Citations

Abstract Background MR‐guided adaptive radiotherapy (ART) allows for daily plan optimization based on patient‐specific anatomy. Accumulated doses, driven by deformable image registration (DIR), of daily fractions can provide cumulative dose metrics and insights into toxicity and tumor control. In prostate ART, inter‐ and intra‐factional deformations, particularly due to bladder and rectum, pose a challenge to accurate DIR generation. Purpose To quantify geometric and dosimetric accuracy of a proposed prostate MR‐to‐MR DIR approach to support MR‐guided ART dose accumulation. Methods We evaluated DIR accuracy in 25 patients treated with 30 Gy in five fractions on a 1.5 T MR‐linac using an adaptive workflow. For all patients, a reference MR was used for planning, with three images collected at each fraction: adapt MR for adaptive planning, verify MR for pretreatment position verification and beam‐on for capturing anatomy during radiation delivery. We assessed three DIR approaches: intensity‐based, intensity‐based with controlling structures (CS), and intensity‐based with controlling structures and points of interest (CS + P). DIRs were performed between the reference and fraction images and within fractions (adapt‐to‐verify and adapt‐to‐beam‐on). For the evaluation, we propagated CTV, bladder, and rectum contours using the DIRs and compared each to manually delineated contours using Dice similarity coefficient, mean distance to agreement, and dose–volume metrics. Results CS and CS + P improved geometric agreement between manual and propagated contours over intensity‐only DIR. For example, mean distance to agreement (DTA mean ) for reference‐to‐beam‐on intensity‐only DIR was 0.131 ± 0.009 cm (CTV), 0.46 ± 0.08 cm (bladder), and 0.154 ± 0.013 cm (rectum). For the CS, the DTA mean values were 0.018 ± 0.002, 0.388 ± 0.14, and 0.036 ± 0.013 cm. Finally, for CS + P, these values were 0.015 ± 0.001, 0.025 ± 0.004, and 0.021 ± 0.002 cm. Dosimetrically, comparing CS and CS + P for reference to beam‐on DIRs resulted in a change of CTV D98% from [−29 cGy, 19 cGy] to [−18 cGy, 26 cGy], bladder D5cc from [−51 cGy, 544 cGy] to [−79 cGy, 36 cGy], and rectum D1cc from [−106 cGy, 72 cGy] to [−52 cGy, 74 cGy]. Conclusion CS improved geometric and dosimetric accuracy over intensity‐only DIR, with CS + P providing further performance improvement, particularly for bladder. However, session image segmentation remains a challenge, which may be addressed with automated contouring.

BACKGROUND AND OBJECTIVES: Unruptured intracranial aneurysms (UIAs) are increasingly detected and require careful management to prevent rupture. No externally validated score currently predicts procedural risk to guide treatment decisions. We developed and validated 2 predictive scores for complications after endovascular treatment (EVT) or neurosurgical treatment (NT) of UIA using routinely collected clinical and aneurysmal features. METHODS: We conducted a multicenter retrospective study including patients with UIA treated with EVT or NT across 15 neurovascular centers (2014-2024). Predictive models were built using multivariable logistic regression, with variables derived from Delphi consensus. The primary outcome was a composite safety end point: new neurological deficits, modified Rankin Scale (mRS) worsening (≥1 point or mRS 2-5 within 30 days), or procedural death. Internal validation used bootstrapping, and external validation was performed temporally and institutionally. Model performance was assessed using area under the receiver operating characteristic curve (AUROC) and calibration. Final scores, named Morbidity and Mortality Associated Risk in the Treatment of UIAs (MARTA)-EVT and MARTA-NT, were compared with existing models identified through systematic review. RESULTS: Among 2647 patients (1907 EVT and 740 NT), procedural complications occurred in 6.3% (EVT) and 12.8% (NT). Independent predictors included age, baseline mRS, aneurysm location, size, morphology, and procedural factors. MARTA-EVT (AUROC = 0.68, 95% CI = 0.57-0.78) and MARTA-NT (AUROC = 0.65, 95% CI = 0.54-0.77) showed moderate discrimination and good calibration. MARTA-EVT outperformed existing models; MARTA-NT performed similarly to SAFETEA. Predictive models are available open-source: https://martascoreapp.shinyapps.io/martascoreapp/. CONCLUSION: MARTA-EVT and MARTA-NT are validated tools for predicting procedural risks in UIA treatment and may support patient counseling and clinical decision making.

Sharing research code in an open access version-controlled repository offers significant benefits for both science as a whole and for individual researchers. In this article, we focus on this practice, which is fully aligned with the NIH’s Gold Standard Science (GSS) program as well as FAIR (findable, accessible, interoperable, reusable) and TRUST (transparency, responsibility, user focus, sustainability, technology) principles. Gold Standard Science supports open science by emphasizing transparency, reproducibility, and the use of best practices that enable others to verify and extend research. Pairing a research article’s cited data snapshot with a versioned, environment-specific code release, deposited in a companion code repository, ensures that, upon submission to a medical journal, readers and reviewers can directly verify results. An executable and updatable companion code repository complements, rather than replaces, established research data repositories. When code underlying medical research results is made openly available, then other scientists can inspect, run, and validate analyses. These activities enhance reproducibility, which is a core aim of GSS. Shared code also facilitates collaborative innovation by allowing researchers to extend the utility of the code to new datasets and applications. For researchers, code sharing can increase visibility, credibility, and citation impact. Demonstrating transparency through shared executable and updatable code builds trust with journal readers, peer reviewers, funders, and peers. Shared code in an open access repository signals adherence to high standards of scientific integrity and attracts opportunities for collaboration. A researcher who shares code receives recognition as a leader in reproducible, trustworthy research consistent with NIH’s GSS principles.

Background REM sleep behaviour disorder (RBD) is a prodrome of α -synucleinopathy, yet mechanistic pathways are unresolved. Narcolepsy type 1 with RBD (NT1-RBD) provides a human model of orexin deficiency. We tested whether REM motor semiology differs categorically between isolated RBD (iRBD) and NT1-RBD. Methods We retrospectively analyzed blinded video-polysomnographic scorings from 57 patients (iRBD n = 34; NT1-RBD n = 23). Across 857 REM events (iRBD 717; NT1-RBD 140), we classified topography (head/neck, trunk, upper, lower limbs), complexity (elementary vs. complex), content (scenic, violent, self-referential), vocal/orofacial features, spatial distribution and laterality using a pre-specified codebook. The patient was the primary unit of inference. Binary features used Fisher’s exact tests with Cohen’s h ; the per-patient complex-event proportion used Mann–Whitney and Cliff’s δ (bootstrap 95% CI). Robustness checks comprised Beta-Binomial posteriors (Beta [1,1]) and patient-label permutation tests (10,000 permutations). Results REM motor phenotypes diverged categorically. Lower-limb dominance occurred in 18/23 (78.3%) NT1-RBD vs. 7/34 (20.6%) iRBD (Fisher p < 0.0001; Cohen’s h ≈ +1.23), whereas upper-limb dominance occurred in 24/34 (70.6%) iRBD vs. 2/23 (8.7%) NT1-RBD ( p < 0.0001; h ≈ −1.40). Any complex event was present in 27/34 (79.4%) iRBD vs. 3/23 (13.0%) NT1-RBD ( p < 0.0001; h ≈ −1.46); violent enactments in 16/34 (47.1%) vs. 0/23 (0%) ( p < 0.0001; h ≈ −1.51). The per-patient complex-event proportion was higher in iRBD [median 0.21 (0.05–0.33)] than NT1-RBD [0.00 (0.00–0.00)] (Mann–Whitney p < 0.0001; Cliff’s δ = −0.665; 95% CI −0.853 to −0.441). Event-level summaries were concordant; permutation p -values were 0.0001 for upper-limb involvement and 0.0083 for complex behaviour. Conclusion iRBD and NT1-RBD exhibit qualitatively distinct REM motor phenotypes: upper-body-dominant, complex/scenic behaviours in iRBD versus elementary, predominantly bilateral lower-limb behaviours with notable trunk recruitment in NT1-RBD, supported by large effect sizes and convergent robustness checks. These findings motivate mechanistic studies of hypothalamic-brainstem-cortical integration in REM and suggest that semiological profiling may aid stratification in prodromal neurodegeneration.

Background: Vertebral body tethering (VBT) for adolescent idiopathic scoliosis (AIS) is an alternative to posterior fusion. There are limited prospective, multicenter data available on VBT following US Food and Drug Administration approval. We hypothesize that curve correction on first postoperative standing (first erect, FE) imaging is associated with higher rates of successful correction at final follow-up. Methods: All qualifying patients with AIS who underwent thoracic and lumbar VBT between 2019 and 2022 were prospectively enrolled from 9 institutions. Radiographic and clinical data were compared preoperatively, at FE, and at final follow-up with minimum of 2 years. Success was defined as major curve magnitude of ≤35° at final follow-up and no fusion surgery. Results: One hundred twenty-seven patients were enrolled (79.5% female), with mean follow-up 2.4 years. Mean age at surgery was 12.9 ± 1.4 years, most had bone age of Sanders 4 or lower (93/112, 83.0%). In average, 7.6 ± 1.7 levels were tethered. Mean preoperative major curve magnitude was 50 ± 8°, with mean initial correction at FE of 29 ± 8° (% correction, 39 ± 18%). At final follow-up, mean curve magnitude was maintained at 26 ± 11° (% correction, 45 ± 23%) despite 29% of tether breakage. Patients who had mean FE curve magnitude of ≤35° were 88% successful compared with only 60% in those with >35° on FE (p = 0.0021). Patients showed stable sagittal alignment across all timepoints. Scoliosis Research Society-22 scores improved significantly by 2 years (p < 0.0001). Conclusion: This was the first prospective, multicenter study to assess outcomes of VBT for patients with AIS. VBT shows promise, but optimal results may depend on careful patient selection and surgical technique. FE major curve magnitude of ≤35° was associated with 88% success rate compared with only 60% success for those with poor correction. Level of Evidence: Level II . See Instructions for Authors for a complete description of levels of evidence.

476 Background: Outcomes remain poor for patients with advanced/metastatic CCA treated with first-line gemcitabine-cisplatin +/- anti-PD(L)1. Lirafugratinib is the first highly selective, irreversible FGFR2 inhibitor designed to target oncogenic FGFR2 driver alterations and resistance mutations. ReFocus (NCT04526106) is an open-label, multicenter phase 1/2 study in patients with advanced/metastatic CCA and other solid tumors with FGFRok2 alterations. Methods: Pivotal cohort of patients (n=116) with advanced/metastatic CCA harboring FGFR2 f/r previously treated with ≥1 systemic therapy and FGFR i-naive were treated with oral lirafugratinib 70 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was confirmed ORR per RECIST v1.1 by independent review committee (IRC). Key secondary endpoint was duration of response (DOR); other secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and quality of life per EORTC QLC-C30. Results: As of 27SEP2024, the primary efficacy analysis of IRC-assessed data (n=114) and the secondary analysis of investigator-assessed data (n=116) set was done. The primary efficacy analysis excluded 2 patients as not available. Median age 57 years with 61.4% female. IRC-assessed ORR was 47%, and median DOR was 11.8 months (mos) (95% CI, 7.5-13.0), where 76.2% of responses lasted >6 mos. Median PFS was 11.3 mos (95% CI, 9.2, 14.8), with 12-month rate of 49.2%. Median OS was 22.8 mos (95% CI, 17.3-27.2), with 12-month rate of 74.6%. DCR was 96.5%. Common grade ≥3 on-target, off-tumor treatment-related adverse events (TRAEs) included palmar-plantar erythrodysesthesia (32.8%) and stomatitis (12.1%). TRAEs led to dose reductions of 75.9%, dose interruption of 82.8%, and treatment discontinuation of 4.3%. QoL was maintained. Conclusions: Lirafugratinib demonstrated clinically meaningful anti-tumor activity (ORR, DOR, and PFS), manageable and tolerable safety in CCA FGFR2 f/r patients. Clinical trial information: NCT04526106 . Best Overall Response, n (%) IRC c Investigator d Complete Response Partial Response Stable Disease Progression Disease Not Evaluable 3 (2.6)50 (43.9)57 (50.0)3 (2.6)1 (0.9) 061 (52.6)51 (44.0)3 (2.6)1 (0.9) ORR a , n (%)95% CI 53 (46.5)37.1, 56.1 61 (52.6)43.1, 61.9 DCR b , n (%)95% CI 110 (96.5)91.3, 99.0 112 (96.6)91.4, 99.1 a ORR defined as proportion achieving confirmed response of complete response or partial response per RECIST v1.1. b DCR defined as proportion with confirmed response of complete response, partial response, or stable disease per RECIST v1.1. c Primary Efficacy Analysis Set. d Secondary Efficacy Analysis Set. Percentages based on number of patients in the analysis set for each treatment arm. Exact Clopper-Pearson used for 95% CI. IRC and investigator assessments are based on different populations and cannot compare directly.

ABSTRACT Obstructive sleep apnea (OSA) is a common, heritable disorder with diverse clinical presentations and etiologies. We conducted a genome-wide association meta-analysis of 492,107 individuals, including 46,028 OSA cases, identifying 14 genome-wide significant loci, eight of which are novel. Analyses adjusting for body mass index (BMI) revealed three loci independent of obesity, implicating alternative biological pathways contributing to disease. Integrative functional analyses, including chromatin interaction mapping, fine-mapping, and eQTL colocalization, prioritized candidate effector genes. Notably, implicated genes in chondrocytes were associated with craniofacial morphology in both mouse and human multivariate genotype-phenotype mapping, supporting a role for craniofacial structure in OSA risk. These findings highlight key genetic pathways (obesity-related, neurological, and craniofacial) underlying the development of OSA, offering new insights into its complex etiology.

Abstract INTRODUCTION Tau species lacking truncation of the N‐terminal region, including plasma N‐terminal tau fragment 1 (NT1), have been previously associated with cognitive decline, neurodegeneration, and tau pathology in late‐onset sporadic Alzheimer's disease (AD). METHODS Here, we examined cross‐sectional and longitudinal plasma NT1 as a possible predictor of cognitive, clinical, and core AD biomarker trajectories in autosomal dominant AD (ADAD). RESULTS NT1 levels in ADAD mutation carriers (MC; n = 132) increased across the disease continuum, compared to non‐carriers (NC; n = 75), becoming elevated about a decade prior to estimated symptom onset. Cross‐sectional and longitudinal NT1 levels in MC were associated with clinical, cognitive, and biomarker changes. NT1 increases continued in symptomatic phases of disease, a distinct trajectory from that seen with CSF p‐tau217 and other phospho‐tau species. DISCUSSION Together, our results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related clinical, cognitive, and biomarker outcomes. Highlights Leveraging a deeply phenotyped cohort of individuals carrying a pathogenic variant for autosomal dominant Alzheimer's disease (ADAD) and their non‐carrier family members, our results suggest that plasma N‐terminal tau fragment 1 (NT1) levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with cerebrospinal fluid (CSF) measures of tau pathology but less so with CSF or imaging measures of β‐amyloid pathology. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related tau pathology and neurodegeneration across a wide spectrum of disease.

Background: Institutions that participate in PCORnet ® transform their local electronic health record (EHR) data into the PCORnet ® Common Data Model (CDM), which is then used to generate data extracts for PCORnet ® Studies. PCORnet ® Studies can also include institutions that do not participate in PCORnet, and for these organizations, the cost of instantiating a PCORnet ® CDM can be prohibitive. Fast Health care Interoperability Resources (FHIR) provides an alternative method of obtaining EHR data. Objective: To determine whether data obtained through FHIR might be a viable study solution for those sites that do not participate in PCORnet. ® This mixed-methods project had 2 objectives: (1) survey sites participating in PCORnet on the availability of FHIR (FHIR survey); (2) compare the coverage of a FHIR-based data extract using REDCap with one from the PCORnet ® CDM across 3 sites (FHIR extract). Methods: (1) FHIR survey: A series of questions were asked about the use of FHIR in a production capacity. (2) FHIR extract: REDCap FHIR and PCORnet ® CDM extracts were created based on study variables from 2 prior PCORnet ® Studies. Data were extracted for 40 patients and concordance measures were computed between the 2 sources. Results: (1) FHIR survey: Of responding organizations, 73% (n=49) reported that FHIR was deployed in a production capacity. (2) FHIR extract: Results were highly variable. Cohen kappa ranged from 0.01 to 0.76 for certain diagnoses, 0.24 to 0.84 for laboratory results, and 0.1 to 0.87 for medications. Conclusions: Despite differences in data, certain studies may be well-suited for FHIR-based extracts.