Multimodal Alzheimer’s disease (AD) cohorts capture cognition, function, neuroimaging, and fluid biomarkers, yet overall disease severity remains difficult to summarize on a single clinically meaningful scale. The apolipoprotein E ε4 (APOE ε4) allele is the strongest common genetic risk factor for late-onset AD, but its association with “progression” has been inconsistent because earlier placement along the disease continuum is often conflated with faster within-stage decline. Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we analyzed an amyloid-positive baseline cohort (N = 1058) and a longitudinal subset (N = 932; ≥ 2 visits and ≥ 4 of 13 measures per visit). Measures included standardized cognitive and functional assessments, structural and functional neuroimaging, cerebrospinal fluid biomarkers of amyloid‑beta and tau pathology, and plasma neurofilament light protein as a marker of neuroaxonal injury. Magnetic resonance imaging (MRI) volumes were adjusted using amyloid-negative cognitively normal controls with quadratic age and intracranial volume terms. Probabilistic principal component analysis (PPCA) was used to derive a latent severity coordinate, defined as the first principal component (PC1). Hierarchical Bayesian random-intercept and random-slope models were used to estimate individual trajectories, partition APOE ε4 effects into baseline severity and within-stage rate, and generate genotype-stratified ages at prespecified severity landmarks. Axis stability was assessed with 100 bootstrap refits, and predictive performance was assessed with participant-level fivefold cross-validation. The PC1 explained 38.7
Recent work shows that text-only reinforcement learning with verifiable rewards (RLVR) can match or outperform image-text RLVR on multimodal medical VQA benchmarks, suggesting current evaluation protocols may fail to measure causal visual dependence. We introduce a counterfactual evaluation framework using real, blank, and shuffled images across four medical VQA benchmarks: PathVQA, PMC-VQA, SLAKE, and VQA-RAD. Beyond accuracy, we measure Visual Reliance Score (VRS), Image Sensitivity (IS), and introduce Hallucinated Visual Reasoning Rate (HVRR) to detect cases where models generate visual claims despite producing image-invariant answers. Our findings reveal that RLVR improves accuracy while degrading visual grounding: text-only RLVR achieves negative VRS on PathVQA (-0.09), performing better with mismatched images, while image-text RLVR reduces image sensitivity to 39.8
PURPOSE:Angiosarcoma and epithelioid hemangioendothelioma (EHE) are two rare vascular sarcomas with limited therapeutic options. Prior reports have shown sensitivity to microtubule-targeting agents in these histologies. We report the efficacy and safety of eribulin in these vascular sarcomas in a pooled analysis of two parallel phase 2 studies. PATIENTS AND METHODS:Patients more than age 18 years with metastatic or recurrent angiosarcoma or EHE were treated with eribulin (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST 1.1. RESULTS:Twenty-nine patients were accrued to the study, with 25 (85%) having had prior taxane exposure. We observed an ORR of 17% for angiosarcomas, with 6 of 23 (26%) patients achieving disease stability for greater than 6 months, and an ORR of 33% (2/6) for EHE, with two of six continuing treatment for over 12 months. Five patients experienced a >1.3-fold time to progression ratio (TTP2/TTP1) on eribulin compared with the immediately prior therapy. Eribulin tolerability was consistent with published data. CONCLUSIONS:Eribulin showed clinical activity in this largely taxane-pretreated population. Future studies will be needed to confirm activity. See related commentary by Chen, p. 2130.
STUDY OBJECTIVES:To investigate the prescription patterns for hypnotics among patients <18 years in Japan. METHODS:We conducted a descriptive epidemiologic study using a claims database in Japan. We included patients aged 0-17 years with first-time prescriptions for hypnotics between June 2021 and June 2023. Hypnotics were classified as melatonin, melatonin receptor agonists (MRAs), dual orexin receptor antagonists (DORAs), Z-drugs, and benzodiazepines. We described the types of hypnotics, dosages, prescription duration, comorbidities, and concomitant medications for overall and by age groups. RESULTS:The study included 21 145 patients; 1983 aged 0-6 years, 3901 aged 7-11 years, 6664 aged 12-14 years, and 8597 aged 15-17 years. The initial prescribed hypnotics were melatonin (33.9%), MRAs (30.9%), DORAs (18.8%), Z-drugs (10.1%), and benzodiazepines (6.3%). Melatonin was more likely to be prescribed to patients age 0-11 years, MRAs to those aged 0-17 years, and DORAs to patients ages 15-17 years. The most common mental health-related comorbidities were autism spectrum disorder (32.5%), depression (23.4%), attention-deficit hyperactivity disorder (19.8%), and anxiety disorder (18.2%). CONCLUSIONS:Melatonin was most frequently prescribed in children for a longer duration than other hypnotics, while MRAs were prescribed across all age groups and DORAs mainly to adolescents. These age-specific patterns suggest that the drug selection was conducted according to patient's age, since pediatric insomnia might be correlated with psychiatric disorders related to developmental stage. Future research should investigate the long-term effects of hypnotic prescriptions with consideration of comorbid conditions.
BACKGROUND:The visual interpretation of amyloid PET scans, or visual read (VR), is the most common technique used in clinical practice to identify the presence of cerebral amyloid plaques. Amyloid status (positive or negative) determined by VR or using a Centiloid (CL) cut-off shows high overall concordance. However, discordant cases can occur where the VR is positive, but the CL is below the positivity cut-off, or vice versa. OBJECTIVES:The objective of this analysis was to evaluate the rate of discordance and explore potential causes, particularly the role of amyloid tracer uptake in the white matter (WM), when determining amyloid status using VR and CL in screening for the elenbecestat phase 3 studies in early Alzheimer's disease (AD). DESIGN:Amyloid PET scans using either Florbetapir (Amyvid™), Florbetaben (Neuraceq™) or Flutemetamol (Vizamyl™) from 3,232 participants (1507 VR- and 1725 VR+) with cognitive impairment screened for the elenbecestat phase 3 studies in early AD were visually interpreted at screening by trained neuroradiologists and quantified using CL values. SETTING:Academic and clinical centers INTERVENTION/MEASUREMENTS: Quantitatively, amyloid positivity was defined as CL > 32.21. The number of positive cortical regions was determined by counting the number of regions with a standardized uptake value ratio (SUVr) that exceeded 1.17. PET SUVr levels in the cerebral WM were measured using an eroded WM region of interest (ROI). Statistical tests were conducted to detect differences among the four concordance groups, defined by the relationship of VR and CL status (positive or negative). Additionally, tests examined the relationship between uptake in the WM and rates and type of discordance. Receiver operating characteristic (ROC) analysis and DeLong's test were also used to examine the effect of different tracers on the discordant rates. RESULT:Discordance was observed in 6.53% of cases (n=211), with VR+/CL- in 4.61% (n=149) and VR-/CL+ in 1.92% (n=62). VR+/CL- discordant cases had significantly fewer amyloid-positive cortical regions compared to both VR+/CL+ and VR-/CL+ cases. VR-/CL+ cases had a significantly higher WM uptake than VR-/CL- and VR+/CL- cases. Our findings revealed a relationship between WM uptake and rates and types of discordance. High WM uptake can erroneously lead to CL+, due to gray matter (GM) contamination from the WM, and VR- status, due to reduced contrast between WM and GM, resulting in VR-/CL+ cases. Conversely, low WM uptake can result in an underestimation of CL values, inaccurately classifying a scan as CL-, and at the same time, the increased contrast may result in a VR+, thereby increasing the occurrence of discordant VR+/CL- cases. CONCLUSION:Variations in WM uptake significantly contribute to discordances by introducing positive or negative bias in CL values and altering the GM to WM contrast, which forms the basis of the VR. Nevertheless, the rates of discordant cases are low and VR represents a robust and validated method to determine the presence of amyloid deposition. VR enables enrolling patients with amyloid beta pathology, as seen on amyloid PET scans, whereas CL scaling was developed to provide standardized units that more consistently characterize longitudinal amyloid‑β change. These findings reflect the complementary roles of VR and CL in amyloid PET evaluation, with implications for refining diagnostic accuracy and disease monitoring in AD clinical trials and practice.
