Dose

Designing effective chemotherapy regimens is hindered by tumor heterogeneity and drug resistance, which complicate the deployment of patient-specific model-based optimal control across diverse populations. We develop and compare closed-loop deep reinforcement learning (DRL) dosing policies with continuous (TD3) and discrete (DQN) action spaces trained on a high-dimensional heterogeneous tumor model. The DRL policies are benchmarked against a Pontryagin's Maximum Principle (PMP)-derived open-loop benchmark. We assess generalization under parametric heterogeneity using a 100-patient virtual cohort with plus or minus 10 percent uniform perturbations in growth and drug-sensitivity parameters. Across this cohort, TD3 achieves higher average tumor reduction, while DQN yields tighter inter-patient dosing consistency, revealing a clear efficacy-consistency trade-off in this study. Our simulations assume full observation of all tumor subpopulations; translation to sparse and noisy clinical measurements will require partial-observability formulations and/or state estimation. Overall, the results show that simulation-trained DRL can learn state-dependent feedback dosing policies that complement open-loop optimal control benchmarks.

Architecture category. Hybrid method: a physics-based analytical pencil-beam (PB) dose engine followed by a 3-D convolutional residual-correction network (RepVGG-U-Net). We addressed the DoseRAD2026 proton dose-prediction task with PyDoseRT Proton, a GPU-accelerated engine implemented in PyTorch and augmented by a learned residual toward Monte Carlo (MC) accuracy. A double-Gaussian PB kernel was calibrated to GATE/Geant4 integrated depth doses in water in two stages: a classical per-energy curve fit, then a gradient-based fit of the full 3-D dose through the PyTorch physics engine as it retains a differentiable execution path for gradient-based optimization of dose-dependent objectives. The engine computes each beamlet on a beam's-eye-view (BEV) lattice with variance-preserving Gaussian splitting, an analytic nuclear halo, and a Fermi-Eyges heterogeneity term, then rotates the result into the patient frame. Additionally, a compact residual U-Net predicts an additive correction in BEV space. It is conditioned on voxelwise material-label embeddings, a discrete energy embedding and spot size. The same model was used for all anatomical sites (thoracic and abdominal). It was trained with a patient-space L1 objective emphasizing the scored high-dose region and multi-scale BEV deep supervision. The submitted CT configuration obtained preliminary-test beamlet MAE 0.0066, image-z IDD distance 0.0025, plan MAE 0.0049, 98.30% gamma pass rate (1%/1 mm), and DVH error 0.460.

Activation steering turns localized representations into control directions, but localization alone does not reveal whether a direction has a selective operating regime. We introduce Predictive Memory Localization (PML), which treats the measured-grid intervention path as the predictive object of memory localization. PML separates random-calibrated target movement from semantic-neighbor and capability damage, and compares static localization and supervised geometry with a strength-disjoint low-dose causal response. Our frozen study covers 3,000 records from nine datasets and fourteen domains, yielding 30,000 distinct record-direction-layer paths and 210,000 distinct path-strength evaluations. At layer 7, the geometry-derived RFM/AGOP direction reaches 13.1% target-any and 12.3% clean-any, exceeding random by 3.6 and 3.4 percentage points under a record-paired bootstrap. Across record-, dataset-, and domain-grouped splits, responses at $|α|=0.1$ are the strongest signal for outcomes at disjoint strengths $|α|\in\{0.25,0.5\}$. On held-out records, a predictor-driven selector chooses a coefficient or abstains, improves utility and reduces semantic-neighbor damage relative to a train-tuned fixed-strength policy, and avoids most evaluations in a dense scan. Across three residual-norm-matched base models, learned directions retain selective-path gains and low-dose responses yield 0.801-0.828 record-held-out macro AUROC. PML therefore turns memory localization into a falsifiable forecast of margin-level selective outcomes and a risk-aware intervention decision.

Most radiotherapy dose-prediction models use only CT images and anatomical structures, although intensity-modulated proton therapy (IMPT) dose also depends strongly on beam geometry and available clinical datasets are often small. We present DoseBridge, a denoising diffusion bridge model that uses the patient CT as a structured bridge endpoint and encodes plan-specific beam geometry in a spatially aligned beam mask. Multiscale fusion combines CT, target, organ-at-risk, and beam-mask representations with 1.95% additional parameters. DoseBridge was retrospectively evaluated on single-institution CT images and treatment plans from 52 patients with advanced-stage lung cancer treated with 60 Gy in 30 fractions; 42 cases were used for training and 10 for testing. Performance was assessed using image-similarity, dose-volume, and Lyman-Kutcher-Burman normal-tissue complication probability (NTCP) metrics and compared with two deep-learning models. On the test cohort, DoseBridge achieved a mean absolute error of 4.170 Gy, peak signal-to-noise ratio of 23.06 dB, and structural similarity index of 0.798, outperforming both comparison models on these metrics. Clinical target volume D95 differed from the reference dose by 0.62 +/- 1.6 Gy; signed organ-at-risk mean-dose differences ranged from -0.32 to 0.24 Gy, and NTCP differences were -0.40 +/- 2.2 and 0.52 +/- 3.4 percentage points for acute esophagitis and radiation pneumonitis, respectively. Changing only the beam mask redirected predicted low-dose entrance regions while preserving the high-dose target region. To our knowledge, DoseBridge is the first denoising diffusion bridge model for radiotherapy dose prediction. These results support its feasibility as a beam-aware planning prior for lung IMPT, pending evaluation in larger external cohorts.

Distance-based reliability estimation assumes that a representation's geometry reflects its trustworthiness, yet this assumption is rarely tested under training interventions that reshape geometry directly. We audit this assumption under domain-adversarial representation learning using a disentanglement dose-response ladder. Three checkpoint families share the same architecture and a 16-dimensional representation, differing only in orthogonality strength (lambda = 0, 1, 5). Representation geometry changed substantially with disentanglement strength: the condition number shifted by two orders of magnitude (Kendall tau = 0.84, exact p = 2.8e-5). This change was not accompanied by improved reliability estimation: Mahalanobis-distance AUROC (ISIC-test vs. PAD-UFES) remained flat and below chance (about 0.40) at every level, with no significant association with any of five geometry metrics tested. The same failure was observed for cosine-to-centroid and pooled k-nearest-neighbor scorers, plus three non-distance-based scorers: an energy-based confidence score, Virtual-Logit Matching, and a kernel density estimator. Seven of eight scorers converged on the same result; the energy-based score showed an isolated upward trend that we report but do not treat as evidence against the overall pattern. A supervised probe with no access to the training objective recovered domain membership from the identical embeddings at 0.72-0.81 AUROC across every level, showing that the relevant information was not absent from the representation. These findings indicate that classification performance alone can overlook whether information in a learned representation is organized in a form that downstream reliability estimators can use. Information can remain decodable while becoming largely inaccessible to non-probing reliability estimators.

The convergence of the Metaverse and Large Language Model (LLM)-based AI agent is catalyzing a shift toward autonomous, immersive, and personalized pedagogical frameworks in medical education. This paper presents a novel agentic AI-driven immersive simulation specifically designed for High Dose Rate (HDR) vaginal cylinder (VC) brachytherapy in cancer care. By integrating Virtual Reality (VR) and mobile computing, the system establishes a high-fidelity, risk-free environment that allows trainees to master complex procedural skills without the facility or safety constraints posed by physical anatomy or live radioactive sources. A core contribution of this work is the seamless integration of a knowledge-aware assistant leveraging Retrieval-Augmented Generation (RAG) to ground agent interactions in authoritative clinical guidelines. This architecture also enables an interactive agent to provide natural language interfaces and hands-free, real-time guidance during intricate medical maneuvers. We validate the proposed system through a prototype deployment comprising a Meta Quest 3 interface linked to a local GPU-accelerated AI backend, demonstrating a feasible architecture for HDR brachytherapy simulation. Experimental results indicate that the system maintains suitable end-to-end latency and high context precision, answer completeness, and relevance in the RAG-enhanced pedagogical support.

Functional Magnetic Resonance Imaging ( fMRI ) data are often pooled into collaborative multi-site consortia, as deep learning models for analyses require large datasets to generalize well. While Federated Learning (FL) offers a privacy-preserving paradigm for collaborative training, standard approaches continue to struggle with statistical heterogeneity. In particular, site differences pose a key challenge in multi-site data settings. Additionally, existing FL approaches for fMRI rely on static Functional Connectivity ( FC), omitting dynamic information in brain networks. To address this, we propose FedDOSE, a novel framework that explicitly decomposes site differences for analysis of dynamic FC (dFC). FedDOSE introduces a Modularity-Guided Tucker Decomposition block to encode high-dimensional dFC tensors and capture modular-level spatio-temporal patterns efficiently. Class-specific prototypes are generated across all sites and subsequently aligned at the global level by using a combination of Optimal Transport (OT) barycenter formulation and Procrustes analysis. Extensive experiments for diagnosing Autism Spectrum Disorder (ASD) and Attention-Deficit Hyperactivity Disorder (ADHD) on three multi-site resting-state fMRI datasets: ABIDE-I, ABIDE-II, and ADHD-200, demonstrate that FedDOSE outperforms state-of-the-art methods in ASD and ADHD detection. Our results highlight its effectiveness in learning robust representations from multi-site datasets for reliable analysis.

Large language models are increasingly used as synthetic research participants and are often validated by whether their marginal responses resemble human data. We study a fixed panel of sixteen lightweight persona-conditioned GPT-4.1 configurations in repeated strategic games. The panel met preregistered broad-reference condition-mean criteria in three of four repeated-game cells; the sole miss was 0.011 below the lower reference bound. Variation was strongly prompt-indexed, but its share depended on uncertainty assumptions: fixed-panel symmetric-Dirichlet sensitivities produced median between-prompt shares of 63%-71% under Jeffreys alpha=0.5 and 47%-53% under alpha=1, while finite-opportunity plug-in estimates were 85%-96%. Aggregate continuation-probability contrasts were +0.083 and +0.078, with conservative simultaneous 95% intervals [-0.171, +0.330] and [-0.181, +0.330]. The treatment jointly changed the continuation process and its textual representation. A separate wording-and-position operation shifted cooperation from 0/40 to 37/40 in the bare configuration, and a label conflict also revealed representation control. The original persona-level p13 result was not prospectively family-controlled, while a post-adjudication exact gate was structurally underpowered; p13 is therefore a replication target rather than a finding. External review exposed family-error, dependence, construct, and boundary-uncertainty defects, and zero-call reanalysis changed the interpretation without rewriting the historical record. The registered marginal criteria could be passed without precisely estimating the treatment-response object. A public capsule verifies 4,916 confirmatory Phase 3-5 runs with no live model calls. The results concern one fixed model-prompt panel and do not establish human substitutability.

Background. Predicting conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is central to trial enrichment and care planning, yet existing models provide no individual-level uncertainty estimates and rarely include transparent leakage audits. We introduce the first application of persistent homology to longitudinal clinical trajectory point clouds for this task, and the first split-conformal individual risk guarantee for any AD-conversion model. Methods. We analysed 741 MCI subjects (240 converters, 32.4%) from ADNI with a uniform 4-year follow-up cap. Five leakage sources were corrected; without them a naive pipeline achieved AUC=0.934, inflated by +0.075. Vietoris-Rips persistent homology and sublevel-set proxies were combined with trajectory slopes and engineered features (76 total) in a stacking ensemble evaluated by 5-fold cross-validation. Results. Cox and Random Survival Forest models with TDA features achieved concordance C=0.799 and C=0.826 versus C=0.753 and C=0.812 without (+0.045 and +0.014). The primary nested AUC is 0.840 (same-fold bound 0.866); external AUC was 0.879 on a zero-overlap ADNI-2/GO/3 cohort. H0 persistence entropy was the top SHAP feature and significantly associated with APOE4 dosage (Spearman r=-0.191, p<0.0001, Bonferroni-corrected). Cross-conformal coverage was 90.4%+-2.2% (target 90%); empirical external coverage 96.9%. Maximum fairness gap in false-negative rate across seven subgroups was 0.092. Conclusions. We propose H0 persistence entropy as a topological biomarker of cognitive decline and demonstrate that a leakage-audited, conformally calibrated pipeline reaches competitive accuracy with individual-level uncertainty quantification not previously available for this task.

Mobile C-arm cone-beam computed tomography (CBCT) has been widely used for real-time intraoperative 3D imaging. However, current practice often mechanically applies the fan-beam CT criterion of "180° plus fan angle" in pursuit of "data completeness" in reconstruction. This review argues that, under the single circular trajectory of three-dimensional cone-beam geometry, complete data are mathematically unattainable; moreover, blindly increasing sampling may exacerbate the trade-off among intraoperative image quality (Q), imaging time (T), and radiation dose (D). Against this background, this review reframes the evaluation of intraoperative CBCT around "data sufficiency" rather than "data completeness." This perspective moves beyond the excessive pursuit of absolute mathematical and analytic accuracy, and instead emphasizes task-specific minimum image-quality thresholds required for clinical decision-making. By synthesizing evidence from multiple clinical scenarios, this review suggests that approximation errors can be acceptable when clinical decision-making requirements are satisfied, thereby achieving a Q-T-D balance.

In this document, we describe characteristics and technical details of the multimodal biosignal dataset DOSE-I of procedural sedation for endoscopy published on zenodo. The DOSE-I dataset includes 78.5 hours of recording in 171 records ranging from 6.7 to 70.8 minutes (mean: 27.5, SD: 11.6) of 281 endoscopic procedures. 1129 (median: 6 per record) transitions of consciousness and 7328 (median: 39 per record) individual sedation depth labels were recorded. In addition to clinically annotated biosignals, the DOSE-I dataset provides detailed static data about the respective study subject and metadata about the respective recordings. To further support future research, we provide details about artifact detection and preprocessed pEEG features, too. C code used for this preprocessing is provided separately via Github.

Medication errors, particularly dosing errors in clinical trials (CT), can lead to patient harm, adverse drug events and worse patient outcomes. Dosing errors are preventable, and early identification can improve trial integrity and mitigate subsequent clinical and financial burden. This study aims to detect dosing errors within CT protocols by evaluating text representations of trial information using transformer-based language models trained on biomedical corpora. CT textual data was encoded using several models, including ClinicalBERT, PubMedBERT, BioBERT, and MedCPT, and integrated with categorical features. These text embeddings were used as input to classical machine learning models and neural network architectures within an experimental framework. Performance was primarily assessed using ROC-AUC with respect to predicting dosage error. Under a logistic regression baseline, BioBERT consistently outperformed alternative encoders, achieving an ROC-AUC of 0.794, a 3.95% improvement over the ClinicalBERT baseline. Combining multiple embeddings did not yield improvements, indicating that domain alignment outweighs representational stacking. Gradient boosting models, support vector classifiers, logistic regression, and residual neural networks achieved the strongest performance for predicting dosage error, achieving ROC-AUCs: 0.821 to 0.853. Overall, the integration of domain-specific transformer embeddings with structured metadata enables discrimination of trials meeting a predefined elevated dosing error risk criterion, advancing safety monitoring and supporting informed regulatory decision-making.

Single-cell drug perturbation models should capture transcriptional response magnitude and whether a treatment changes the proliferative state of the cell. This is difficult because cell-cycle variation is often treated as a nuisance factor, and benchmark processing rarely makes drug-induced phase changes a primary prediction target. We introduce scCycleMol, a cell-cycle-aware perturbation prediction framework built on a curated 24-hour SciPlex3 benchmark with standardized molecule identities, dose and cell-line metadata, modeled genes, and expression-derived cell-cycle supervision. scCycleMol derives cell-cycle supervision from the treated state and applies it to predicted treated expression without using phase as an input covariate. The model includes a learnable full-expression cell-cycle head with circular G1/S/G2M targets, and we evaluate readout-only supervision (with stop-gradient) versus closed-loop supervision (backpropagating through decoder, dose-response module, and drug representation). We also compare molecular representations and pretraining sources to isolate the effect of the cell-cycle objective. On a processed 24-hour SciPlex3 benchmark (635,541 cells, 186 perturbations, 188 compound embeddings, 3 cell lines, 4 doses plus DMSO, 5,080 genes), the best LINCS-pretrained circular variant reaches 0.9093 mean all-gene R-squared and 0.6843 mean DE-gene R-squared. Under matched preprocessing, closed-loop cell-cycle supervision improves phase accuracy by 0.54-0.62 points while keeping mean all-gene R-squared within 0.003 of matched chemCPA no-cell-cycle models; Tahoe-pretrained readout-only circular supervision achieves the strongest phase accuracy at 0.9609.

A central premise of autonomous scientific imaging is that smarter navigation, whether Bayesian, RL-based, or otherwise adaptive, is the principal lever for sample-efficient acquisition. We present evidence to the contrary in scanning transmission electron microscopy (STEM), an atomic-resolution imaging modality whose every measurement deposits damaging electron dose. We introduce STEMGym, an open-source Gymnasium benchmark of 15 physics-simulated STEM worlds spanning five materials, three difficulty levels, and four characterisation tasks, scored by the Dose-Efficiency Curve area (DEC-AUC), a single scalar capturing the information-vs-dose Pareto frontier. Across 33 agent configurations under realistic dose budgets, the dominant determinant of dose efficiency is the analyst (perception) pipeline, not the navigator: pairing a trained CNN analyst with naïve raster scanning raises DEC-AUC by 5.5x over a CNN-free raster baseline (0.287 vs.\ 0.052), while substituting Bayesian or adaptive finite-state-machine navigation for raster yields no statistically significant further gain. Production-tier vision-language models further underperform task-specific CNNs by {\sim}13x on crystallographic defect analysis. By decoupling perception, navigation, and planning under a unified dose budget, STEMGym reframes where ML effort should be invested in autonomous electron microscopy and provides the measurement infrastructure to test it.

Predicting a patient's physiological trajectory under a planned treatment sequence is a prospective interventional problem, not standard time-series extrapolation. We study this problem in glucose management, where insulin and carbohydrate records are policy-dependent: future drivers are coupled to patient state, behavior, and clinical decision rules, so observational forecasting accuracy alone does not guarantee correct responses to planned interventions. We introduce Interventional Flow Matching (IFM), a continuous-time generative framework for physiologically constrained prospective forecasting. IFM conditions a flow-matching velocity field on patient history and planned future drivers in a bounded latent glucose space. Rather than embedding strict mechanistic glucose--insulin ODE equations or enforcing causality through rollout-based simulations, IFM uses a solver-free regularization: it penalizes the Jacobian of the instantaneous velocity field with respect to smoothed treatment drivers. This imposes signed, dose-bounded local sensitivities directly on the learned dynamics: insulin lowers glucose, carbohydrates raise it, and both responses remain within plausible ranges. On a simulated UVA/Padova type 1 diabetes cohort, IFM achieves the strongest balance between observed-driver RMSE and interventional response metrics. Across experiments, it consistently produces physiologically correct responses to both insulin and carbohydrate drivers while maintaining high directional, and ranking consistency.

Positron emission tomography (PET) seeks to balance diagnostic quality with ra-diation dose. Low-count PET noise is non-Gaussian, non-stationary, and spatial-ly dependent. It scales directly with local activity and is shaped by iterative recon-struction and physical corrections. Standard denoising diffusion probabilistic models (DDPMs) ignore these PET properties. Their forward process adds iso-tropic, homoscedastic Gaussian noise to the target. Such an approach fails to cap-ture the realistic physical degradation generated by the imaging system. To ad-dress the above limitations, this study introduces a heteroscedastic residual diffu-sion model (HDDPM) for low-count brain PET recovery in which the forward corruption is itself intensity-aware. We designed a fixed, Poisson-based variance module to generate voxel-wise noise maps. These maps naturally place stronger noise perturbation on low-activity regions than high-activity ones, meanwhile the network predicts the low-to-standard-count residual under explicit dose-fraction conditioning. We evaluated our proposed model (HDDPM) alongside generative frameworks across three different scanners, using both internal and external da-tasets at various simulated dose levels (1% to 50%). HDDPM and isotropic DDPM showed comparable overall image quality, but HDDPM stood out in the lowest-dose (1%) external scans. It is highly reliable and significantly reduces measurement errors in both high- and low-activity regions, compared to the standard model. These results support that heteroscedastic noising with the pro-posed HDDPM is feasible, and it provides a physically motivated inductive bias for quantitative low-count PET recovery by reflecting the activity-dependent noise structure of PET.

LLM agents mis-call tools, and the natural guess is that the model failed to see the right tool in a crowded harness. We show the opposite through a lens concurrent work sets aside -- the model's attention to labeled tool-definition segments. On real BFCL failures, by per-candidate attention argmax the model attends most to the correct tool 80% of the time (vs. 21% chance), and the gold is the under-attended segment on only 10%: it looks at the right tool and still picks wrong. This directly refutes the intuitive "crowded-harness / lost-in-the-middle" explanation: the failure is at the decision readout, not the harness, and we pin it there three ways. (1) Input vs. readout: repairing the prompt (reordering or duplicating the gold tool) recovers <=23% of failures, while readout-side interventions recover 59-91%. (2) Representation-invariance: two gold-pointed interventions in different representations -- an additive attention-logit bias and a residual-stream steering vector -- recover largely the same failures (per-task Jaccard 0.865 pooled, 0.79-0.91 per model), so the bottleneck is localized to the readout independent of which representation is poked. (3) A training-free, gold-free selector: per-segment attention closes most of the gold-free-vs-oracle gap on BFCL (+11.9 pts pooled function-name selection vs. +17.9-pt oracle headroom) and adds +14.9 pts on Seal-Tools; every model positive (exact McNemar p<=8e-4 each). Scopes differ: the causal attention-bias dose-response is bidirectional and monotonic on 10 mask-honoring models (3-32B), the full 0.5-32B span carrying only the correlational diagnostic; the deployable selector is evaluated on 5 single-turn models and does not yet transfer to a multi-turn loop.

Estimating the probability that a treatment outperforms a control for an individual patient, called the Individual Probability of Treatment Benefit (IPTB), offers a clinically intuitive alternative to population-average metrics. However, existing methods for IPTB estimation are largely confined to binary treatment settings, despite the prevalence of dose-varying interventions in clinical practice. We propose a general framework for IPTB estimation with ordinal outcomes under discrete dose assignments, called Dose-AIPTB (Dose Attention-based IPTB). Our approach recasts the problem as binary classification over the unobserved sign of the individual treatment effect, constructing pseudo-labels from covariate-similar pairwise comparisons and aggregating them via attention mechanisms or Nadaraya-Watson kernel regression. This formulation naturally accommodates multiple discrete dose levels, extending beyond the binary treatment paradigm. Through numerical experiments on real-world and synthetic data under covariate shift, varying sample sizes, and heterogeneous outcomes, we demonstrate that attention-based aggregation consistently outperforms kernel alternatives. The framework provides a foundation for personalized dose selection grounded in individual-level benefit probabilities. Codes implementing the model are publicly available at https://github.com/NTAILab/AIPTBDose.

Most existing deep learning-based PET image denoising methods assume a fixed and known dose reduction factor (DRF) for low-dose PET images. However, these methods encounter significant performance degradation when the DRF varies beyond the assumed one in practical applications. To address the challenge posed by varied DRFs, several preliminary studies focus on the task of universal PET image denoising, aiming to train a universal model over low-dose data across DRFs. Nonetheless, these vanilla universal models often struggle with misaligned styles present in different DRF data, leading to the \textit{style elimination issue} with a significant over-smoothing effect. To deal with this issue, we innovatively introduce domain generalization to PET image denoising and propose a universal PET image denoising network (UniPET) to achieve high-quality PET image denoising across diverse DRFs. UniPET comprises two primary innovations: a style alignment network (SAN) and a region-aware learning strategy (RALS). Specifically, SAN utilizes style alignment techniques derived from domain generalization to align and recover styles across different DRFs, ensuring the model's generalizability across various DRFs while effectively preserving styles. Furthermore, to enhance style recovery, RALS distinguishes between flat and stylized regions, exclusively conducting adversarial learning on the latter, thereby more effectively guiding the model's focus towards learning stylized regions. It is demonstrated that our proposed UniPET can adaptively recover different DRF styles and achieve high-quality PET image denoising across DRFs. Comprehensive experiments show that UniPET exhibits comparable performance to individual DRF-specific models at specific DRFs and realizes state-of-the-art performance in universal PET image denoising quantitatively, perceptually, and clinically.

Background and purpose: oART enables daily plan adaptation to interfraction anatomical variations, but cumulative dose estimation remains limited by DIR, segmentation, and anatomical uncertainties. We introduce IMPACT-DoseAcc, an uncertainty-aware dose accumulation framework, within IMPACT for semantic feature-driven image analysis. The framework is modality- and disease-agnostic and is applied to CBCT-guided oART for cervical cancer (LACC). Material and Methods: Nine LACC patients were retrospectively analyzed using daily CBCT-derived virtual CTs for dose recalculation. IMPACT-DoseAcc focuses on uncertainty from DIR, without modeling vCT-generation uncertainty. Two DIR uncertainty strategies were tested within IMPACT-Reg: a Bayesian segmentation-guided approach using one probabilistic model to quantify anatomical uncertainty, and an ensemble of segmentation models targeting structures to capture epistemic variability. Voxel-wise uncertainty maps were propagated through dose warping and accumulation to generate probabilistic dose-volume histograms. Ensemble uncertainty was quantified from voxel-wise standard deviation across deformation fields, and geometric error was assessed using surface distance between warped and validated contours. Anatomical-variability weighting refined aggregation. Results: Ensemble DIR uncertainty correlated with geometric error, with Pearson coefficients of 0.63 for CTVt and 0.66 for bladder. For CTVt, pDVHs achieved 96.3 +/- 3.9% coverage, showing calibration of propagated uncertainty. Weighting stabilized estimates across fractions and organs. Conclusions: IMPACT-DoseAcc propagates registration-driven uncertainty to cumulative dose metrics, improving interpretation of accumulated dose under anatomical variations. Its 3DSlicer integration supports reproducible, uncertainty-informed ART workflows.

Large language models (LLMs) are increasingly used for everyday health questions, including whether a user can safely take another dose of an over-the-counter (OTC) medication. Yet this common safety-relevant setting remains underexplored in existing medical QA evaluations, where correct answers require tracking dose timing, computing rolling 24-hour intake, following product-label constraints, and handling incomplete medication histories. We introduce DOSEBENCH, a focused benchmark of 81 curated OTC dosing scenarios focused on adult acetaminophen and ibuprofen use, with manually annotated gold references. We evaluate four LLMs across repeated runs using metrics for decision correctness, consistency, explanation verifiability, failure types, and confidence-related signals, resulting in 1,620 model responses. Our results show that models frequently struggle with rolling-window reasoning and ambiguity-sensitive cases and that stable or confident-looking responses can still violate dosing constraints. These findings suggest that OTC dosing QA provides a narrow yet practical testbed for evaluating temporal reasoning, constraint following, and safety-relevant uncertainty handling in medical QA.

Accurate prediction of polymerization dynamics is essential for process design, control, and optimization. Yet, purely mechanistic models require labor-intensive parameterization of partially characterized kinetics, while purely data-driven models demand large, diverse datasets that are costly to obtain, particularly in early-design stages. We propose a hybrid Neural Ordinary Differential Equation (NODE) framework for data-efficient modeling of free-radical polymerization. Using batch polymerization of methyl methacrylate (MMA) as a case study, the mechanistic mass balances are retained explicitly, and only the partially-characterized effective radical concentration governing monomer consumption is learned from data through a neural network surrogate, while established reactions such as initiator decomposition, propagation, and termination remain physically modeled. The hybrid NODE is evaluated against a discrete-time feedforward neural network and a purely data-driven NODE under sparse data conditions, with models trained on as few as ten measurements under both regular and irregular sampling. The hybrid NODE consistently achieves lower prediction errors and more physically consistent extrapolations than both purely data-driven baselines. In a generalization scenario with noisy data and unseen operating conditions, the hybrid NODE achieves an RMSE of 0.013, compared to 0.31 for the data-driven NODE and 0.68 for the discrete-time model, demonstrating that learning only a closure term rather than the full dynamics is sufficient for reliable prediction under limited data availability.

Accurately modeling crop response to Nitrogen (N) fertilization is a fundamental challenge in precision agriculture, as it impacts both economic returns and environmental sustainability. Existing approaches either rely on predefined parametric forms or opaque machine learning models, limiting their ability to interpret or discover site-specific functional relationships from data. In this work, we propose a neuro symbolic regression (SR) approach to learn parametric N-response curves without assuming a predefined functional form. Our approach integrates a transformer-based Multi-Set Symbolic Skeleton Prediction strategy, enabling the discovery of shared functional structures across multiple subdomains or management zones (MZs). By constructing diverse input subsets and enforcing consistency across them, the method recovers robust symbolic skeletons that are subsequently fitted to observed data using a genetic algorithm. This framework was first evaluated on synthetic one-dimensional problems to assess its robustness under varying levels of epistemic uncertainty. The results demonstrate the ability of the proposed SR approach to recover correct expressions even in data-scarce regimes. In this work, we present the results of applying our method to real-world winter wheat data, learning distinct parametric N-response curves for different MZs within a field. The results show that the discovered expressions not only achieve lower fitting errors than traditional models such as quadratic-plateau and exponential functions, but also capture diverse functional behaviors across spatial regions. This demonstrates the potential that neuro SR has to enable the discovery of site-specific agronomic relationships and support informed decision-making in precision agriculture.

Text-to-image models trained on large-scale data often inevitably ingest unsafe content. While some people observe input-output amplifications, it remains unclear whether and how training data composition directly drives model output safety or by other factors. We shed light on this question by isolating this variable: we train the same text-to-image model on datasets that differ \emph{only} in their fraction of unsafe images (0% to 9.6%), across several dataset scales (100K to 8M). Then we generate images with the resulting models, and evaluate them with four independent safety classifiers. Output unsafety rises monotonically from 16.6% at 0% contamination to 25.5% at 5%. A factorial design reveals that the \emph{proportion}, not the absolute count, of unsafe training images is the operative variable. The 16.6% irreducible baseline at zero contamination implicates the other components, e.g. frozen text encoder, as a residual safety risk -- confirmed by a text encoder ablation showing that SafeCLIP reduces this floor to 9.6%, while the dose-response effect persists across all three encoders tested. Critically, no quality degradation in terms of FID, CLIPscore and ImageReward accompanies safety filtering. These results establish that data curation and text encoder safety are complementary and independently effective interventions. At the same time, the remaining level of unsafety poses questions for future research about emerging capabilities and compositionality.

Estimating how an outcome responds to a continuous treatment (the Average Dose-Response Function, or ADRF) is a core causal-inference primitive. However, when outcomes possess heavy tails, standard robust double machine learning (DML) deliberately suppresses these extremes to stabilize the bulk average. In high-stakes settings, such as financial returns or climate losses, this omitted 1-in-1000 extreme event is the actual target quantity. Furthermore, current methods that read the tail from a model's residuals suffer from circular dependence, causing tail shape inferences to shift drastically based solely on whether the core estimator is switched between Huber and Welsch. The research proposes an ADRF estimator that emits a structured tail-shape output alongside the standard point estimate. Its tail diagnostic (PDHTE+JK) evaluates the per-treatment tail shape from the outcome centered by a pilot median, successfully breaking the circular dependence and rendering the diagnostic invariant to the choice of core method. The output encompasses four treatment-conditional quantities: tail shape $\hatξ(t)$, deep-tail return levels $\hat{Q}_α(t)$, conditional shortfalls $\hat{S}_α(t)$, the recovered mean ADRF, and an explicit refusal mechanism that declines extrapolation when extreme-value modeling is unsupported by the data. Compared to kernel-weighted quantile regression (QR), the proposed estimator reduces deep-tail ($α=0.001$) return-level MAE by 11% and conditional-shortfall MAE by 25.5% across a heavy-tailed panel. It also achieves a 20-29% MAE reduction in sample-scarce regimes ($n\le2000$). On freMTPL2 motor-insurance claims, it successfully triggered an explicit extrapolation refusal on the log-claim scale, which neither QR nor loss-only DML can produce.

Objective: To describe the design and early clinical evaluation of The Daily Dose (TDD), an LLM-driven, automated clinical summarization and clinical-trial identification system integrated into routine radiation oncology practice. Design: Mixed-methods evaluation using a cross-sectional, anonymous clinician survey administered after 1 month of system deployment. Exposure: Daily automated delivery of physician-specific email summaries generated using RadOnc-GPT, including patient schedules, concise EHR-derived clinical-status summaries, and automated identification of potentially relevant clinical trials for new or consult visits. Main Outcomes and Measures: Primary outcomes included self-reported usability, satisfaction, perceived usefulness, perceived impact on workflow, time savings, and intention for continued use. Internal consistency reliability was assessed using Cronbach's $α$. Results: Among 55 respondents, 52 (94.5%) worked in radiation oncology, and 38 (69.1%) were attending physicians. Most participants (83.6%) reported using TDD daily or several times per week. Mean (SD) scores were 3.89 (1.04) for usability and satisfaction, 3.43 (1.24) for perceived usefulness, and 3.80 (1.17) for impact and future use (5-point Likert scale). Overall satisfaction was positively associated with perceived time savings ($p < .001$). Participants reported variable time savings, with 27% estimating $\geq 10$ minutes saved per day. The questionnaire demonstrated excellent internal consistency (overall Cronbach's $α$ = 0.97).

Causal inference, estimating causal effects from observational data, is a fundamental tool in many disciplines. Of particular importance across a variety of domains is the continuous treatment setting, where the variable of intervention has a continuous range. This setting is far less explored and represents a substantial shift from the binary treatment setting, with models needing to represent effects across a continuum of treatment values. In this paper, we present the first causal foundation model for the continuous treatment setting. Our model meta-learns the ability to predict causal effects across a wide variety of unseen tasks without additional training or fine-tuning. First, we design a novel prior over data-generating processes with continuous treatment variables in order to generate a rich causal training corpus. We then train a transformer to reconstruct individual treatment-response curves given only observational data, leveraging in-context learning to amortize expensive Bayesian posterior inference. Our model achieves state-of-the-art performance on individual treatment-response curve reconstruction tasks compared to causal models which are trained specifically for those tasks. Inference code (including trained model weights) can be found at https://github.com/layer6ai-labs/CCPFN-inference .

Volumetric Modulated Arc Therapy (VMAT) is a cornerstone of modern radiation therapy, enabling highly conformal tumor irradiation and healthy-tissue sparing. Yet, its planning solves inverse and nested optimization for multi-leaf collimators, monitor units and dose parameters, while enforcing their consistency to ensure mechanical deliverability. Nevertheless, this process often requires repeated re-optimization when treatment configurations change, resulting in substantial planning time per patient. To address these problems, we present a diffusion-driven Learning-to-Optimize (L2O) method for end-to-end VMAT planning. A distribution-matching distilled diffusion model learns a clinically feasible manifold of fluence maps, enabling their one-shot generation. On top of this, an LSTM-based L2O module learns gradient update dynamics to swiftly refine fluence maps toward prescribed dose objectives during inference. Experimental results on clinical and public prostate cancer cohorts demonstrate improved planning efficiency, flexibility, and machine deliverability over currently available end-to-end VMAT planners.

Anatomical structure masks are widely adopted in radiotherapy dose prediction, as they provide explicit geometric constraints that facilitate structure-dose coupling. However, conventional manual delineation of these masks requires precise annotation of structure boundaries relevant to radiotherapy, which is time-consuming and labor-intensive. To address these limitations, we propose a scribble-guided dose prediction framework that relies solely on anatomical structures annotated with sparse scribbles. Specifically, we design a Scribble Completion Module (SCM) to generate dense anatomical masks by propagating sparse scribble labels to semantically similar voxels. During the propagation process, a supervoxel-based regularization is introduced to preserve geometric boundary consistency to ensure anatomical plausibility. Furthermore, we propose a Structure-Guided Dose Generation Module (SGDGM) to strengthen the correspondence between sparse structural cues and dose distribution. Herein, the completed dense masks derived from scribbles serve as structural guidance to condition the dose prediction network. This scribble-mask-dose consistency encourages high-dose concentration within target volumes while effectively sparing surrounding organs-at-risk. Extensive experiments on the open-source GDP-HMM dataset demonstrate that the proposed method maintains superior dose prediction performance while substantially reducing annotation cost, providing a practical paradigm for dose prediction under sparse structural annotation. The code and reannotated scribbles are made publicly available at https://github.com/iCherishxixixi/ScribbleDose.

Voxel-wise dose prediction is a critical yet challenging task in practical radiotherapy (RT) planning, as bespoke models trained from scratch often struggle to generalize across diverse clinical settings. Meanwhile, generative models trained on billion-scale datasets from vision domains have achieved impressive performance. Herein, we propose DiffKT3D, a unified Any2Any 3D diffusion framework that leverages prior knowledge from pretrained video diffusion models for efficient and clinically meaningful dose prediction. To enable flexible conditioning across multiple clinical modalities (CT, anatomical structures, body, beam settings, etc.), we introduce an Any2Any conditional paradigm utilizing modality-specific embeddings without cross-attention overhead. Further, we design a novel reinforcement learning (RL) post-training mechanism guided by a clinically-informed Scorecard explicitly tailored to institutional treatment preferences. Compared with winner of GDP-HMM challenge, DiffKT3D sets a new state-of-the-art in dose prediction by reducing voxel-level MAE from 2.07 to 1.93. In addition, DiffKT3D achieves superior image quality and preference match. These results demonstrate that transferring diffusion priors via modality-aware conditioning and clinically aligned RL post-training can provide a robust and generalizable solution for RT planning across various clinical scenarios.

Unobserved confounding prevents standard covariate adjustment from identifying causal response functions in observational studies. Proxy causal learning addresses this problem through bridge equations involving treatment- and outcome-inducing proxies, avoiding direct recovery of the latent confounder. Existing doubly robust proxy estimators combine outcome and treatment bridges, but typically rely on fixed kernels, sieves, or low-dimensional semiparametric models; existing neural proxy methods are more flexible, but are largely single-bridge estimators. We develop a neural doubly robust framework for proxy causal learning with continuous and structured treatments. Our method introduces a neural mean-embedding estimator for the treatment bridge, combines it with a neural outcome bridge, and estimates the doubly robust correction through a final regression stage. The framework covers population, heterogeneous, and conditional dose-response functions, yielding full response-curve estimators rather than binary-treatment effects. The algorithms use two stages for each bridge and history-aware updates of the final linear layers to stabilize stochastic multi-stage training. We prove consistency of the algorithms showing that the doubly robust error is controlled by the final averaging and regression errors together with the smaller of the outcome- and treatment-side weak-norm bridge errors. Across synthetic and image-valued benchmarks, the proposed estimators outperform existing baselines and single-bridge neural estimators, showing the benefit of combining learned outcome and treatment bridges in a doubly robust construction. Our implementation is available at https://github.com/BariscanBozkurt/DRPCL-Neural-Mean-Embedding.

Question: Does atomic fact-checking, which decomposes AI treatment recommendations into individually verifiable claims linked to source guideline documents, increase clinician trust compared to traditional explainability approaches? Findings: In this randomized trial of 356 clinicians generating 7,476 trust ratings, atomic fact-checking produced a large effect on trust (Cohen's d = 0.94), increasing the proportion of clinicians expressing trust from 26.9% to 66.5%. Traditional transparency mechanisms showed a dose-response gradient of improvement over baseline (d = 0.25 to 0.50). Meaning: Decomposing AI recommendations into individually verifiable claims linked to source guidelines produces substantially higher clinician trust than traditional explainability approaches in high-stakes clinical decisions.

Chemotherapy dose optimization can be formulated as a dynamic treatment regime, requiring sequential decisions under uncertainty that must balance tumor suppression against toxicity. However, most reinforcement learning approaches assume full observability of the patient state, a condition rarely met in clinical practice. We investigate whether memory-augmented policies can improve chemotherapy control under partial observability. To this end, we employ a recurrent TD3-based approach with separate LSTM actor-critic networks and evaluate it on the AhnChemoEnv benchmark from DTR-Bench, considering both off-policy and on-policy recurrent architectures against feed-forward TD3 and Soft Actor-Critic. Pharmacokinetic and pharmacodynamic variability are held fixed to isolate hidden-state uncertainty and observation noise and to avoid confounding effects from inter-patient variability. Across ten random seeds, recurrence yields modest benefit under full observability but substantially stronger and more stable performance under partial observability, with more consistent tumor suppression and improved normal-cell preservation. These findings indicate that memory-based policies are particularly beneficial when clinically relevant state information is incomplete or noisy.

Recursive language-model loops often settle into recognizable attractor-like patterns. The practical question is how much injected text is needed to move a settled loop somewhere else, and whether that move lasts. We study this in 30-step recursive loops by separating the model from the context-update rule: append, replace, and dialog updates expose different histories to the same generator. The main result is that persistent redirection in append-mode recursive loops is memory-policy-conditioned. Under a 12,000-character tail clip, destination-coherent persistence plateaus near 16 percent and retained source-basin escape near 36 percent at dose 400; neither crosses 50 percent. Under a full-history protocol, retained source-basin escape crosses 50 percent near 400 tokens and saturates at 75-80 percent by 1,500 tokens; destination-coherent persistence first reaches 0.50 near 1,500 tokens (Wilson 95 percent CI [0.41, 0.61]). A four-step falsification battery (heterogeneity control, granularity sweep with hierarchical macro-merge, transition-entropy diagnostic, and long-horizon trajectory continuation) recasts the high-dose destination-coherent dip as a finite-horizon, endpoint-definition-sensitive feature rather than a stable structural asymmetry. Half the canonical magnitude is endpoint timing; the residual drops 73 percent from -0.143 at step 29 to -0.039 at step 79 under the frozen canonical cluster basis, bootstrap interval straddling zero. Replace-mode raw switching is near-saturated under the default protocol but largely reflects state-reset overwrite: insert-mode probes drop it to 12-32 percent. We report 37 experiments on gpt-4o-mini with within-vendor replication on gpt-4.1-nano. Recursive-loop evaluations should distinguish transient movement from durable escape, subtract stochastic floors, and treat context-update rules as safety-relevant design choices.

Double-machine-learning pipelines for the Average Dose-Response Function rely on kernel-weighted local-linear smoothers, which inherit unbounded functional influence: a single outlier within a kernel window biases the curve across the entire window. We introduce SHIFT (Self-calibrated Heavy-tail Inlier-Fit with Tempering), a robust DML estimator combining cross-fit nuisance orthogonalization with a kernel-local Welsch-loss second stage optimized by Graduated Non-Convexity, and -- the principal design choice -- a defensive OLS refit whose inlier cutoff is scaled by post-GNC residual MAD rather than the raw-outcome MAD. On a localized-contamination stress test at $p=0.25$ this design choice drops level-RMSE from 1.03 to 0.33 while leaving clean and uniformly-contaminated runs unchanged. Across 1,400 main-sweep fits, SHIFT has competitive worst-case shape recovery (RMSE $0.325$ at $p=0.25$, second to Huber-DML's $0.276$); among the three methods with worst-case RMSE below $0.35$, only SHIFT emits a non-uniform per-sample weight vector, recovering the ground-truth outlier mask at mean $F_1 \approx 0.96$ (range $0.945$--$0.968$) on Gaussian-jump DGPs. We pair the estimator with a six-technique Extreme Value Theory diagnostic suite (Hill, GPD-MLE/PWM, GEV, Mean Excess, parameter stability, causal tail coefficient) that lets a practitioner distinguish Frechet from Weibull regimes and choose between SHIFT and L1 alternatives on empirical grounds. Extensions to binary-treatment CATE (Huber pseudo-outcome X-Learner) and time-series ADRF (block-CV + rolling MAD) are included. A counter-intuitive ablation: linear nuisance models (Ridge, Lasso) outperform gradient-boosted nuisances for robust DML under uniform contamination, inverting the usual more-flexible-is-better heuristic.

Microscopy-based phenotypic profiling is scalable for drug discovery but lacks the mechanistic depth of transcriptomics, which remains costly and scarce. Existing multimodal approaches either use images to support other modalities or naively align representations by sample identity, ignoring cell-type and dose variations in weakly paired data-limiting generalization to unseen interventions. In this paper, we introduce an intervention-aware distillation framework that leverages perturbational transcriptomics to guide image representation learning. A transcriptome-conditioned teacher integrates gene expression and intervention metadata to produce soft distributions over a chemistry-aware codebook organized by drug similarity. The teacher employs a fine-tuned single-cell foundation model to encode cell-type context and disentangle dose effects. An image-only student learns to predict these distributions from microscopy alone, distilling mechanistic knowledge while operating independently at test time. This design emphasizes intervention semantics rather than identity alignment and explicitly handles dose and cell-type mismatches. We provide theoretical guarantees showing that transcriptomic guidance tightens the risk bound for image-based prediction. On Cell Painting and RxRx datasets paired with L1000, our method significantly improves one-shot transfer to unseen interventions and drug-target gene discovery compared to self-supervised and alignment baselines.

High-quality and diverse multimodal data are essential for improving vision-language models (VLMs), yet existing datasets often contain noisy, redundant, and poorly aligned samples. To address these problems, data filtering is commonly used to enhance the efficiency and performance of multimodal learning, but it introduces extra computational cost because filtering models are usually trained on the same data they are meant to screen. To reduce this cost, we study DOSE, which explores whether off-the-shelf pretrained models that have never seen the target data can be used to select training samples for larger and stronger multimodal models without any task-specific training. Even without fine-tuning, these models can effectively assess text quality and image-text alignment to guide data selection. Based on this, we build a joint quality-alignment distribution and apply adaptive weighted sampling to select informative samples while maintaining long-tail diversity. This approach enhances data diversity, enabling models trained on DOSE-filtered data to match or surpass those trained on the full dataset on standard VQA and math benchmarks. Extensive experiments demonstrate its effectiveness, efficiency, and scalability.

Radiotherapy (RT) planning is complex, subjective, and time-intensive. Advances with artificial intelligence (AI) promise to improve its precision and efficiency, but progress is often limited by the scarcity of large, standardized datasets. To address this, we introduce the Automated Iterative RT Planning (AIRTP) system, a scalable solution for generating high-quality treatment plans. This scalable solution is designed to generate substantial volumes of consistently high-quality treatment plans, overcoming a key obstacle in the advancement of AI-driven RT planning. Our AIRTP pipeline adheres to clinical guidelines and automates essential steps, including organ-at-risk (OAR) contouring, helper structure creation, beam setup, optimization, and plan quality improvement, using AI integrated with RT planning software like Varian Eclipse. Furthermore, a novel approach for determining optimization parameters to reproduce 3D dose distributions, i.e. a method to convert dose predictions to deliverable treatment plans constrained by machine limitations is proposed. A comparative analysis of plan quality reveals that our automated pipeline produces treatment plans of quality comparable to those generated manually, which traditionally require several hours of labor per plan. Committed to public research, the first data release of our AIRTP pipeline includes nine cohorts covering head-and-neck and lung cancer sites to support an AAPM 2025 challenge. To our best knowledge, this dataset features more than 10 times number of plans compared to the largest existing well-curated public dataset. Repo: https://github.com/RiqiangGao/GDP-HMM_AAPMChallenge.