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Background Patient complaints provide a complementary lens on surgical safety, yet prior analyses have been small and specialty specific. We aimed to characterise themes, perioperative processes, system factors and outcomes in surgical complaints using a scalable, large language model (LLM)-assisted approach. Methods We performed a national, retrospective, cross-sectional, sequential methods study of publicly available investigation reports from the Aotearoa New Zealand Health and Disability Commissioner. All reports published since 1998 were retrieved and screened for relevance across all surgical specialties. A fixed-parameter LLM workflow extracted demographics, clinical context, complications, breached patient rights, system factors and outcomes. An inductive LLM-supported thematic synthesis generated complaint themes, followed by rescoring of theme relevance across reports. Human validation supported the LLM-assisted process (Cohen’s κ >0.85). Results Of 1827 reports screened, 650 involved surgical care. Postoperative complications were frequent (84.2%), commonly accompanied by permanent disability (33.2%) or death (24.2%). Delays in recognition of deterioration (76.1%), escalation (58.3%) and definitive management (49.5%) of complications were common and associated with higher mortality. Prominent themes concerned postoperative clinical management/monitoring, communication/informed consent and professional conduct/competence. Technical/procedural errors and medication errors were comparatively less common. Breaches are most often related to reasonable care and skill, and to informed consent, with marked variation across specialties. Conclusions Complaints about surgical care predominantly reflect postoperative monitoring, escalation and communication rather than intraoperative technical errors. System priorities should include robust deterioration recognition and response, reliable handover and escalation pathways, and strengthened consent and communication processes. An LLM-assisted pipeline can scale complaint analysis to support organisational learning and quality improvement.

Abstract Background Current literature suggestsisocitrate dehydrogenase (IDH)-mutant astrocytoma contains several molecular subgroups. In this study, we are interested in determining the connection between different molecular subgroups with grade and/or survival. Methods A cohort of 470 Mayo Clinic adult patients (≥18 years, 56.2% male) with primary IDH-mutant astrocytoma diagnosed by World Health Organization (WHO) 2021 criteria were examined. Results were validated in an independent cohort of 614 Mayo Clinic Neuropathology consult patients and 235 The Cancer Genome Atlas (TCGA) patients. Results The Mayo Clinic Practice cohort confirmed the association of CDKN2A/B deletion with overall survival (OS, homozygous vs hemizygous vs intact, 2.7 vs 9.6 vs 17.2 years, P < .001). Phosphatase and tensin homolog (PTEN) deletion was also associated with poor OS (7.3 vs 17.4 years, P < .001). Increased number of copy number alterations was associated with OS (continuous variable, HR = 1.027, P < .001). Carrying one or more copies of the germline risk allele at rs55705857 was associated with earlier age of onset (median age 33 vs 35 years, P = .01), and a shorter OS after adjusting for age, grade, sex and treatment (HR = 1.81, P = .007). The Mayo Clinic Neuropathology Consult cohort and TCGA were utilized to validate age of onset and survival, respectively. Unsupervised clustering of the copy number alterations identified several clinically significant groups that may define pathways to disease progression. Losses of chromosomes 11p, 13q, 1p, and 10q were all associated with reduced overall survival in the Mayo Clinic cohort. Conclusions Patients with hemizygous loss of CDKN2A/B, loss of PTEN, increased number of copy number alterations, specific chromosomal arm losses or rs55705857 germline risk allele have reduced overall survival.

Abstract Early-onset Alzheimer’s disease (EOAD) and Late-onset AD (LOAD) differ in clinical presentations and rates of progression. We aimed to compare baseline and longitudinal tau PET burden, and their relationship with clinical variables in amyloid-PET positive, cognitively impaired participants from the Longitudinal Early-Onset Alzheimer’s Disease Study (EOAD; n=390) and Alzheimer’s Disease Neuroimaging Initiative (LOAD; n=211). Patients with EOAD showed higher baseline tau PET retention, broader neuroanatomical involvement and faster accumulation rates over time compared to LOAD, after adjusting for amyloid load and clinical stage. Tau PET showed stronger correlations with baseline amyloid burden and clinical measures of global cognition and function in EOAD than LOAD. We conclude that earlier age of onset in AD is linked to a more aggressive tauopathy, which in turn is a primary driver of clinical decline. These findings suggest that optimal therapeutic targets and strategies may differ between EOAD and LOAD. One Sentence Summary Younger patients with Alzheimer’s disease show more aggressive tau spread, suggesting age of onset defines distinct disease pathways with key clinical implications.

Abstract Recent updates to monocyte count thresholds recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML. However, the clinical validity of these changes remains uncertain without incorporating biological and genomic factors. In this study, we analyzed a cohort of 911 patients (249 with OM-CMML, 359 with overt CMML, and 303 with myelodysplastic syndromes) using unsupervised clustering to evaluate the role of genomic determinants in refining CMML diagnosis. Our findings show that CMML molecular signatures (biallelic TET2 mutations or SRSF2-TET2 comutations) are linked to a distinct transcriptome, monocytic bias, classical monocytosis, and a higher risk of progression to overt CMML in OM-CMML cases. We developed a weighted genomic model and diagnostic workflow showing that combining genomic signatures with bone marrow monocyte frequencies in OM-CMML more accurately predicts progression to overt CMML. These findings support integrating genomic determinants and our clinic-ready diagnostic workflow into the CMML diagnostic framework to improve accuracy. Significance: Through comprehensive clinical and genomic profiling of a large patient cohort, alongside immunophenotypic and transcriptional cellular analyses, this study provides evidence that incorporating genomic determinants into the diagnostic criteria for OM-CMML improves diagnostic accuracy and refines the identification of early-stage CMML, thereby preventing misclassification.

Abstract Background There is an unmet need for ulcerative colitis (UC) treatments that show improved effectiveness while maintaining safety profiles comparable with existing advanced therapies. Dual targeted therapy (DTT) has been proposed as a strategy to combine benefits of different advanced therapies to improve outcomes. The ExiGem study (NCT06095128) aims to assess the efficacy and safety of combined therapy with vedolizumab (VDZ) and tofacitinib (TOF) in adults with UC. We report results for the induction phase from the first 24 patients. Methods ExiGem is an ongoing phase 4, single-arm, multicentre study including adults with moderately to severely active UC (complete Mayo [cMayo] score of 6–12 with a rectal bleeding subscore ≥ 1 and centrally read endoscopic subscore ≥ 2). Eligible patients have previously had an inadequate response, loss of response, or intolerance to 1 or 2 anti-tumour necrosis factor α treatments. Patients receive induction therapy with intravenous (IV) VDZ 300 mg at weeks 0, 2, and 6 plus twice-daily oral TOF 10 mg for 8 weeks and then VDZ 300 mg IV monotherapy as maintenance from week 14. The primary endpoint is the proportion of patients in clinical remission by cMayo score at week 8. Secondary endpoints include clinical response and clinical remission by modified Mayo (mMayo) score at week 8. Changes in faecal calprotectin (FCP) levels and endoscopic improvement were evaluated. Efficacy data were analysed using non-responder imputation. For the final analysis a pre-specified Bayesian approach will be used. The safety profile of DTT was evaluated. Results Patient baseline characteristics are shown in Table 1. At week 8, 12/24 patients (50%) and 14/24 patients (58%) had clinical remission assessed by cMayo and mMayo scores, respectively; these rates were higher than pre-specified benchmark rates (Figure 1). Clinical response was observed in 21/24 patients (88%). At week 8, 14/24 patients (58%) showed endoscopic improvement, and 12/21 patients (57%) had normalization of FCP levels (< 250 µg/g). Treatment-emergent adverse events (TEAEs) were experienced by 10 patients (42%), and 1 serious TEAE was reported (suspected viral infection). One severe adverse event (AE; cough) and 2 moderate AEs (herpes zoster, drug intolerance) were considered related to TOF. No moderate or severe AEs were considered related to VDZ. One patient withdrew from the study before week 8 owing to intolerance to TOF. Conclusion Initial data suggest that induction with a combination of VDZ and TOF can produce improved rates of response and remission in patients with UC with a comparable safety profile to existing advanced monotherapies. Further data, including outcomes of VDZ maintenance as monotherapy, are pending. Conflict of interest: Prof. Dr. Yarur, Andres: Andres Yarur has served as an advisory board member for Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Roche/Genentech, and Takeda. This study was funded by Takeda Pharmaceuticals U.S.A., Inc. Medical writing support was provided by Adam Errington PhD of PharmaGenesis Cardiff, Cardiff, UK, and funded by Takeda Pharmaceuticals U.S.A., Inc. Barnes, Edward: Personal Fees: Consultant for Takeda, Pfizer, Roche, Merck, Abbvie, Eli Lilly. Bristol Myers Squibb, Celltrion, Johnson and Johnson. Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI. Ha, Christina: Christina Ha has served as an advisory board member for AbbVie, Bausch Health, Johnson & Johnson, Lilly, Merck, Takeda, and Sanofi has received educational programming support from AbbVie, Celltrion, Johnson & Johnson, Lilly, Pfizer, and Takeda and has received consulting fees from AbbVie. Hudesman, David: Consultant: Abbvie, Abivax, BMS, Biocon, Eli Lilly, Fresenius Kabi, Pfizer, Prometheus, CorEvitas, Takeda, Johnson and Johnson, Sanofi Research Support: Johnson and Johnson, Pfizer Jairath, Vipul: Consulting Fees: Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Lukin, Dana: Dana Lukin has served as a consultant/advisory board member for AbbVie, AltruBio, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Palatin, Pfizer, Prime, PSI, Takeda, and Vedanta has received grants from Boehringer Ingelheim and Johnson & Johnson and serves as a speaker for AbbVie and Johnson & Johnson. Rubin, David T.: Grant support: Takeda Pharmaceuticals. Consultant: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx. Schreiber, Stefan Wolfgang: Stefan Schreiber has received consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring, Fresenius, Galapagos, Genentech, Gilead, GlaxoSmithKline, I-MAB Biopharma, Janssen, Merck, Novartis/Sandoz, Pfizer, Protagonist, Takeda, and Ventyx Biosciences. Gower, Megan: Megan Gower is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Jones, Stephen: Stephen Jones is an independent medical consultant who provides services for Takeda Pharmaceuticals U.S.A., Inc. Robinson, Ian: Ian Robinson is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Sanchirico, Marie: Marie Sanchirico is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Yajnik, Vijay: Vijay Yajnik is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc.

Background/Objectives: Postoperative opioid exposure after lumbar fusion remains a key clinical concern. Understanding which perioperative factors are associated with lower postoperative opioid use may help optimize recovery after minimally invasive (MIS) transforaminal lumbar interbody fusion (TLIF). This study aimed to determine if patients undergoing MIS-TLIF under spinal anesthesia (SA) showed lower postoperative opioid use compared to those undergoing MIS-TLIF under general anesthesia (GA). Methods: We retrospectively studied all adult patients (>18 years) undergoing 1- and contiguous 2-level MIS-TLIFs performed by a single surgeon. Patients undergoing the procedure under GA were compared to those undergoing the procedure under SA. Postoperative oral opioid use, up to 3 months post discharge, was collected. A 1:1 propensity score matching (PSM) protocol was implemented. Each outcome variable was initially assessed using univariate regression. Predictor variables with a p-value < 0.2 were included in the multivariate regression model. This was a retrospective, non-randomized study, and residual confounding cannot be excluded despite PSM. Results: The matched groups (n = 50 in each group) did not differ significantly depending on demographics or levels fused. Before regression, mean number of postoperative opioid prescriptions (p = 0.03), mean total operating room (OR) time in minutes (p < 0.01), and median length of stay (LOS) in days (p = 0.03) were significantly different. Multivariate regression showed that the GA group received 216.5 more total morphine milligram equivalents than the SA group (95% CI = 0.7–432.2, p = 0.049). The days of opioid use were higher in the GA group by 3.8 days (95% CI = 0.5 to 7.1, p = 0.025). On multivariate regression, LOS in hours was greater in the GA group by 14.1 h (p = 0.042). Conclusions: SA is an effective anesthetic modality for spinal surgery with the advantages of reduced postoperative opioid use, reduced OR time, and shorter LOS compared to GA.

Abstract INTRODUCTION The genetic basis of sporadic early‐onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late‐onset Alzheimer's disease (LOAD) polygenic risk in EOAD. METHODS A LOAD polygenic score (PGS) was calculated in the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. RESULTS Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset ( p = 0.106) or with cognitive performance ( p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal‐associated protein 25 (SNAP‐25) ( p = 2.3 × 10 −5 ). DISCUSSION While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. Highlights LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal‐associated protein 25 (SNAP‐25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD.

Abstract Motivation: Epilepsy is a diverse group of neurological disorders affecting over 50 million people worldwide. While common epilepsy types are well studied, rare epilepsies—often severe and genetically complex—pose significant challenges in diagnosis, research, and treatment. Accurate and interoperable etiology and disease classifications are critical for improving data sharing, supporting clinical decision-making, and advancing rare disease research. Results: To enhance the accuracy of epilepsy-related disease concept representation within the Mondo Disease Ontology (Mondo), we conducted a series of expert-driven workshops in collaboration with the team from the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP). Specialists in epileptology, genetics, neurodevelopment, biomedical ontology, and patient community advocates systematically reviewed and revised the epilepsy hierarchy in Mondo, aligning it with the International League Against Epilepsy (ILAE) classification system. These updates include reclassification of epilepsy subtypes, including syndromes, age-related epilepsies, and developmental epileptic encephalopathies, resulting in a more granular, standardized, and clinically relevant structure. Mondo now offers an enhanced framework for integrating epilepsy data across resources, enabling improved interoperability and facilitating rare disease research and data curation, with continued efforts underway to further refine and expand this integration.

ABSTRACT Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS) 1,2 . We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET) 3 , termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) 4 , which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD) 5,6 , which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewing’s sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold 3 . Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.