Citations

Abstract Background Cone‐beam computed tomography (CBCT) is essential for image‐guided particle therapy (IGPT), providing daily patient positioning, anatomical monitoring, and treatment verification. However, conventional single‐detector CBCT suffers from poor soft‐tissue contrast, long acquisition times, and motion artifacts, reducing its effectiveness for adaptive radiotherapy workflows. Addressing these challenges requires an advanced CBCT reconstruction approach capable of enhancing image quality while reducing scan time and radiation exposure. Purpose This study introduces a Dual Detector Combined Scanning (DDCS) CBCT reconstruction algorithm to overcome conventional CBCT limitations. By integrating a dual‐source, orthogonal imaging setup, DDCS significantly reduces scanning time and imaging artifacts. A modified Parker‐weighting algorithm further improves image reconstruction accuracy, ensuring high‐fidelity visualization. The goal is to enhance adaptive radiotherapy by improving real‐time patient positioning, dose verification, and motion management. Methods A dual‐detector CBCT system was designed to acquire orthogonal projections simultaneously, reducing scan time and improving data completeness. A modified Parker‐weighting algorithm corrected angular overlap distortions, ensuring better reconstruction accuracy. The system was evaluated using numerical and physical phantom studies to assess spatial resolution, contrast‐to‐noise ratio (CNR), and artifact reduction. Additionally, a dynamic phantom simulated respiratory motion, validating motion robustness for adaptive radiotherapy. Performance was compared against single‐detector CBCT, focusing on image fidelity, noise suppression, and computational efficiency. Results DDCS‐CBCT demonstrated higher CNR, reduced motion artifacts, and improved spatial resolution, leading to more accurate anatomical visualization. The system's efficiency enables faster, more reliable patient setup in IGPT while maintaining a lower imaging dose. Conclusion The proposed DDCS‐CBCT approach significantly improves imaging accuracy, reduces scan time, and enhances real‐time volumetric guidance in IGRT/IGPT. These findings support the clinical feasibility of the DDCS system and its integration into online adaptive radiotherapy workflows.

Abstract The external globus pallidus (GPe) has traditionally been viewed as a relay nucleus within the basal ganglia (BG), but accumulating evidence indicates a more dynamic role in reinforcement learning (RL). One key characteristic of GPe activity—transient pauses in high-frequency discharge (HFD) neurons—is preserved across species, yet its potential implications in RL remains unclear. Here, we developed a neurophysiologically grounded computational model to investigate the origin and role of GPe pauses in RL. Our model successfully replicated a range of empirical observations, including pause dynamics during learning and cue-related activity modulation. We demonstrated that the GPe-subthalamic nucleus (STN) circuit functions analogously to a denoising autoencoder, modulating baseline excitability in downstream BG circuits and that GPe pauses emerge as circuit-level consequences of strong, convergent inhibition from the GPe to STN. Simulations and in vivo recordings revealed that the activity of GPe-STN projecting neurons increases following sudden environmental changes, promoting adaptive exploration by disrupting action value contrast. Intriguingly, this same configuration impairs performance with extended training, suggesting that habitual behavior may benefit from weakened GPe-to-STN projections. These findings provide a unifying framework for understanding GPe pause dynamics and highlight circuit-level distinctions supporting the balance between flexibility and proficiency in RL.

Abstract Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. Leveraging comparison cohorts of diffuse large B-cell lymphoma, NOS (DLBCL-NOS) and Burkitt lymphoma (BL), and molecular frameworks described in these entities, our analysis revealed a heterogenous molecular landscape, reminiscent of DLBCL-NOS but with an enrichment of BL features. By cell-of-origin classification, 59% were germinal center B-cell–like (GCB), and 25% were activated B-cell–like (ABC). LymphGen, a genetic classifier for DLBCL-NOS, assigned a genetic subtype to 34% of HGBCL-NOS. Although classification rate was lower than in DLBCL-NOS (66%), assigned subtypes spanned the spectrum of LymphGen classes, including 31% of ABCs classified as MCD. Features differentiating HGBCL-NOS from DLBCL-NOS included MYC rearrangement (47% vs 6%); dark zone signature (DZsig) expression (45% vs 7%); and more frequent mutation of ID3, MYC, CCND3, and TP53, all common to BL. A genetic classifier that differentiates DLBCL-NOS from BL classified 53% of DZsig+ tumors as BL-like, and those classified as DLBCL-like were frequently BCL2-rearranged. Among DZsig− GCB tumors, 95% were DLBCL-like. Centralized pathology review reclassified almost half of tumors as DLBCL-NOS but did not identify a more homogenous HGBCL-NOS population, with no difference in features between confirmed and reclassified tumors. In conclusion, molecular testing enables a subset of HGBCL-NOS to be assigned to established categories. Based on rarity and diagnostic challenges, broader inclusion of HGBCL-NOS should be considered in biomarker-driven DLBCL trials.

ABSTRACT Background Functional lumen imaging probe (FLIP) utility is established in treatment‐naïve achalasia but less clear following lower esophageal sphincter (LES) directed therapy. Methods Achalasia patients with LES directed therapy across three tertiary care centers between 2017 and 2024 with post‐treatment FLIP and timed barium esophagram (TBE) were retrospectively identified. Reduced esophagogastric junction (EGJ) opening was defined by distensibility index (DI) < 2 mm 2 /mmHg and diameter < 12 mm. Abnormal emptying on TBE was defined as column height ≥ 5 cm at 5 min and/or retained tablet. Eckardt scores ≤ 3 defined clinical response. Key Results The study included 222 patients (46% peroral endoscopic myotomy, 46% laparoscopic Heller myotomy, 8% pneumatic dilation) with a median of 1.4 years to post‐treatment TBE/FLIP. Abnormal emptying on TBE was associated with a narrower median EGJ diameter (13.2 vs. 14.8 mm, p = 0.008), a greater frequency of EGJ diameter < 12 mm (36% vs. 21%, p = 0.012), and a smaller change in EGJ diameter (+4.6 vs. +8.6 mm, p = 0.002). Abnormal emptying on TBE occurred more frequently in patients with EGJ DI < 2 mm 2 /mmHg (8.5% vs. 2.6%, p = 0.052), but was not associated with median EGJ DI (4.5 vs. 5.1 mm 2 /mmHg, p = 0.29) nor median change in EGJ DI (+2.9 vs. +3.9 mm 2 /mmHg, p = 0.25). Patients with reduced EGJ DI or EGJ diameter more often had abnormal TBE (37% vs. 22%, p = 0.012). Only the change in DI (+3.8 vs. +1.5 mm 2 /mmHg, p = 0.012) and diameter (+8.2 vs. +1.6 mm, p = 0.002) on FLIP was associated with a clinical response based on Eckardt ≤ 3. Conclusions and Inferences FLIP following achalasia therapy generally correlates with TBE, although discrepant findings are not uncommon. In particular, FLIP EGJ‐diameter has a strong association with esophageal emptying on TBE. Both TBE and FLIP have limited association with clinical response based on Eckardt, with change in DI and diameter on FLIP most strongly associated. Consequently, FLIP as part of multimodal assessment appears useful in the longitudinal follow‐up of treated achalasia.

Importance Monoclonal gammopathy of undetermined significance (MGUS) is associated with an increased risk of cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have demonstrated cardiorenal benefits in patients with type 2 diabetes, but their effectiveness in patients with MGUS remains unexplored. Objective To assess the effectiveness of GLP-1 RAs for primary prevention of major adverse cardiovascular and cerebrovascular events (MACCE) in patients with MGUS and diabetes. Design, Setting, and Participants This retrospective cohort study used a propensity score–matched analysis of data from the TriNetX Global Database, encompassing patients diagnosed with diabetes and MGUS between January 1, 2018, and January 13, 2023. Patients with prior heart failure (HF), ischemic heart disease, coronary revascularization, or stroke or transient ischemic attack before MGUS diagnosis were excluded. The cohort was divided into 2 groups: GLP-1 RA users and nonusers at baseline. After 1:1 propensity score matching, GLP-1 RA users and nonusers were compared up to 5 years from the MGUS diagnosis date. Data analyses were completed January 19, 2025. Exposure GLP-1 RA use within 1 year before MGUS diagnosis. Main Outcomes and Measures The primary end point was MACCE, defined as a composite of all-cause mortality, new-onset HF, acute coronary syndrome, and stroke or transient ischemic attack. Secondary end points included individual MACCE components, decompensated HF, and acute kidney injury or end-stage kidney disease. Results A total of 4871 patients with MGUS (mean [SD] age, 68.9 [10.1] years; 2366 [48.5%] male) were included (473 GLP-1 RA users and 4398 non-users). A total of 460 users were matched to 460 nonusers, with balanced characteristics (mean [SD] age, 65.0 [10.6] vs 65.1 [11.0] years; 229 [49.7%] male vs 234 [50.8%] male), including 14 patients (3.0%) vs 13 patients (2.8%) identifying as Asian, 8 (21.3%) vs 92 (20.0%) as Black or African American, 25 patients (5.4%) vs 20 patients (4.3%) as Hispanic or Latino, and 243 patients (52.8%) vs 250 patients (54.3%) as White. GLP-1 RA use was associated with a significantly lower risk of MACCE (hazard ratio [HR], 0.75; 95% CI, 0.60-0.93). Significant reductions were also observed in all-cause mortality (HR, 0.57; 95% CI, 0.37-0.87), new-onset HF (HR, 0.69; 95% CI, 0.54-0.90), decompensated HF (HR, 0.60; 95% CI, 0.43-0.84), and acute kidney injury or end-stage kidney disease (HR, 0.73; 95% CI, 0.57-0.92). Conclusions and Relevance The findings of this cohort study of GLP-1 RA use vs no use in patients with MGUS and diabetes suggest the potential of GLP-1 RA for primary prevention of MACCE. These findings warrant further investigation in prospective randomized trials.