Background: Cardiac auscultation is an essential component of clinical examination but is often challenging to achieve proficiency in. Self-contained, multisensory learning resources that incorporate simultaneous visual and haptic stimuli offer a unique approach to supporting learners in acquiring this core skill. Objective: This pilot study of both medical students and clinical educators evaluated the utility of a novel iPhone app, Haptic Heart, which generates haptic vibrations to simulate heart sounds and murmurs. We aimed to explore the perceptions of students and educators when using haptics as a learning resource and the underlying reasons behind these perceptions and to gather lessons that would inform future development of the resource. Methods: Clinical-year medical students from the Lincoln Medical School with access to an iPhone were invited to trial Haptic Heart between October 2023 and December 2024. Cardiology specialists involved in clinical education were also invited to take part. After using the app, participants were asked to complete a modified version of the 12-item Evaluation of Technology-Enhanced Learning Materials: Learner Perceptions questionnaire that included additional free-text items. Educators were also asked to comment on the resource’s authenticity and perceived usefulness. Quantitative responses were analyzed using descriptive statistics; free-text responses were analyzed for common themes. Results: A total of 21 students and 18 educators completed the evaluation. Both cohorts returned positive responses across nearly all questionnaire items, with students showing near universal agreement that the app was of excellent quality (21/21, 100%), supported their learning needs (21/21, 100%), and would change their clinical practice (20/21, 95.2%). Educators similarly rated the resource highly for learning utility (16/18, 88.9%) and authenticity (13/18, 72.2%). Reported technical difficulties were minimal for students (1/21, 4.8%) and educators (2/18, 11.1%). Analysis of free-text responses suggested that learners valued the ability to “feel” murmurs and to vary heart rate. Educators highlighted the resource’s novelty and innovation, although some noted concerns about audio quality when using a stethoscope to auscultate haptic vibrations directly. Conclusions: This pilot evaluation demonstrates the potential of smartphone-based haptic technology as a tool for medical education. Haptic Heart was perceived by both students and educators as an innovative educational tool for cardiac auscultation. Further work should focus on expanding the range of haptic patterns provided and exploring the effectiveness of these resources on learning.
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<![CDATA[Study ties higher schizophrenia rates in Black Americans to neighborhood vulnerability, spotlighting faster early-psychosis care and social supports.]]>
ASGCT 2026: Beverly Davidson Offers Vehicle and Route for Huntington’s Disease Gene Therapy
BOSTON – Geneticist Beverly Davidson, PhD, received the 2026 Outstanding Achievement Award from the American Society of Gene and Cell Therapy (ASGCT). Davidson is currently the chief scientific strategy officer at the Children’s Hospital of Philadelphia (CHOP) and a former president of ASGCT.
Some of the research Davidson presented was conducted at a new biotech company she co-founded called Latus Bio, which earlier this month announced it had raised $97 million in a Series A round. The company develops novel AAVs to specifically target central nervous system (CNS) disorders, with a lead program in Huntington’s disease (HD).
After thanking her mentors—Bill Kelly, MD, Michael Welsh, MD, and Kathy High, MD—Davidson turned her attention to presenting new advances in engineered gene therapies. Throughout her career, she has focused on improving adeno-associated viruses (AAVs) for CNS gene therapies, with a particular emphasis now on HD. Key elements include selecting the right cargo and developing the appropriate delivery vehicle. Her goal is to scale lab research in neurons, mouse models, and non-human primates (NHPs) to treat patients, including adults with HD.
Major hurdles to tackling genetic diseases of the brain include scalability and a lack of potency, Davidson said. The search for alternative AAV serotypes to AAV2 that could target neuronal cells began back in 2000. IV administration does not provide sufficient targeting to the brain. Even AAVs that have been engineered to enter the brain from the blood have high peripheral exposure and a high cost of goods per patient, which significantly lowers scalability and impact. (In one study, liver biodistribution of AAV was many orders of magnitude higher than in the CNS.)
Davidson focused on HD, the late-onset, dominantly inherited genetic disease. The identification of the gene harboring the HD mutation in the early 1990s by a consortium of researchers was one of the biggest success stories in human genetics. Even more remarkable was the underlying disease mechanism—the expansion in exon 1 of the gene of a triplet repeat sequence (CAG) producing an abnormally long string of glutamine residues in the huntingtin protein.
The right target
One of the major challenges in devising a gene therapy for HD is ensuring that the therapeutic reaches the right network—the deep brain and cortical areas. Therapies have to reach the right circuit, and the right cells in those circuits, Davidson said. Over the years, her group has tailored AAVs for delivery to the brain, inserting peptides into exposed loops of the virion to allow for targeting and unbiased diversity for blood-to-brain delivery. Nowadays, she said, machine learning approaches can be applied for further capsid improvements.
Davidson’s CHOP lab developed a method for screening AAVs with enhanced potency for CNS therapies. After generating huge libraries containing tens of millions of novel capsids, the group performed serial enrichments to identify the most attractive capsids. After screening pools of injected capsids into two species of monkeys, a winning capsid emerged: AAV-DB-3.
Davidson’s group infused AAV-DB-3 into NHPs, looking for targeting to the putamen (base of the forebrain) and caudate regions. Those results were published in Nature Communications in 2025. “AAV-DB-3 really stood out for its ability to transduce deep layer cortical neurons that are important” in HD, Davidson said. Moreover, the results were achieved with relatively low doses and only required a single infusion per hemisphere, outperforming the widely used AAV5.
Somatic instability
With a promising delivery vehicle identified, Davidson next addressed the therapeutic strategy, which takes aim at the somatic expansion of the CAG repeat. This codon grows longer over time in certain cells in the brain, sometimes expanding to hundreds of repeats.
MSH3 is a DNA repair protein that is required for CAG repeat expansions, as seen in mouse models of HD and other triplet repeat disorders, including myotonic dystrophy. Research led by Paul Ranum, PhD, who is a co-founder of Latus Bio, posted in a preprint on bioRxiv earlier this year, modeled the impact of lowering levels of MSH3 on somatic instability.
Ranum and colleagues used an artificial microRNA showed to lower MSH3 levels in NHPs by 48-94 percent. Computational modeling suggests that this would reduce somatic instability and delay onset of HD symptoms by many years. Early studies using a well-known HD mouse model, the Q111 mouse, to assess biodistribution, quantify knockdowns, and assess the impact on somatic CAG repeat expansion. AAV-DB-3 expression is highest in the striatum and cortex at 16 weeks, dropping MSH3 levels by 50%.
Davidson closed by emphasizing the need to ensure scalability for treatment beyond ultra-rare disorders. Latus hopes to file an Investigational New Drug application for its HD therapy, LTS-201, in the second half of 2026. At least two other biotech companies are also targeting MSH3 by other means.
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ASGCT 2026: AI-Optimized Cas12l Gene Editor Offers Compact Cas9 Alternative
BOSTON — In a potentially significant advance for the genome editing field, researchers from the biotechnology company Caszyme and the Vilnius University Institute of Biotechnology in Lithuania have developed a potent and compact variant of Cas12l nuclease. Giedrius Gasiūnas, PhD, Caszyme co-founder and CEO, presented highlights of the research at ASGCT.
The work represents “a great example of the potential of continued mining for novel Cas effectors within the bacterial metagenomic diversity dark matter,” said Rodolphe Barrangou, PhD, Editor in Chief of The CRISPR Journal, which will shortly be publishing a paper on the Lithuanian team’s results.
“We need more diverse effectors to address the technical shortcomings of the CRISPR toolbox,” Barrangou continued. “This study is a great illustration of the potential of mining bacterial diversity.”
The Lithuanian team, including veteran gene editor Virginijus Siksnys, PhD—winner of the 2018 Kavli Prize with Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, for CRISPR gene editing—used a hybrid approach to optimize Cas12l. By combining cryo-electron microscopy (cryo-EM) structure-guided design with artificial intelligence (AI) protein language models, the team was able to engineer a variant (Asp2Cas12l M82) that overcomes the known efficiency limitations of the Cas12l family.
Although Cas9 has widespread utility, including clinical applications, researchers have long considered its relatively large size and requirement for G-rich protospacer adjacent motifs (PAMs) problematic. The Cas12l family, discovered in the Armatimonadota bacterial phylum, offers a more compact size (867 amino acids) and recognition of a C-rich PAM site.
But wild-type Cas12l enzymes exhibit lower editing efficiencies and higher target-to-target variation compared to Cas9. According to Gasiūnas, the new M82 variant is “reliable, precise and adaptable,” and shows promise for a wide range of therapeutic applications.
“Through our continued work exploring novel Cas systems, Caszyme is focused on advancing technologies that move beyond promise into practical use.”
Path to potency
The engineering of the M82 variant proceeded in two steps. First, the Caszyme researchers solved the 3D structure of Asp2Cas12l complexed with an sgRNA and DNA to high resolution (2.51 Å). This revealed a unique “bracelet” architecture whereby the nuclease encircles the DNA target via interlocking helical bundles and a proline-rich string.
Next, the team introduced arginine substitutions at dozens of positions in the molecule to enhance electrostatic attraction to the negatively charged DNA backbone. This work included the production of an M67 variant, which provided a 7-fold improvement in indel editing over the wild-type nuclease.
To engineer further refinements, the Caszyme group turned to AI, specifically the ESM-2 protein large language model. This model predicted evolutionary hotspots considered likely to preserve or enhance function. Integrating these AI-derived substitutions—Q572R in the bridge helix and F607S in the RuvC domain—resulted in the final M82 Cas12l variant, illustrating the value of AI-supported engineering rather than deploying protein-directed evolution.
Rivaling Cas9
Gasiūnas presented data showing that M82 possesses good activity across recalcitrant gene targets, reducing the target-to-target variation that plagues many novel nucleases. In head-to-head comparisons in HEK293T cells, M82 demonstrated an average indel editing rate of 67.4%, nearly identical to that of Cas9 at overlapping target sites. This potency was consistently maintained across several delivery formats, including plasmid DNA, mRNA, and ribonucleoprotein complexes.
The Caszyme group also showed excellent M82 efficiency in homology-directed repair (HDR). In experiments targeting the AAVS1 locus, M82 facilitated a site-specific gene insertion frequency of 39%, outperforming Cas9 in the same context. Using single-stranded donor templates, HDR rates reached as high as 56%. Gasiūnas suggested that the staggered cut produced by Cas12l may inherently steer DNA repair toward precise correction rather than stochastic indels. With regard to safety, Caszyme found that M82 Cas12l maintained a high degree of on-target precision. Secondary editing signals were largely detected at or near the lower limits of assay sensitivity, suggesting a low risk of off-target cleavage.
The compact size of the M82 variant makes it an attractive candidate for adeno-associated virus-mediated delivery, which has strict limits on cargo size. “It is no secret that the CRISPR space has faced challenges and concerns in recent years,” Gasiūnas said. “However, we are confident in M82’s ability to create headroom for scientists to stand up and innovate within.”
Crowded field
Cas12l is not the only compact Cas nuclease gaining attention, of course. In a talk preceding Gasiūnas’ presentation, Zhaoshi Wu, PhD, co-founder and chief technology officer of Shanghai-based Castalysis Bioscience, presented an update on Cas12n, details of which were first published in Molecular Cell in 2023. The nuclease was touted as being the first independent CRISPR-Cas complete gene family uncovered by Chinese scientists within China’s territory.
Touted as a next-gen ultra-compact gene editing system, Cas12n (branded as alphaCas) consists of just 450 amino acids, and possesses structural similarity to TnpB. Cryo-EM structural analysis led the Chinese investigators to optimize the molecule for non-viral in vivo delivery. Preclinical experiments showed robust genome editing in a mouse model by targeting PCSK9 using lipid nanoparticle delivery, resulting in sharp drop in serum LDL levels.
Wu said his company is on target to begin its first clinical before the end of 2026. But he faced an uncomfortable moment during audience questions. Fyodor Urnov, PhD, challenged Wu’s claim that an inherent advantage of Cas12n was its safety profile compared to Cas9. Urnov pointed out that Intellia Therapeutics has two ongoing Phase III in vivo trials using CRISPR-Cas9 that show no immunogenicity concerns using LNP delivery.
Urnov later congratulated Wu on the rest of the company’s data and wished them success.
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ASGCT 2026: Rare Instance of AAV Integration into Human Genome Linked to Brain Tumor
BOSTON — A team at Children’s Hospital of Philadelphia (CHOP) led by Rebecca Ahrens-Niklas, MD, PhD, and Lindsey George, MD, has described a case of a brain tumor linked to a rare integration of adeno-associated virus (AAV).
George presented the work at the American Society of Gene and Cell Therapy (ASGCT) conference in a plenary talk selected as the “presidential abstract” by ASGCT president, Terry Flotte, MD. The study, “Neuroepithelial tumor with AAV integration after intracisternal magna vector delivery,” was published in the New England Journal of Medicine.
Over the past 25 years, some 6,000 patients have been treated with some form of AAV gene therapy. In all that time, George said, there have been no established long-term safety concerns, although genome integration events have been reported in mouse and dog studies. But the case documented by George and colleagues at CHOP suggests that the gene therapy field may need to pay more attention to this potential occurrence.
The story began with a 5-year-old boy with an inherited lysosomal disorder, severe MPS1 deficiency (Hurler subtype). The patient received enzyme replacement therapy at six weeks of age, followed by a cord blood stem cell transplant at age four months.
Investigators chose to perform gene therapy when the patient was 13 months old to deliver the iduronidase (IDUA) gene. The vector chosen was an AAV9 serotype, using a cytomegalovirus enhancer and a chicken beta-actin promoter driving the gene. The virus was administered into the boy’s cisterna magna in the base of the skull.
When the boy was five years old, a routine neurological scan revealed a large intraventricular mass that had not been observed two years earlier. Analysis of the tumor revealed it was a PLAG1-driven neuroepithelial tumor—indeed, PLAG1 expression was almost 300 times higher than in other central nervous system tumors studied at CHOP. (PLAG1 is usually only expressed during embryogenesis.)
Surgery to remove the tumor was successful. Eight months after surgery, there are no signs of tumor growth. The boy is also showing advanced neurocognitive function.
Tumor typing
George described RNA sequencing of the tumor, which revealed the fusion of a fragment of the AAV9 vector cassette to exon 5 of the PLAG1 gene on chromosome 8. The resulting transcript is predicted to encode a PLAG1 derivative containing five zinc-finger DNA-binding domains and a C-terminal transcriptional activation domain, which was previously reported to function as a transcriptional activator.
Curiously, the chimeric junction also included a segment of human chromosome 10, which George suspects originated during the vector manufacturing process. The integration event was present in about 40% of the total reads, suggesting integration into one of the two PLAG1 alleles.
George concluded her talk by noting that while the clinical outcome in this patient is so far encouraging, this is evidence that AAV integration can be associated with oncogenesis. The study underscores the need to monitor the most heavily transduced tissues after AAV gene therapy.
While the gene therapy community should be cautious in extrapolating this single case report across all AAV gene therapy programs, George said the study supports the use of the lowest feasible vector dose as well as tissue-specific promoters.
George noted that detection of the integrated AAV vector DNA was challenging, in part because of rearrangements of vector DNA. The use of several complementary techniques—long-read DNA sequencing, targeted PCR amplification, and RNA sequencing—was required to confirm the integration.
George and coworkers closed their paper, noting that, “Our findings support the hypothesis that rare AAV integration can contribute to human oncogenesis, which emphasizes the need to optimize gene delivery methods and monitor transduced tissues after treatment.”
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Exosome-based therapy for epilepsy: a systematic review and meta-analysis of preclinical studies
ObjectiveThis study aims to quantitatively assess the efficacy of exosome therapy for epilepsy through a systematic review and meta-analysis of preclinical animal experiments. We seek to clarify its overall effects on seizure reduction, cognitive function preservation, and neuroinflammation suppression.MethodsA systematic search was conducted across four English-language and four Chinese databases to include epilepsy animal studies. Continuous outcomes were synthesized using standardized mean differences (SMD) and 95% confidence intervals (CI), with fixed or random effects models selected based on heterogeneity.ResultsA total of eight preclinical studies were included. The overall meta-analysis revealed that exosome treatment significantly reduced the duration of seizures (SMD = −2.30, 95% CI −4.24 to −0.36), decreased the frequency of spontaneous recurrent seizures (SMD = −1.38, 95% CI −2.17 to −0.58), and prolonged the seizure latency (SMD = 1.49, 95% CI 0.08–2.90). In terms of cognitive function, exosomes significantly shortened the escape latency in the Morris water maze (SMD = −1.38, 95% CI −2.17 to −0.58), increased the percentage of time spent in the target quadrant (SMD = 3.69, 95% CI 0.30–7.08), and enhanced the number of platform crossings (SMD = 1.41, 95% CI 0.60–2.21), with no significant changes in swimming speed. Neuropathological analysis indicated that exosome treatment significantly increased the number of hippocampal neurons (SMD = 4.48, 95% CI 1.46–7.49) and markedly reduced levels of glial fibrillary acidic protein (GFAP) (SMD = −3.61, 95% CI −7.08 to −0.14), ionized calcium-binding adaptor molecule 1 (IBA-1) (SMD = −10.27, 95% CI −20.29 to −0.25), tumor necrosis factor-alpha (TNF-α) (SMD = −2.95, 95% CI −4.21 to −1.69), and interleukin-1 beta (IL-1β) (SMD = −7.39, 95% CI −14.64 to −0.13). Although some outcomes exhibited heterogeneity and publication bias, the corrected primary effects remained statistically significant. The source of exosomes, administration route, and dosage may be critical variables influencing their efficacy.ConclusionExosome therapy improves seizure phenotypes and protects cognitive function in epilepsy models by suppressing neuroinflammation to promote neuronal survival, providing evidence for further mechanistic and clinical translation studies.
Molecular mechanisms of autophagy-lysosomal pathway dysfunction in neurodegenerative diseases and therapeutic strategies for lysosomal repair: a review
The autophagy-lysosomal pathway (ALP) is a critical intracellular protein degradation system responsible for maintaining proteostasis and metabolic balance within cells. Dysfunction of this pathway has been increasingly recognized as a key pathological basis underlying various neurodegenerative diseases (NDs). This review provides a comprehensive overview of the molecular mechanisms by which ALP impairment contributes to defective protein degradation in neurodegeneration. We focus on the impact of lysosomal structural integrity and functional imbalance on cellular fate, highlighting the interplay between protein oxidative damage and degradation system dysregulation. Furthermore, we summarize the current therapeutic strategies aimed at lysosomal repair, evaluating their potential clinical applications and efficacy. By integrating the latest research advances, this review aims to deepen the understanding of the pathological mechanisms of autophagy-lysosomal pathway dysfunction in neurodegenerative diseases, clarify the key molecular targets of lysosomal damage and repair, and provide theoretical basis for target screening and validation and practical reference for the development of targeted drugs for neurodegenerative diseases.
A hierarchical machine learning model for predicting self-harm and suicidal behaviour in hospitalised patients with schizophrenia using clinical history and nursing observations
ObjectiveThis study aimed to develop and evaluate a two-layered machine learning framework that combines admission clinical information with longitudinal nursing observations to identify schizophrenia inpatients at high risk of self-harm or suicidal acts.MethodsWe retrospectively reviewed the records of 477 patients with schizophrenia hospitalised in Liaoning Province between July 2021 and July 2024. According to whether at least one self-injurious or suicidal episode was documented during the index admission, 159 individuals were assigned to a high-risk group and 318 to a non-high-risk group. At admission, 18 baseline variables (including age, sex, history of self-harm, hopelessness/depression, and educational attainment) were extracted from electronic medical records, and 39 nurse-rated behavioural items were scored weekly using the Psychiatric Patient Nursing Observation Scale. Static and dynamic feature sets were used to train six classifiers [regularized logistic regression (LR), support vector machine (SVM), extreme gradient boosting, random forest, multi-layer perceptron, and K-nearest neighbours]. The best static model (regularized LR) and the best dynamic model (SVM) were combined through probability-level weighted fusion to generate a hierarchical risk score.ResultsMultivariable analysis of admission features showed that previous self-harm [odds ratio (OR) = 4.323], hopelessness/depression (OR = 3.090), younger age (OR = 0.938), and higher educational level (OR = 1.357) were independent predictors of self-harm/suicidal behaviour. Among dynamic indicators, negative self-evaluation (OR = 2.303), self-reported depression (OR = 1.812), insomnia (OR = 1.768), talking to oneself (OR = 1.733), crying (OR = 1.700), and reduced conversation with others (OR = 1.422) remained significant. The optimised static LR model achieved an area under the curve (AUC) of 0.7564, and the dynamic SVM model reached an AUC of 0.8531. Their fusion further improved performance (AUC = 0.9048; sensitivity 0.8542; specificity 0.7789; accuracy 0.8042). This hierarchical model outperformed the best flat combined-feature model (SVM; AUC = 0.9022) in sensitivity (0.8542 vs. 0.6667), indicating a more clinically appropriate detection of high-risk patients.ConclusionA hierarchical machine learning approach that integrates baseline clinical history with repeated nursing assessments can effectively flag schizophrenia inpatients at high risk for self-harm and suicidal behaviour, supporting timely and individualised preventive strategies in psychiatric wards.
Context-dependent interaction between oxytocin gene polymorphisms and alcohol dependence in modulating negative emotions during acute alcohol withdrawal in adult males
ObjectiveThe importance of multiple gene-environment interaction (G × E) has been highlighted in understanding the etiology of negative emotions. This study examines the impact of oxytocin (OXT) polymorphisms (rs2740210, rs6133010, and rs2740209) in combination with alcohol dependence on anxiety and depression symptoms during acute alcohol withdrawal under different social and environmental contexts.MethodA total of 414 Chinese Han male adults undergoing acute alcohol withdrawal were recruited. Participants provided blood samples for genotyping, self-reported measures of depression and anxiety, assessments of alcohol dependence severity, and demographic information regarding social and environmental contexts.ResultsResults revealed a positive correlation between severity of alcohol dependence and symptoms of depression and anxiety, while oxytocin polymorphism did not have a direct effect on depressive and anxiety symptoms. A significant interaction between OXT polymorphism (rs2740210 and rs2740209) and alcohol dependence in relation to anxiety symptoms solely among adults living with family and/or those who were married was observed. Further analyses indicate that the GG and CC genotypes are risk genotypes, while the T allele (rs2740210) and G allele (rs2740209) are non-risk alleles in the interaction between OXT genotypes (rs2740210, rs2740209) and alcohol dependence on anxiety among the aforementioned participants.ConclusionsThese findings provide evidence for distinct G × E interaction effects on anxiety and depression symptoms during acute alcohol withdrawal, supporting the weak diathesis-stress model. Furthermore, the study highlights the importance of considering environmental factors when investigating the role of oxytocin as a biological substrate underlying social bonding and the regulation of negative emotions.
Validation of a criterion-based screening and triage pathway for adult ADHD: a prospective observational study of safety and operational efficiency
BackgroundThe increasing demand for adult attention-deficit hyperactivity disorder (ADHD) assessments has required the development of efficient triage pathways. This study provides a formal assessment of a criterion-based screening model designed to prioritise patient safety and operational efficiency within a National Health Service (NHS) specialist secondary care setting.MethodsA prospective observational validation design was employed, involving 49 consecutive adults referred for ADHD assessment none of whom had a previous ADHD diagnosis. The Comprehensive ADHD Screening Questionnaire (CASQ), a clinician-administered instrument based on DSM-5 criteria, was utilised by four trained Physician Assistants. To ensure an assessment of triage safety, a universal assessment model was adopted: all participants received a blinded, gold-standard diagnostic assessment (NICE-compliant) regardless of the initial triage recommendation thereby eliminating verification bias. The primary outcome measure was the Number Needed to Harm (NNH), defined as the number of people screened before a single false-negative result occurs.ResultsOf the 48 participants who completed the diagnostic process, six (12.5%) received an ADHD diagnosis. The triage pathway correctly identified all six cases, resulting in a sensitivity of 100.0% (95% CI: 61.0%–100.0%) and an infinite NNH. Specificity was 45.2% (95% CI: 31.2%–59.9%), with a positive predictive value of 20.7%. The pathway permitted 39.6% (n = 19) of referrals to be triaged to alternative pathways rather than full ADHD assessment, potentially saving significant specialist clinician time. Exploratory analyses indicated that score magnitude did not reliably distinguish between true and false positives within the group triaged as appropriate for further assessment.ConclusionsThese preliminary findings suggest that criterion-based screening conducted by appropriately trained non-specialist clinicians can achieve high levels of safety whilst improving service efficiency. The findings support the feasibility of task-shifting models in adult ADHD services, provided that triage thresholds are calibrated to prioritise sensitivity. These results require replication in adequately powered multi-site studies before firm conclusions regarding pathway safety can be drawn. Further research is required to establish inter-rater reliability and cost-effectiveness across diverse clinical settings.