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PubMed2026

Tripled-Stranded Antisense Oligonucleotide for Biomarker-Activated Suppression of Essential Genes.

Conditional activation of antisense oligonucleotides (ASOs) is a promising strategy for selective suppression of cancer cells without affecting normal cells. In this study, we developed a tripled-stranded ASO (tsASO) that is rendered inactive through complexation with two additional oligonucleotides. The key innovation is the use of partial overlap between the parent ASO and the biomarker sequence, combined with toehold-mediated strand displacement, enabling precise conditional activation. The tsASO effectively triggered RNase H-mediated degradation of DYNC1I2 and DARS1 RNAs exclusively in the presence of the ERBB2 sequence. In cell-free systems, the tsASO demonstrated high cleavage efficiency (up to 81%), comparable to the parent ASO efficiency, with minimal background activity in the absence of the biomarker sequence, validating the concept at the molecular level. However, in cells using lipid-based transfection, the tsASO exhibited nonspecific cytotoxicity that did not correlate with biomarker presence or target gene expression. Detailed analysis showed no clear support for known sequence-driven toxicity mechanisms (CpG/TLR9, G-quadruplexes) in the nonimmune cell lines, suggesting that the primary limitation is intracellular delivery rather than the tsASO design. Future work should focus on optimizing delivery platforms to achieve controlled cellular uptake and biomarker-dependent release, unlocking the therapeutic potential of this conditional gene silencing approach.

Oligonucleotides, Antisense↗
PubMed2026

CNOT1 is a potential YTHDF2 target that orchestrates maternal mRNA decay and zygotic genome activation during goat embryogenesis.

Timely and efficient degradation of maternal mRNA is essential for early embryonic development, which occurs from fertilization through the initiation of zygotic genome activation (ZGA). Yet, the regulatory mechanisms governing this process remain poorly characterized. In the present study, we investigated the function of CCR4-NOT transcription complex subunit 1 (CNOT1) during goat embryogenesis. We found that CNOT1 was upregulated during mammalian ZGA, and that its knockdown led to developmental arrest and a marked reduction in blastocyst formation. Moreover, CNOT1 knockdown impaired nascent RNA activity, resulting in 814 upregulated and 1014 downregulated genes, which were enriched for RNA splicing, regulation of chromosome organization, and RNA localization. RNA splicing analysis revealed differential splicing events in 2959 genes, of which 259 were downregulated following CNOT1 knockdown. Notably, CNOT1 was predicted to crosstalk with the m6A reader YTHDF2. Knockdown of YTHDF2 resulted in CNOT1 downregulation at the 8-cell stage in goats and increased transcription levels around polyadenylation sites during ZGA in mice. Together, these findings indicate that CNOT1 is a potential YTHDF2 target that orchestrates maternal mRNA decay and ZGA during goat embryogenesis. Our work provides new insight into the complex regulatory landscape underlying ZGA and may inform strategies to improve the efficiency of goat embryogenesis.

Animals↗
PubMed2026

Molecular Determinants and Therapeutic Targeting of Stop Codon Readthrough in Eukaryotic Translation.

Accurate translation termination is essential for proteome integrity and in eukaryotes is primarily governed by the release factors eRF1 and eRF3, which ensure precise recognition of stop codons and efficient release of nascent polypeptides. However, proteome integrity is challenged by mutations that generate premature termination codons (PTCs), leading to truncated, nonfunctional proteins and degradation of the aberrant transcript via nonsense-mediated mRNA decay (NMD). Collectively, these events account for ∼1800 human genetic diseases. Translational readthrough, the process by which near-cognate tRNAs decode stop codons and allow ribosomes to continue elongation beyond the stop codon, represents a possibility to suppress PTCs and restore full-length protein synthesis. Initially discovered in viruses as a mechanism to expand coding capacity, readthrough is now recognized as a regulated feature of eukaryotic gene expression influenced by both cis-acting sequence elements and trans-acting factors. Recent evidence highlights the remarkable context dependence of readthrough, revealing variation across transcripts, tissues, and developmental stages. In this review, we examine the molecular determinants that define stop codon recognition and readthrough efficiency, with particular emphasis on nucleotide context. We further discuss the mechanisms and binding sites of small molecules that promote PTC readthrough, and summarize the clinical development landscape of readthrough-inducing compounds for the treatment of diseases caused by nonsense mutations.

Humans↗
PubMed2026

Innovations in microbial physical mutagenesis for food fermentation: An overview from traditional to emerging technologies.

Microbial strains serve as an important factor affecting fermentation efficiency and product quality. To obtain superior strains, mutation breeding is a classic strategy. Compared to chemical mutagenesis, physical mutagenesis directly induces genomic changes, providing notable advantages such as the elimination of chemical residues and environmental sustainability, hence rendering it a favored method for enhancing food-grade microorganisms. Conventional physical mutagenesis mostly depends on UV, rays, high pressure, or space radiation. As physical technologies advance, emerging methods such as ion implantation, plasma, microwave, ultrasound, and pulsed light are widely utilized for genetic modification. Mutagenesis technologies are progressively transitioning from single-effect to multi-effect synergy. Recent evaluations indicate that emerging technologies can enhance microbial mutation efficiency at the application level relative to established technologies. Nonetheless, the systematic clarification and comparative analysis at the mechanistic level remain inadequate, hindering intuitive comprehension of the qualities and distinctions across techniques. Furthermore, physical mutagenesis encounters several significant obstacles, such as cellular damage, limited rates of advantageous mutations, and laborious screening processes. This review carefully elucidates the mechanisms and properties of physical mutagenesis technology and delineates the distinctions among approaches through comparative analysis. Simultaneously, solutions for optimizing mutagenesis are presented to tackle the principal challenges mentioned above. This review aims to offer a theoretical foundation and practical guidance for the enhanced application of physical mutagenesis technologies in microbial breeding.

Mutagenesis↗
PubMed2026

Biomimetic mesoporous silica nanosphere ameliorate experimental autoimmune uveitis by delivering sCD83.

Autoimmune uveitis (AU) is an autoimmune disease that may lead to blindness, but there are currently no precise targeted therapies for its prevention and treatment. Dendritic cell (DC) is key cell involved in the pathogenesis of AU, and specific regulation of their state can help improve AU. In this work, mesoporous silica nanospheres were loaded with the immunomodulator soluble CD83 (sCD83) and subsequently camouflaged with dendritic cell (DC) membranes to fabricate the nanocarrier DCM@MSN/sCD83 for treating experimental autoimmune uveitis (EAU). Research results show that DCM@MSN/sCD83 effectively alleviated the symptoms of uveitis in EAU, reduced the proportion of CD4+CD25-T cell/CD4+CD25+T cell and the percentage of DC in the eyes and cervical lymph nodes. It also decreased the expression of STING in Müller cell. Furthermore, the efficacy of DCM@MSN/sCD83 was found to be primarily targeting DC, and promoted the expression of IL-10 and TGF-β1 in DC by activating the phosphorylated HIF/STAT3 pathway, to induce the production of CD4+CD25+ T. This effect is superior to nanomedicine loaded with dexamethasone. Moreover，DCM enabled the nanocarriers to efficiently cross the blood-eye barrier and reach cervical lymph nodes, thereby regulating peripheral immunity. This research indicate that cell membrane-modified nanoparticles targeting homologous cells can effectively improve treatment efficiency and duration, which is potential therapy strategy for uveitis.

Animals↗
PubMed2026

A User-Friendly Protocol for Microinjection into Teleost Embryos to Study Gene Function.

Zebrafish (Danio rerio) and medaka (Oryzias latipes) are popular teleost models used in developmental biology and functional genomics. To achieve high-quality and reproducible microinjections, it is essential to have robust protocols for breeding, egg collection, and the precise delivery of genetic material. In this protocol, we present a comprehensive and optimized methodology for setting up breeding tanks under controlled photoperiod conditions to maximize egg yield while minimizing contamination. We provide detailed procedures for sex identification, pair selection, the use of grated breeding inserts, and methods to increase egg collection efficiency. We outline procedures for making injection gel beds, pulling needles, and calibration using one-microliter microcapillaries to achieve consistent nanoliter-scale injections. Our protocol outlines settings for the pico-liter injector that are optimized to deliver a precise amount per pulse with minimal variability. Finally, we demonstrate the application of these methods for gene knockdown using morpholino antisense oligonucleotides, gene knockout using CRISPR-Cas9, and gain-of-function mRNA overexpression experiments. Phenotypic assessments conducted at various developmental stages to evaluate gene-specific effects reveal consistent phenotypic outcomes between the morpholino and CRISPR-Cas9 approaches. This easy and comprehensive protocol enables efficient, precise, and scalable genetic manipulation of zebrafish and medaka embryos, thereby supporting advanced functional studies in developmental biology and disease modeling. To our knowledge, this is the first unified protocol for both zebrafish and medaka microinjection systems achieving 97.7% phenotype penetrance in CRISPR-Cas9 knockouts with precision together with a triple validation approach that confirms gene function across multiple techniques.

Animals↗
PubMed2026

Viral replication through phase separation: Cytosolic and nuclear condensates.

Replication of many RNA and DNA viruses occurs within specialized intracellular hubs organized as membraneless biomolecular condensates (BCs) driven by liquid-liquid phase separation. As obligate intracellular parasites, viruses depend on the host cell machinery to complete their replication cycles and therefore actively remodel the intracellular environment to favor viral genome replication, transcription, and assembly. Cytosolic and nuclear phase-separated replication compartments (RC) provide concentrated and dynamic platforms that promote efficient interactions between viral genomes and viral or host proteins essential for infection. The formation of viral replication BCs is typically facilitated by viral proteins enriched in intrinsically disordered regions and low-complexity domains, which enable multivalent interactions with viral nucleic acids and cellular factors. These interactions are mediated by diverse biophysical forces, including hydrophobic and π interactions, hydrogen bonding, molecular crowding, and osmotic effects. Throughout infection, viral BCs remain highly dynamic, allowing continuous exchange of components and functional maturation of replication hubs. Their properties and activities are further regulated by post-translational modifications of viral and host proteins, such as phosphorylation, acetylation, and methylation. In this review, we summarize current evidence supporting liquid-liquid phase separation as a central organizing principle of viral RCs. We focus on representative RNA and DNA viruses that replicate in the cytosol or nucleus, highlighting virus-specific strategies, conserved mechanisms, and the consequences of BC formation for viral replication efficiency, host antiviral responses, and therapeutic intervention.

Phase Separation↗
PubMed2026

Bioprospecting microbial genomes to expand the biocatalytic toolbox of rubber oxygenases.

A set of rubber oxygenases was discovered through phylogenetic analysis and AI-based structural modeling of complexes of the putative enzymes with a substrate mimicking cis-1,4-polyisoprene. Sixteen candidate proteins were selected from thermophilic microorganisms, all sequence-related to the Latex clearing protein from Streptomyces sp. K30 (LcpK30). Sequence truncation and solubility tags were then evaluated to enhance protein expression, with the SUMO tag proving to be the most effective. Including LcpK30, nine heme-containing oxygenases were successfully expressed in E. coli NEB 10-beta cells, purified (35-157 mg L-1 yield) and characterized. Steady-state kinetics revealed significant rubber latex-degrading properties for six of them, with the truncated SUMO-fused LcpK30 (SUMO-LcpK30T) showing activity in agreement with literature. Notably, the catalytic efficiencies of all the expressed homologs lay within one order of magnitude and the oxygenase from Thermomonospora echinospora was found to be particularly promising in terms of activity, especially at high latex concentrations (more than 1% w/v). The analysis of reaction mixtures by both HPLC and HPLC-MS confirmed the oxidation of cis-1,4-polyisoprene to form the expected isoprenoid oligomers (n = 2-12), whose distribution was consistent with the usual endo-type cleavage pattern in all but one case. This bioprospecting effort afforded a platform of new rubber-degrading enzymes with diverse efficiencies and product profiles, capable of adapting to targeted applications.

Oxygenases↗
PubMed2026

A novel urease-producing strain effectively induces cadmium biomineralization under low-temperature stress.

Microbially induced carbonate precipitation (MICP) has been widely used to immobilize Cadmium (Cd) in contaminated soils in mining-affected regions. However, its remediation efficacy under low-temperature stress, as well as the nucleation process that regulates Cd biomineralization via carbonate precipitation by psychrophilic bacteria, has yet to be investigated. Here, we isolated Pseudomonas sp. J-6, a novel urease-producing strain from tailings in high-altitude cold regions, exhibiting unparalleled cold adaptability at 5 °C and achieving 95.85 % Cd removal efficiency by MICP at 10 °C. Furthermore, the coprecipitation process of Ca1-xCdxCO3 was clarified through the continuous observation of the precipitates after the low-temperature MICP reaction. The crystal morphology transitioned from loose vaterite in the early stage to a dense square-block morphology in the middle stage. Cd2+ progressively shifted from a surface-bound state to lattice incorporation, ultimately resulting in the formation of stable Cd-substituted calcite crystals. In this process, low temperatures led to the formation of larger, highly ordered Cd-substituted calcite crystals, thereby strengthening Cd sequestration and its long-term stability. In addition, under low-temperature stress, Pseudomonas sp. J-6 induced MICP reaction decreased the bioavailable Cd in alpine slag soil by 44.85 % and enhanced physical properties. In the freeze-thaw cycles, the remediation efficiency remained stable. This study clarified the biomineralization potential in high-altitude cryogenic environments and the nucleation process of Cd biomineralization by psychrophilic bacteria-induced carbonate precipitation, filling a critical research gap in its application under extreme conditions and highlighting its promise for sustainable remediation of heavy metal pollution under low-temperature stress.

Cadmium↗
PubMed2026

Boosting domestic wastewater treatment with quorum signal-augmented heterotrophic nitrification-aerobic denitrification bacterial-algal aerobic granular sludge.

The aerobic bacterial-algal granular sludge (ABGS) enhanced with heterotrophic nitrification-aerobic denitrification (HN-AD) bacteria, as a novel symbiotic technology, exhibits fluctuating treatment efficiency and unstable performance primarily due to the unstable symbiotic relationship. This study proposes an innovative approach to strengthening the bacteria-algae symbiosis by introducing exogenous signaling molecules. Concurrently, high-throughput, correlation analysis of environmental factors and metagenomic sequencing techniques are employed to elucidate the enhancement mechanisms of the signaling molecules. The results demonstrate that signaling molecule enhancement boosted total nitrogen (TN) removal efficiency by 24.51 % in the bacteria-algae symbiotic system (X1). Scanning electron microscopy (SEM) characterization revealed that the addition of signaling molecules resulted in more compact aerobic granular sludge (AGS) and markedly improved stability. High-throughput sequencing showed signaling molecules enriched denitrifying bacteria (Hydrogenophaga, Pseudoxanthomonas, Thauera, Zoogloea) and organic-degrading Desulfomicrobium, optimizing microbial diversity and enhancing nitrogen/organic removal. Correlation analysis of environmental factors indicate that the addition of C8-HSL facilitates the enrichment and functional activation of specific genera. Metagenomic analysis revealed that signaling molecules enhanced the system's denitrification performance by modulating gene expression and associated metabolic pathways. Quantitative polymerase chain reaction (qPCR) analysis further confirmed that the signaling molecules upregulated the expression of the napA, nirK, and nirS genes. An increased abundance of the napA gene facilitated aerobic denitrification (NO₃⁻-N→NO₂⁻-N), while upregulated abundance of the nirK and nirS genes accelerated nitrite reduction (NO₂⁻-N→N₂). This study aims to provide theoretical and practical foundations for implementing advanced bacteria-algae symbiotic technologies.

Denitrification↗
PubMed2026

Evaluation of one-step amplicon-based targeted enrichment for SARS-CoV-2 whole-genome sequencing using the Midnight amplicon scheme.

Genomic surveillance proved invaluable during the COVID-19 pandemic for tracking SARS-CoV-2 variants and guiding outbreak responses, underscoring the ongoing need to reduce whole-genome sequencing (WGS) costs and improve workflow efficiency to ensure accessibility in resource limited settings. Here, we evaluated a one-step reverse transcription polymerase chain reaction (RT-PCR) approach using the Midnight V2 primer scheme for targeted amplification of the SARS-CoV-2 genome, assessed its compatibility with Illumina sequencing, and compared its performance to a well-established two-step method. Initially, we determined optimal RT-PCR reaction conditions using the Midnight V2 primer panel for the one-step RT-PCR kit and scaled reaction volumes for both RT-PCR and library preparation. Clinical specimens (n = 53) that had undergone routine WGS for surveillance purposes using the established two-step RT-PCR method were compared using the one-step RT-PCR assay. For samples with genome completeness greater than 70%, both methods gave comparable results with similar sequence coverage and 100% concordance for lineage assignment. Further investigation revealed a higher percentage of reads aligning to the SARS-CoV-2 genome with a greater depth of coverage using the one-step method compared to the two-step method. Finally, analysis of scaled one-step and library reaction volumes revealed significant cost savings for samples undergoing WGS. Overall, the results presented here verify the accuracy and reproducibility of one-step targeted amplification and offer an efficient and cost-effective workflow for routine SARS-CoV-2 genomic surveillance.

Humans↗
PubMed2026

Fasting-refeeding regimes induce compensatory growth and muscle transcriptomic remodeling in juvenile Qihe gibel carp (Carassius gibelio var. Qihe).

Compensatory growth, an important adaptive response in fish, holds considerable potential for improving feeding efficiency in aquaculture. To identify an optimal fasting-refeeding strategy for juvenile Qihe gibel carp (Carassius gibelio var. Qihe) and to clarify the mechanisms underlying the compensatory growth, we divided two-month-old fish into four groups, namely S0 group (continuous feeding for 28 days), S2 group (4 cycles of 2-day fasting followed by 5-day refeeding), S4 group (fasting for 4 days followed by refeeding for 24 days), and S8 group (fasting for 8 days followed by refeeding for 20 days), then growth performance, muscle tissue morphology, biochemical responses, and muscle transcriptomic profiles under different feeding regimes were investigated. After a 28-day aquaculture experiment, fish in the S4 group exhibited significantly greater body length and weight than those in the S0, S2, and S8 groups, indicating over-compensatory growth. Histological analysis further showed that muscle growth in the S4 group was mainly associated with myofiber hyperplasia. Different feeding regimes also induced distinct changes in hepatic antioxidant and metabolic enzyme activities, as well as intestinal digestive enzyme activities. Transcriptome analysis revealed that the forkhead box O (FoxO) signaling pathway was significantly enriched during compensatory growth. Key genes, including serum/glucocorticoid regulated kinase 1 (sgk1) and insulin receptor substrate 1 (irs1), were predicted to play important roles in this process. Overall, these results indicate that fasting for 4 days followed by refeeding for 24 days (the S4 regime) is the optimal strategy for inducing compensatory growth in juvenile Qihe gibel carp. This study provides new insights into the morphological, physiological, and molecular basis of compensatory growth and offers a scientific foundation for developing efficient and sustainable feeding strategies for this species.

Animals↗
PubMed2026

Improving Sleep and PTSD Outcomes in Service Members: A Randomized Controlled Trial Examining the Long-Term Effects of an Integrated Treatment.

Trauma-induced sleep disturbances often persist after successful posttraumatic stress disorder (PTSD) treatment. While integrated protocols combining sleep and exposure-based treatments may maximize outcomes, prior studies are limited and have largely relied on subjective sleep measures or failed to include long-term follow up assessments. Active-duty service members with PTSD (n = 82) were randomly assigned to Compressed Prolonged Exposure (CPE) treatment or Trauma Management Therapy (TMT), which integrates exposure therapy with sleep hygiene training and other skills-based interventions. PTSD symptoms and actigraphy-based sleep were measured at baseline, posttreatment, 3- and 6-month follow-up and data were compared between groups and across time. Posttreatment, both groups showed negligible to small changes in sleep compared to baseline. However, the TMT group evidenced improvements in most sleep parameters by the 3- and 6-month follow-ups, while sleep health generally worsened in the CPE group over time. Between groups, those randomized to TMT exhibited better sleep efficiency (g = 0.24) and onset latency (g = -0.34) at 3-month follow-up, and better sleep quality (g = 0.70), efficiency (g = 0.51), and wake after sleep onset (g = -0.52) at 6-month follow-up. Within both treatment groups, poorer sleep at the 6-month follow-up was correlated with greater PTSD symptom severity measured at the same time point. Integrated treatment for sleep and PTSD produced superior objective sleep outcomes compared to exposure alone, with the most meaningful improvements in sleep observed 6 months after treatment completion. Several critical directions for future studies are discussed.

Humans↗
PubMed2026

Moderate expression and activity of flocculins underlie the characteristic flocculation phenotype of Saccharomyces pastorianus.

Flocculation is a key technological trait in lager brewing, governing fermentation performance, yeast recovery, and beer quality. In the allo-aneuploid hybrid yeast Saccharomyces pastorianus, the genetic basis of flocculation remains poorly resolved due to its complex dual sub-genome architecture. Here, we systematically re-annotated and functionally characterized the complete FLO gene repertoire of the Group II strain CBS 1483. Thirteen FLO genes were identified, including allelic variants and a previously uncharacterized adhesin, Flo12, containing a Hyphal_reg_CWP domain instead of the canonical PA14 lectin-binding domain. Structural modeling revealed strong conservation of Ca²+-binding residues in PA14 domains, alongside repeat-region diversification likely contributing to functional variability. Using optogenetic expression in a FLO-null background, we demonstrated that SpcI-FLO9-1 and SpcI-FLO9-2_1 are the strongest drivers of flocculation, exhibiting NewFlo-like sugar sensitivity. Transcriptomic analysis during 17°P wort fermentation showed dynamic induction of these genes coinciding with flocculation onset. Surprisingly, deletion of both loci in CBS 1483 did not abolish but only delayed sedimentation in wort, accompanied by improved maltose utilization and attenuation. These findings reveal functional redundancy and compensatory mechanisms within the FLO network of lager yeast, highlighting the genetic complexity underlying flocculation, and providing a molecular framework to inform yeast selection, strain development, and optimization of the lager fermentation processes.IMPORTANCEFlocculation, the process by which yeast cells aggregate and settle, is essential for producing clear, high-quality lager beer, and for efficient yeast recovery during brewing. However, the genetic basis of this trait in lager yeast has remained poorly understood because these strains possess unusually complex hybrid genomes. In this study, we systematically identified and characterized the complete set of flocculation genes in the industrial lager yeast Saccharomyces pastorianus CBS 1483. We demonstrated that lager yeast flocculation is not controlled by a single dominant gene, but instead emerges from the combined action of several moderately active adhesion proteins that are expressed at low levels during fermentation. Surprisingly, deleting the two strongest candidate genes only delayed, rather than eliminated, sedimentation, revealing a robust compensatory network that preserves brewing performance. These findings refine the current understanding of yeast flocculation and provide a molecular framework for developing brewing strains with improved fermentation efficiency, product consistency, and flavor quality.

Saccharomyces pastorianus↗
PubMed2026

Pedagogical Efficacy of LLM-Generated Synthetic Data Versus Real-World Clinical Records: A Randomized Controlled Non-Inferiority Trial.

BACKGROUND: Expert-reviewed clinical cases generated by large language models (LLMs) may supplement case resources in medical education, but their short-term educational performance relative to real-case-derived teaching materials remains uncertain. We compared immediate post-training test performance after teaching with the two types of case materials and assessed non-inferiority against a prespecified margin. METHODS: We conducted a prospective, parallel-group, randomized non-inferiority trial. Through the Wenjuanxing online platform, participants were randomized 1:1 to learn with either real-case-derived teaching cases compiled by clinicians and reviewed by experts or AI-generated clinical cases produced by Gemini 3.0 Pro from fully de-identified matched real cases and reviewed by three senior general surgery specialists with full-professor rank. The primary outcome was the total score on an independent 10-item immediate post-training test (0-10 points), with a prespecified non-inferiority margin of -0.5 points. Secondary outcomes included the training-phase performance score, learning efficiency index, single-item mental effort rating, case realism, and case-source judgment. RESULTS: A total of 403 participants were randomized, of whom 386 were included in the modified intention-to-treat analysis: 192 in the real-case group and 194 in the AI-generated case group. The mean post-training test score was 4.95 (SD, 3.35) in the real-case group and 4.61 (SD, 3.35) in the AI-generated case group. The mean difference (AI-generated minus real-case group) was -0.335 points (95% CI, -1.006 to 0.337). Because the lower bound of the confidence interval was below the prespecified non-inferiority margin of -0.5 points, non-inferiority was not demonstrated (one-sided P = 0.314). No significant between-group differences were observed in the training-phase performance score, learning efficiency index, or single-item mental effort rating. AI-generated cases received lower realism ratings for Level 3 cases. The proportion of participants with at least one high-confidence completely incorrect response was 1.6% in the real-case group and 2.1% in the AI-generated case group. CONCLUSIONS: In this short-term, text-based online case-learning setting, no statistically significant between-group difference was observed in immediate post-training test performance; however, non-inferiority of AI-generated clinical cases relative to real-case-derived teaching materials was not demonstrated.

Humans↗
PubMed2026

The Case for Master Protocols for Rare Neurological Diseases.

Master protocol trials allow for simultaneous multiple hypothesis testing within a common framework and might be applicable for rare diseases. In May 2025, the Network for Excellence in Neuroscience Clinical Trials convened a multistakeholder conference to discuss master protocol trials in rare neurological disorders. In this paper, we explore how master protocol trial designs may apply to rare neurological disorders, using the neuronal ceroid lipofuscinoses as an example. Through shared protocol elements and trial infrastructure, master protocols may decrease cost and improve efficiency in testing potential therapeutics in rare disease, accelerating the delivery of urgently needed therapies to patients. ANN NEUROL 2026;100:477-486.

Humans↗
PubMed2026

Effectiveness of Wearable Digital Therapeutics in Improving Sleep Outcomes Among Individuals With Insomnia: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Wearable devices are increasingly used for sleep monitoring and as adjunctive treatment. Existing meta-analyses mostly pool composite digital therapies and rarely isolate stand-alone wearables or distinguish between objective and subjective end points. Whether stand-alone wearable interventions improve sleep outcomes in adults with insomnia, and which factors moderate treatment heterogeneity, remains unclear. OBJECTIVE: This study aims to evaluate the effectiveness of wearable digital interventions on sleep outcomes in adults with insomnia versus control strategies and explore moderators of effectiveness, including device-wearing position, intervention duration, and control type, using meta-regression. METHODS: This systematic review and meta-analysis was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‑Analyses) 2020 statement and the PRISMA-S (Preferred Reporting Items for Systematic Reviews and Meta‑Analyses Literature Search Extension) guideline. Five electronic databases and clinical trial registries were searched from inception to May 18, 2026. Eligible studies were randomized controlled trials (RCTs) evaluating wearable digital interventions in adults with insomnia compared with sham, waitlist, usual care, or active control conditions and had an intervention duration of at least 1 week. Study screening, data extraction, and risk-of-bias assessment were carried out independently by 2 reviewers. Pooled estimates were calculated using a restricted maximum likelihood random-effects model with the Hartung-Knapp-Sidik-Jonkman correction. Heterogeneity was assessed using the I² statistic, and 95% prediction intervals (PIs) were calculated for the primary analyses. The certainty of evidence was rated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS: Sixteen RCTs (N=910) were included. Wearable digital interventions were associated with a significant reduction in objective sleep-onset latency (SOL; mean difference [MD] -4.52, 95% CI -8.38 to -0.67, PI -9.52 to 0.47 min) and a significant improvement in subjective sleep efficiency (SE; MD 2.00%, 95% CI 1.90%-2.11%, PI 1.85%-2.15%). Subjective total sleep time (TST) also showed a significant increase (MD 19.11, 95% CI 2.98-35.24, PI -16.20 to 54.43 minutes). Meta-regression showed that control type, intervention duration, and device location did not explain the heterogeneity of the insomnia severity index (ISI) (R²=0). Sensitivity analysis confirmed the robustness of pooled ISI estimates, and an Egger test indicated no small-study effects (P=.07). Certainty of evidence ranged from moderate to high. CONCLUSIONS: Wearable digital interventions provide selective benefits for objective SOL, subjective SE, and subjective TST in adults with insomnia, with no improvement in overall ISI. Despite statistically significant effects on several sleep parameters, wide PIs, substantial heterogeneity, and limited study numbers indicate preliminary, nonconclusive findings. Wearables should be viewed as affordable adjunctive tools requiring further validation, not substitutes for first-line cognitive behavioral therapy for insomnia. Large-scale, long-term RCTs with standardized protocols and patient-level external validation are required to consolidate the evidence base.

Humans↗
PubMed2026

Artificial intelligence-supported double reading in European population breast cancer screening: A systematic review and meta-analysis of prospective programs.

BACKGROUND: Most European population mammography screening programs rely on double reading with arbitration, a model that delivers mortality benefit but is increasingly challenged by radiologist workload, variable specificity, and interval cancers. Artificial intelligence (AI) is being evaluated to support or optimize these established European screening pathways. PURPOSE: To synthesize prospective or program-embedded evaluations of AI conducted within European-style population screening programs and to estimate exploratory program-level absolute risk differences (RDs) per 1000 examinations for cancer detection rate (CDR) and recall. MATERIALS AND METHODS: We performed a prespecified, focused evidence synthesis of three large studies embedded within routine population screening programs operating under European-relevant workflows: MASAI (randomized AI-supported risk triage within a national program), ScreenTrustCAD (prospective paired-reader evaluation with AI as an independent reader in a double-reading framework), and PRAIM (nationwide decision-referral implementation). Outcomes were harmonized as AI-control RDs per 1000 examinations. Random-effects pooling used Hartung-Knapp-Sidik-Jonkman models. For the paired-reader design, sensitivity analyses applied a Kish effective sample-size approach across plausible within-examination correlations (ρ = 0.3-0.8). Positive predictive value (PPV) and workflow/time outcomes were summarized descriptively. RESULTS: Across 597,419 examinations, the pooled CDR RD was +0.9 per 1000 (95% CI -0.0 to +1.8; I2 ≈ 12%), consistent with a modest directional increase with borderline statistical uncertainty. The pooled recall RD was -0.6 per 1000 (95% CI -3.1 to +2.1; I2 ≈ 41-43%), indicating no consistent recall increase across screening programs. Where reported, PPV was higher with AI-supported screening. Efficiency signals included 44.3% fewer total readings in MASAI and shorter reading times for AI-normal examinations in PRAIM; in PRAIM, a program-level safety-net mechanism recovered 204 cancers that would otherwise have been missed. CONCLUSION: In European population screening programs characterized by double reading and arbitration, prospective program-embedded evidence suggests that AI integration may yield a small absolute increase in cancer detection (≈1/1000) without a consistent increase in recall, alongside improved PPV and efficiency signals. These findings suggestAI primarily as a complementary reader within European screening workflows, with implementation requiring explicit quality assurance and monitoring of interval cancers and stage distribution.

Humans↗