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10030 Background: CABO is a multi-targeted kinase inhibitor of VEGFR2, c-MET, AXL and RET and has shown clinical evidence of activity in two prior studies of adult and pediatric patients with advanced OS. We report results of a feasibility cohort of CABO + MAP chemotherapy in patients with newly diagnosed high-risk OS. Methods: Patients <40 years, body surface area ≥ 0.8 m 2 and new diagnosis of high-grade OS with metastatic disease and resectable primary tumor were eligible. Patients were enrolled to two CABO dose levels (Dose Level 1 (DL1) 25 mg/m 2 /day, maximum 40 mg/day; Dose Level 2 (DL2) 35 mg/m 2 /day; maximum 60 mg/day) using a modified IQ 3+3 design. CABO was orally administered concomitantly with six 35-day cycles of MAP (cisplatin 60 mg/m 2 on days 1-2 (cycles 1-4), doxorubicin 37.5 mg/m 2 on days 1-2 (with dexrazoxane), methotrexate 12 g/m 2 on days 22, 29) and for 24 weeks as maintenance monotherapy. CABO was held after 7 weeks and resumed during 4 th MAP cycle to allow for primary tumor resection and metastatic surgeries. Dose-limiting toxicities (DLT) were assessed during weeks 1-6 of treatment; additional monitoring for post-surgical complications was conducted through completion of 4 th MAP cycle. The primary endpoint for this cohort was feasibility of combination therapy. Results: Ten patients (median age 11.5 years, 70% male) were enrolled and treated with CABO + MAP (DL1, n=4; DL2, n=6). Median cumulative doses of all MAP agents were maintained throughout treatment with no dose reductions. Concomitant dosing of CABO with MAP was tolerated with no protocol-specified DLTs occurring during the evaluation period. DL2 (35 mg/m 2 ) was established as the recommended dose for further study of combination therapy. Commonly reported adverse events included hematologic toxicities, febrile neutropenia, and alanine/aspartate aminotransferase (AST/ALT) elevation. Interruption of CABO was required in 6 patients for Grade 3+ AST/ALT elevation following methotrexate (n=3), wound complications (n=3), and Grade 3 pneumothorax (n=1). Wounds included two Grade 3 port site events and one Grade 1 primary tumor resection site; two patients later resumed CABO after healing without wound recurrence. Dose reduction of CABO was required in one patient for Grade 4 amylase elevation. Conclusions: The combination of CABO + MAP is feasible with no protocol-specified DLTs during the evaluation period. Generalizability is limited based on cohort size. Further evaluation of CABO + MAP is ongoing in a phase II/III randomized efficacy study in newly diagnosed standard and high-risk patients using CABO dose of 35 mg/m 2 /day (max 60 mg), with delayed initiation of CABO in patients with port placement and early safety monitoring for wound-related events, as well as full study monitoring of dose delivery, wound complications and systemic toxicity. Clinical trial information: NCT05691478 .

Abstract INTRODUCTION Research into cognitive dispersion – a cognitive process score measuring the intra‐individual variability (IIV) across a single testing session – suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early‐onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition. METHODS A total of 309 participants (188 amyloid‐positive EOAD, 43 amyloid‐negative early‐onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion‐related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain‐specific cognitive trajectories, and its convergence with imaging biomarkers. RESULTS EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD‐specific biomarkers. Additionally, cognitive dispersion was associated with 12‐month reliable change across several cognitive domains. DISCUSSION These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Background Patients with chronic obstructive pulmonary disease (COPD) are particularly vulnerable to severe respiratory infections. While COVID-19 vaccination has demonstrated effectiveness in reducing severe disease in the general population, its real-world impact on clinical outcomes among COPD patients remains underexplored. Understanding these outcomes could strengthen vaccination advocacy and guide COPD management strategies. Research Question Does COVID-19 vaccination reduce the risk of mortality, COPD exacerbations, and mechanical ventilation in adults with COPD? Methods We conducted a retrospective, propensity-matched cohort study using the TriNetX US Collaborative Network, which aggregates de-identified electronic health records from 72 healthcare organizations. Adults with COPD were identified using ICD-10 code J44 and spirometric confirmation (FEV1/FVC ≤ 70%). Cohorts were divided by COVID-19 vaccination status, identified through CPT and RxNorm codes. The index date was defined as the earliest qualifying encounter, with outcomes assessed thereafter.Primary outcome was all-cause mortality; secondary outcomes included COPD exacerbation (J44.1) and mechanical ventilation (ICD-10-PCS 5A1945Z). Propensity-score matching (1:1) was performed on age, sex, race, comorbidities, and baseline clinical characteristics, yielding balanced cohorts (n = 3,969 each). Risk ratios (RR), hazard ratios (HR), and Kaplan-Meier survival analyses were calculated, with significance set at p &lt; 0.05. Results After matching, median follow-up was 894 days for the unvaccinated group and 886 days for the vaccinated group. All-cause mortality 23.8% (942/3,954) in unvaccinated vs 11.1% (442/3,968) in vaccinated; RR 2.14 (95% CI 1.93-2.37); HR 1.80 (95% CI 1.60-2.02); p &lt; 0.001. COPD exacerbations 31.3% (1,243/3,969) in unvaccinated vs 25.3% (1,006/3,969) in vaccinated; RR 1.24 (95% CI 1.15-1.33); HR 1.24 (95% CI 1.14-1.35); p &lt; 0.001. Mechanical ventilation 1.8% (72/3,902) in unvaccinated vs 0.8% (30/3,928) in vaccinated; RR 2.42 (95% CI 1.58-3.69); HR 2.06 (95% CI 1.33-3.18); p = 0.001. Kaplan-Meier curves demonstrated consistently higher survival and event-free probabilities among vaccinated patients across all outcomes. Conclusions In this large, real-world analysis, COVID-19 vaccination was associated with significantly lower risks of all-cause mortality, COPD exacerbations, and need for mechanical ventilation. These findings emphasize the importance of vaccination as a key component of COPD care, supporting its inclusion in quality-improvement metrics and clinical counseling for patients with chronic lung disease. This abstract is funded by: None

Abstract Background Obesity contributes to worse symptoms and exacerbations in chronic obstructive pulmonary disease (COPD). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve weight and metabolic profiles and have emerging pulmonary benefits. However, their real-world impact on respiratory outcomes in patients with COPD and obesity is not well established. Research Question Among obese adults with COPD, is GLP-1 RA use associated with reduced risk of COPD exacerbations, acute respiratory failure, and all-cause mortality compared with those not receiving GLP-1 therapy? Methods We conducted a retrospective, propensity-matched cohort study using the TriNetX U.S. Collaborative Network. Adults aged ≥40 years with COPD (ICD-10 J44) and BMI ≥30 kg/m² were included. The exposed cohort comprised patients prescribed GLP-1 RAs (lixisenatide, albiglutide, dulaglutide, liraglutide, semaglutide, or exenatide), while comparators had no exposure. The index event was the first date meeting inclusion criteria. Outcomes were analyzed beginning 180 days after index to minimize reverse causation, excluding those with prior events. Propensity score matching (1:1) balanced demographics, comorbidities, laboratory data, and medication use, yielding 2,795 patients per group. Primary outcomes included the risk (≥1 event within window) of COPD exacerbation, acute respiratory hypoxic and/or hypercapnic failure leading to hospitalization, and all-cause mortality. Risk difference (RD), risk ratio (RR), and odds ratio (OR) were calculated; Kaplan-Meier and log-rank testing assessed time-to-event. Results After matching, baseline characteristics were well balanced. GLP-1 RA use was associated with significantly lower risk across all outcomes:COPD Exacerbation (J44.1): 18.2% (No GLP-1) vs 11.2% (GLP-1); RD 7.0%, RR 1.63 (95% CI 1.36-1.94); p = 0.042.Acute Hypoxic and/or Hypercapnic Respiratory Failure (J96.x): 19.2% vs 11.5%; RD 7.7%, RR 1.67 (1.42-1.96).All-Cause Mortality: 14.6% vs 7.6%; RD 7.0%, RR 1.92 (1.64-2.25); p = 0.010. Kaplan-Meier survival analysis demonstrated significantly improved survival in the GLP-1 group for mortality and COPD exacerbation outcomes. Conclusions In obese adults with COPD, GLP-1 RA therapy was associated with clinically and statistically significant reductions in COPD exacerbations, acute respiratory failure, and all-cause mortality. These findings suggest that GLP-1 RAs may offer dual metabolic and pulmonary benefits and warrant evaluation as adjunctive therapy in future prospective trials. This abstract is funded by: None

Abstract The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer’s disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer’s disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer’s Disease Study. Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer’s disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)—an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer’s disease. Subtype 2/Left temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1/Typical for amnestic presentations, S2/Left Temporal for primary progressive aphasia, and S3/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 ± 0.70 SuStaIn stage/year. Longitudinal voxel-wise linear mixed-effects modelling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1/Typical, bilateral frontal and right temporal in S2/Left Temporal, and bilateral frontotemporal lobes in S3/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3/Posterior compared with the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer’s disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Background: Total knee arthroplasty (TKA) is the treatment of choice for end-stage knee osteoarthritis in many patients. In younger patients with predominantly medial compartment disease, high tibial osteotomy (HTO) is performed as a joint-preserving treatment. However, concerns remain regarding potentially compromised outcomes of TKA after previous HTO given the axial deviation, osteotomy site, secondary surgery, previous hardware, and instrumentation. Therefore, this study compared long-term implant survival, revision, and infection rates, and patient-reported outcomes between patients undergoing TKA after HTO and matched TKA-only controls. Methods: Postoperative complications and revision surgeries were prospectively recorded in patients who underwent TKA from 2000 to 2023 at a single academic center. Patients with previous ipsilateral HTO formed the study group and were propensity matched 1:2 to TKA-only patients without a previous osteotomy based on age, sex, and body mass index. Knee Society Scores (KSS) were collected prospectively. Implant survivorship was analyzed using Kaplan-Meier survival curves and Cox proportional hazards models. Results: The study included 134 HTO-TKA and 268 matched TKA-only patients, with a mean follow-up of 10.5 ± 6.4 years (range: 0-24 years) after TKA. Both groups showed significant postoperative improvements in KSS (p < 0.02) with comparable clinical outcomes (HTO-TKA: 79.0 (6.0), TKA-only: 79.0 (11.8)). Revision arthroplasty rates were 5.2% for HTO-TKA and 4.5% for TKA-only (p = 0.69); the mean time to revision was 8.1 ± 8.7 years vs. 4.4 ± 3.5 years, respectively (p = 0.30). Infection rates were 2.2% and 1.1%, respectively (p = 0.74). Conclusions: Revision and infection rates were comparable between HTO-TKA and matched TKA-only patients, with no statistically significant differences. Our findings demonstrate comparable patient-reported outcomes in both groups. These findings indicate that a previous HTO does not adversely affect TKA implant longevity or clinical outcomes when compared with matched primary TKA patients within the US population. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background Frontotemporal dementia is an umbrella term that encompasses several clinical syndromes with impaired behavioral, language, and motor functions. These syndromes show considerable overlap in clinical features and imaging patterns. Therefore, there is a need to investigate the syndromic heterogeneity in FTD using unbiased data-driven approaches. Methods We used data-driven clustering analysis of structural magnetic resonance imaging (MRI) data on 400 patients with clinical FTD diagnoses [behavioral variant of frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia (svPPA), right temporal variant of frontotemporal dementia (rtvFTD), apraxia of speech with agrammatic aphasia (AOS-PAA), primary progressive apraxia of speech (PPAOS), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and primary progressive aphasia who did not fit into the other diagnostic categories (PPA-other)]. MR images were w-scored relative to cognitively unimpaired individuals, and principal component analysis was performed. A clustering ensemble approach, including hierarchical algorithms, was applied to the MR-based principal components, and imaging and clinical characteristics of the clusters were investigated. Various numbers of clusters ( K = 2, 3, or 4) were evaluated. Results The K = 3 solution offered the most clinically meaningful separation of FTD syndromes. The first cluster captured mostly frontal MRI abnormalities related to the speech, language and behavioral clinical dimensions, including patients with AOS-PAA, PPAOS, PPA-other, and bvFTD. The second cluster captured mostly temporal abnormalities and included mainly patients with svPPA and rtvFTD, but also bvFTD, AOS-PAA, and PPA-other. The third cluster captured cortical and subcortical atrophy, particularly in the midbrain, and included atypical Parkinsonian syndromes, with all PSP and CBS patients captured in this cluster, as well as most PPAOS patients. Considerable overlap of clinical syndromes was noted across these clusters, whereby patients with AOS-PAA, svPPA, PPA-other, and bvFTD were captured in more than one cluster. Discussion Our findings highlight heterogeneity in FTD, which mainly exists along three axes: speech, language and behavioral deficits reflecting frontal atrophy, language deficits reflecting temporal atrophy, and motor and motor speech deficits reflecting mostly midbrain and subcortical atrophy, with cortical involvement.