that the KGA may enable enhancing the scope and yield of screening without substantially increasing reviewer workload.

Ezekiel J. Emanuel and Abe Baker-Butler have been debating the proper place for AI in medicine with American Medical Association CEO John Whyte. Now, they are taking their discussion to STAT’s First Opinion. Read Emanuel and Baker-Butler’s essay below and read Whyte’s essay here.

In 1867, Joseph Lister published his research on carbolic acid and antiseptic surgical technique.  In September 1871, he was summoned to Queen Victoria, who had a rapidly growing abscess in her left armpit. Using his antiseptic surgical technique, Joseph Lister successfully drained the pus. Queen Victoria recovered without fever or other complications. The antiseptic technique quickly gained approval in the U.K. and Europe, but not among American physicians.  

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Nature, Published online: 09 September 2026; doi:10.1038/s41586-026-10954-1

A specific population of macrophages that express high levels of the enzyme PLA2G2D in tumour-draining lymph nodes is associated with poor prognosis in patients, and inhibiting PLA2G2D improves anti-tumour immunity in mouse models.

Nature, Published online: 09 September 2026; doi:10.1038/s41586-026-10979-6

An imaging system developed to record cellular activity throughout the whole body of zebrafish captures cellular organ dynamics and identifies multiple distributed circuits.