Objective: To improve the spatial and temporal resolution of aortic 4D flow MRI through a unified deep learning framework for post-acquisition super-resolution (SR) of reconstructed velocity vector fields. Methods: We propose CURRENT, a recurrent neural network that performs spatial and temporal SR with a single network architecture. Supervised training was conducted using paired low- and high-resolution datasets generated by embedding computational fluid dynamics simulations of aortic flow into in vivo thoracic MRI backgrounds, followed by controlled spatial and temporal downsampling. CURRENT was evaluated for two-fold spatial and temporal SR against 4DFlowNet and for two-fold spatiotemporal SR against sequential spatial and temporal SR pipelines based on 4DFlowNet. Image-based and k-space-based quantitative metrics were considered and conventional interpolation were used as baselines. In addition, the impact of CURRENT's spatiotemporal SR on physics-informed relative pressure estimation was assessed. Finally, the ability of CURRENT to generalize from synthetic training data to in vivo acquisitions was investigated. Results: CURRENT achieved superior spatial SR performance and comparable temporal SR performance to dedicated 4DFlowNet models while providing a unified solution for both tasks. Simultaneous spatiotemporal SR using CURRENT yielded more accurate relative pressure estimates than either spatial or temporal SR alone and outperformed sequential 4DFlowNet-based spatial and temporal SR approaches. Furthermore, the proposed model demonstrated promising generalization to in vivo 4D flow MRI data despite being trained exclusively on synthetic datasets. Conclusion: CURRENT provides a unified framework for spatial and temporal SR of 4D flow MRI. The proposed approach has the potential to enhance physics-based analysis and broaden the applicability of accelerated 4D flow MRI.
Curvilinear structures such as retinal vessels and surface cracks need both pixel-level accuracy and structural continuity. Pixel-wise supervision does not model the connections between pixels, and topology-based losses still produce ordinary masks. Connectivity-based methods predict these connections directly, but they use binary connectivity targets over a fixed local range. Such labels give the same value to thin segments and to thick regions, and they cannot describe connections at larger offsets. To address these limitations, we propose Topology-preserving Multi-offset Affinity Learning (TMAL). TMAL uses soft affinities that emphasize thin regions near the boundary, and it predicts directional affinities at several offsets to reach further. It then combines these affinities with weights that come from the decoder features, so local continuity and wider context are used together. An auxiliary segmentation branch adds region-level supervision and keeps the overlap accuracy high. On the retinal vessel dataset DRIVE and the crack inspection dataset DeepCrack, TMAL reaches the highest Dice, IoU, and clDice scores, and it greatly reduces the connected-component error $\Delta\beta_0$. Code is available at https://github.com/suho-han/TMAL.
Medical images encode intrinsic tissue properties that indicate disease progression, yet these properties remain entangled with the system-dependent physics of image formation. Differentiable inverse rendering asks whether they are recoverable by inverting the imaging system's forward physics rather than through post-hoc correction. We address this in optical coherence tomography (OCT), focusing on the optical attenuation coefficient, a per-pixel marker of pathology and cellular composition. Conventional recovery relies on closed-form inversions limited to simplified light-tissue models, or learned methods coupled to specific imaging configurations. We instead recover per-pixel attenuation from a single OCT image by gradient descent through a differentiable physics-based forward model. We verified the method against analytical solutions, validated it on five in vitro phantoms, and applied it without modification to 29{,}269 clinical intravascular OCT images from 128 patients. The inversion needs no training data or segmentations and is portable across platforms and retrospective archives. Replacing the forward model or recovering another optical parameter leaves the optimization procedure unchanged. We demonstrate per-pixel recovery is tractable because gradient information scales to this high-dimensional problem, where gradient-free methods become intractable. Our work supports quantitative tissue characterization from OCT images and provides a framework for extension across imaging modalities and organ systems.
Background: Diagnostic I-131 whole-body planar imaging in differentiated thyroid cancer (DTC) is count-limited by low administered activity, and quality worsens under rapid acquisition. Models trained on such data struggle because their targets lack photon statistics. Purpose: To test whether high-quality post-therapeutic (PT) I-131 scans can serve as superior training references for enhancing sparse diagnostic planar images, using transfer learning and input-image addition. Methods: In this single-center prospective study, 111 patients were enrolled in PT training (n = 19), diagnostic follow-up (FU) training (n = 58), and FU paired test (n = 34) cohorts. Five Restormer-based models were trained: FU_DLx2 on FU labels; PT_DLx2 transfer-learned on PT data; PT_DLx1+ and PT_DLx2+ with input-image addition; PT_DLx6 as a PT-only reference. Test-time processing used two-step denormalization and Poisson re-scaling to preserve noise statistics. Quality was assessed by PSNR, SSIM, and a blinded dual-reader evaluation of all 34 test-cohort patients. Results: PT_DLx2 achieved the highest PSNR (34.4 +/- 3.6 dB) and SSIM (0.81 +/- 0.07). PT_DLx1+ and PT_DLx2+ were comparable (33.8 and 33.3 dB; SSIM 0.80). FU_DLx2 ranked below the unprocessed fast scan (30.3 vs. 32.0 dB; 0.76 vs. 0.79). Subjectively, PT_DLx2+ scored highest in image quality (4.54 +/- 0.60) and diagnostic confidence (4.54 +/- 0.60), surpassing the reference standard (4.19 +/- 0.83 and 4.31 +/- 0.81; P = 0.005 and P = 0.008). FU_DLx2 and PT_DLx6 scored lowest. Conclusion: Count-rich PT scans provide effective training priors for reconstructing extremely sparse images. Input-image addition and cross-domain transfer learning from PT data outperformed direct training on count-limited diagnostic data, supporting 2x scan acceleration with quality matching or exceeding the unaccelerated standard scan for selected PT-derived configurations.
Magnetic resonance imaging (MRI) pulse sequences organize radiofrequency excitation, gradient encoding, and signal acquisition, determining magnetization evolution and image formation. Sequence research requires translating imaging objectives into executable protocols meeting physical and acquisition constraints, refined via physical simulation, signal reconstruction, and scientific evaluation. Sequence construction, physical verification, parameter search, and assessment involve many tools and manual decisions, limiting automation from objective to verifiable sequence. We develop SmartBloch-Agent, an integrated framework for automated MRI sequence design and optimization. Given objectives and scientific constraints in natural language, an AI agent interprets goals, plans tasks, orchestrates tools, and makes feedback-informed decisions, drawing on a construction module and optimizers for structural design and parameter search. Our GPU-accelerated SmartBloch engine supplies physical computation for both stages, so the framework configures, per sequence and objective, event validation, Full-Bloch magnetization evolution, signal acquisition, image reconstruction, and scientific evaluation, and closes the loop without external MRI simulators. Results return to the agent to guide sequence revision, parameter optimization, and candidate selection, and the design files carry simulation, reconstruction, and evaluation evidence, forming an output package for a real-scanner workflow. Experiments show the framework automatically designs and optimizes MRI sequences for varied objectives and constraints, refines candidates with physical feedback, and improves several parameter-estimation metrics and downstream quantitative reconstruction. SmartBloch-Agent unifies objectives, design, physical execution, and evaluation into a continuous workflow for end-to-end automation of MRI sequence research.
Machine learning models in radiotherapy are commissioned by testing them on cases with known answers, which may not reveal a shortcut that the test cases share with the training data. Frontier language models have recently been reported to read and write the raw weights of small neural networks, an ability called weight-space programming. The purpose of this study was to determine whether such a model, given only a clinical protocol and a network's weights, can audit and repair the network. Networks with 433 to 4,801 parameters were trained to screen head-and-neck planning requests against four rules. Flaws were planted through the training data: confounds that hid each rule, a 3 Gy shift in the cord threshold, and a hidden trigger. Claude Opus 5.5 audited each network blind, without tools, data or code execution, and every claim and repair was tested on about 420,000 requests. The language model named the broken rule in 16 of 18 flawed networks (95% CI 67% to 97%), including all 15 with a confound or a threshold shift. It repaired each of the 16 by changing a median of 3 parameters. Fine-tuning on protocol-labeled requests also repaired every network, but changed nearly every parameter. Each confound and shift it found was visible in single units, and a simple statistic chosen for each flaw type found the same flaws. It cleared 2 of 5 healthy networks without being forced and found 1 of 3 triggers. Testing against the protocol detected every flaw, and black-box testing found the confounds and the shift faster. The results indicate that, in small networks, weight-space programming can locate and repair flaws that silence an input or shift a threshold, but cannot yet certify that a network is correct.
Medical physicists turn a prescription into a delivered dose and check one another's calculations, because one error in a beam calibration or a monitor-unit (MU) calculation can affect every patient treated with it. MedPhysBench has ten seeded generators of calculation items in radiation therapy, diagnostic imaging, nuclear medicine and radiation protection, up to clinical tasks such as a TG-51 calibration worksheet. Reference answers come from code implementing the governing protocols, and a grader converts units and applies tolerance bands. From the same inputs, separate checking items test error detection, showing a colleague's worksheet or only the colleague's result, half correct and half with one planted error. On a held-out test split of 1,200 items (half for two models), 12 models scored 33.3 to 100.0% on calculation. Of the nine answers graded incorrect for the four best (99.3-100.0%), five contained model errors and four followed NCRP Report 151 on points our items misstate or leave open. Below them, most models did worst on level-3 clinical tasks, and Claude Sonnet 5.5 omitted the inverse-square correction in 19 of 20 isocentric MU items. Five models detected at least 96.7% of mostly large planted errors with at most 4% false alarms; for four of the other seven, checking only the result raised false alarms significantly. In an exploratory targeted test with 20 public cases of an omitted inverse-square correction, the three best models tested caught it in every worksheet, and three weaker models accepted 16 to 18 of 20 planted worksheets, one of them while applying the correction in most of its own calculations. Claude Opus 5.5 accepted 6 of 20 wrong results, although it applied the correction in all 20 of its own. We report the effect of two problems in our shielding items, found after the runs, and release the code, per-item outcomes and targeted-test responses.
Computed tomography (CT) provides diverse patient information and various clinical tasks, for which numerous deep learning models have been investigated. Recent years have seen the development of vision-language foundation models that can comprehensively extract clinical features, driven by representation learning that combines CT volumes with radiology reports. Existing approaches typically adopt Contrastive Language-Image Pre-training (CLIP)-based representation learning, where pairs from different cases are, in principle, treated as negative pairs such that the volume and report embeddings are pushed apart. In the biomedical imaging, however, treating different cases as negative pairs is not always appropriate, particularly when clinical similarity exists. In this study, we propose a supervised representation learning framework grounded in clinical knowledge from language foundation models, rather than the weak supervision used in CLIP. Specifically, we utilized a large language model to extract abnormal finding phrases from reports. We then explicitly constructed the target features that the image encoder should output, as the semantic representation of the extracted findings using a biomedical text embedding model. Our Findings-aware Language-Image Pre-training (FiLIP) outperformed weakly supervised approaches in multi-label zero-shot finding classification in both in-domain and external-domain evaluations, and also proved effective when fine-tuned for the downstream task of radiology report generation.
Robust segmentation of biomedical images remains challenging primarily due to ill-defined object boundaries. Although several loss functions have recently been proposed to enhance object boundary recognition, concerns remain about the susceptibility to unstable annotations resulting from boundary ambiguities. Here, we introduce the Peripheral Prototypical Contrastive (PPC) loss, which leverages prototypical contrastive learning to improve boundary recognition and enable stable training even under noisy annotation conditions. The PPC loss utilizes prototype features obtained from local regions near object boundaries, focusing specifically on ambiguous areas that have been challenging for existing approaches. Extensive experiments across multiple datasets demonstrated that the PPC loss consistently improve segmentation performance even under conditions with noisy labels. A newly proposed strategy, which adaptively determines the local region for prototype calculation, enhanced robustness and outperformed existing methods. Our findings indicate the potential of the PPC loss in facilitating scalable and reliable medical image segmentation, including the development of foundation models with imperfect annotations.
Background and purpose: We propose PGPI4MR (prior-guided, physics-informed 4D MRI reconstruction), a deep learning method that leverages information from other respiratory phases or a setup scan, the first 30 s of the same scan, to improve 4D MRI reconstruction without extra scan time. Materials and methods: PGPI4MR is an unrolled network that reconstructs 16 respiratory phases from 60, 30, or 15 s of data, and single 3D volumes, each from 0.29-0.49 s of data, using a setup-scan image. The networks were trained once, on other volunteers, and were not retrained for new volunteers. We evaluated PGPI4MR on measured k-space from three datasets: free-breathing MR-linac (1.5T) and abdominal (3T) scans, and thigh scans with cuff compression (1.5T). All methods, including comparative models, received identical samples and were scored similarly. Results: In vivo, PGPI4MR had the lowest held-out error for 4D MRI at every scan time, and its 16 phases were ready a median of 7.5-13 s after the scan on the 2 GPUs tested. Coupling the 16 respiratory phases reduced the error at 60 s by 9.1% compared with reconstructing each phase alone. For sub-second MRI, the error at 0.49 s was 15.5% lower than that of the best comparison method, classical reconstruction toward the same prior, and on the faster GPU, every 0.29 s window was acquired and reconstructed within 0.5 s. Without retraining, PGPI4MR matched the best methods on the 3T abdominal scans but not on the thigh scans; after retraining on thigh data, it reduced the held-out error by 6.6% relative to the best comparison method. Conclusion: Prior information allowed PGPI4MR to reconstruct 4D and sub-second MRI more accurately than compressed sensing and a published 4D network, within seconds and without extra scan time. This could support 4D MRI for treatment planning and 3D motion monitoring during MR-guided radiotherapy.
T1-T2 correlation MRI has strong potential to quantify microstructural compartments without imposing a biological model. Traditionally, full T1-T2 spectra per voxel are reconstructed with an ill-conditioned and time-consuming Inverse Laplace Transform. We propose to view this challenge as an object detection task: A Detection Transformer (DETR) takes 64 TI/TE signals and directly predicts a set of compartments specified by T1, T2, and signal fraction. We achieve a mean average precision mAP@10 of 76.8% on simulated data, outperforming both our previous model design (53.8%) and regularized NNLS (66.1%). We show that our DETR approach outperforms NNLS in almost every setting across compartment count, compartmental signal fraction, and SNR. Reconstruction is orders of magnitude faster than NNLS. The results are fully reproducible from our public code: github.com/SebastianEndtTHI/t1t2-detr
Ultra-low-field (ULF) Magnetic Resonance Imaging (MRI) offers a portable, low-cost alternative to conventional scanners by operating at field strengths below 10 mT. At these fields, two sensor technologies compete: quantum SQUID (Superconducting Quantum Interference Device) sensors, which provide high sensitivity but require cryogenic cooling, and classical induction coils, which are inexpensive and room-temperature but produce weaker signals. With conventional physics-based imaging, both suffer from low signal-to-noise ratios (SNR). Data-driven reconstruction has overcome similar limits in related inverse problems, but its use for ULF-MRI has been hindered by a lack of open datasets, benchmarks, and flexible simulators. To close this gap, we present OpenULF, a modular, open-source simulation toolkit that generates paired training data and supports end-to-end machine-learning (ML) reconstruction. OpenULF integrates a Bloch-equation-validated physics simulator, calibrated SQUID and coil receiver models, reconstruction ML networks, and an automated design-space exploration engine. Architecturally, a receiver abstract base class, a typed HDF5 contract that decouples physics from learning, and a resumable sweep engine make sensors, models, and datasets independently substitutable. Using OpenULF, we train 774 models across four anatomical datasets and conduct three design-space explorations. The effectiveness of ML reconstruction depends strongly on the dataset and the sensor. We identify a SQUID-to-coil crossover near 450 $\mu$T and demonstrate that sensor hardware and ML model capacity can be traded off during system design. Sensor and reconstruction choices must therefore be co-designed: the best sensor is set by the dataset and field strength, not by SNR.
Multimodal intracranial EEG (iEEG) research for epilepsy surgery combines anatomical and functional imaging, implanted electrode locations, interictal biomarkers, and functional mapping--outputs produced by different applications and reconciled by hand before they can be viewed on the same anatomy. Omni-iEEG Planner is an open-source Python platform that brings these inputs into one patient coordinate frame for research data analysis. The workflow starts from the preoperative T1-weighted MRI, from which FreeSurfer provides the cortical surface and anatomical labels; CT, PET and diffusion MRI are then co-registered to that reference, electrode contacts are detected automatically on the postimplantation CT and reviewed by the analyst, and tractography is reconstructed within the application. Channel-indexed results computed outside the platform, such as high-frequency oscillation counts from pyHFO or time-resolved gamma responses, are projected onto the contacts and the cortical surface with their source units preserved, and interictal and functional evidence remain separate layers. We describe the design and demonstrate representative workflows on de-identified patient data. The platform is not proposed as a method for every laboratory; it is a worked example of how one research group combined multimodal integration with an AI-assisted iEEG analysis tool, pyHFO, in a single open environment that others can adapt to their own pipelines. The design will accommodate further evidence types--model-derived contact scores, virtual implantation and hypothetical resection studies, group-level analyses--as they are implemented. The software is released under the MIT license for research and educational use, not clinical decision-making.
We study short-horizon neonatal seizure prediction on Helsinki-style (HUH) preprocessed EEG feature tables using quantum-inspired reservoir computing. Under strict subject-wise cross-validation on imbalanced preictal--interictal windows, we test whether reservoir constructions shaped after (i) gate-based qubit dynamics and (ii) continuous-variable (bosonic/photonic) dynamics provide a practical sequence encoder relative to strong classical baselines. Both reservoirs are executed here purely in classical simulation on a single GPU; accordingly, we do not claim quantum advantage, but rather evaluate whether quantum-shaped dynamics act as useful, low-footprint random feature maps with a trained linear readout. We compare against Random Forests and RBF--SVMs, and report AUROC, AUPRC, per-subject AUPRC, expected calibration error, and stratified bootstrap confidence intervals. Across our experiments, the CV/bosonic reservoir is consistently competitive and can improve AUPRC over the baselines, while the gate-style reservoir is more sensitive to hyperparameters. These results suggest that quantum-inspired, photonics-motivated reservoirs can be practical sequence encoders for neonatal EEG feature tables under conservative subject-wise evaluation.
Medical imaging has served as primary proving ground for clinical AI, yet a decade of intense research has not translated into proportionate bedside impact. We argue that this gap is not primarily a product of insufficient algorithmic performance, inadequate regulation, or limited explainability. Rather, it reflects a structural misalignment, between how AI systems are designed and evaluated, and how clinical decisions are made. This work identifies 8 interconnected dimensions of this misalignment: 1) the dominance of pixel-only models in a multimodal clinical world; 2) the erosion of physician trust through opaque and inflexible systems; 3) the unfulfilled promise of foundation models in data-sparse medical domains; 4) the persistent bottleneck of non-shareable under-curated datasets; 5) the gap between validated algorithms and deployable clinical platforms; 6) the slow, unmonitored translation of evidence into routine practice; 7) the risk of AI displacing rather than extending physician judgment; and 8) the failure of prediction-centric AI to generate actionable, agentic clinical guidance. For each dimension, we reframe the problem and propose a path forward, culminating in a vision of physician-centered AI solutions with agentic reasoning that extend, rather than replace, clinical judgment.
Background: Digital health technologies allow for frequent, remote gait monitoring in people with multiple sclerosis (MS). However, to differentiate daily variability from actual disease progression in longitudinal data, established minimal clinically important differences (MCID) are required. Currently, there is limited literature defining these thresholds for digital gait metrics. Objective: To establish MCIDs for digital gait measures reflecting progression in MS. Methods: Digital gait measures were captured via daily, remote, smartphone-based Two-Minute Walk Tests in CONSONANCE (NCT03523858), a phase 3b study of ocrelizumab in progressive MS. Using an anchor-based approach, median changes from baseline at Week 96 on digital gait measures were computed for patients showing clinically meaningful worsening on either Timed 25-Foot Walk, Ambulation Score, Expanded Disability Status Scale, or 12-item Multiple Sclerosis Walking Scale. These changes were subsequently triangulated to derive the MCID estimates. Results: 243 patients with progressive MS (female: n=125 (51%); mean [SD] age: 49.3 [9.3]; mean [SD] EDSS: 4.8 [1.4]) had digital gait data available at baseline and Week 96. Median changes were generally consistent across anchors. Triangulated MCIDs are: Step Velocity = -0.16 m/s, Step Velocity Scaled to Walking Time = -0.18 m/s, Step Duration = 0.06 s, Step Length = -0.07 m, Total Number of Steps = -28, and Total Distance Walked = -24 m. Conclusion: These MCIDs provide a framework for interpreting meaningful gait changes and integrating digital measures into MS outcome evaluation. Beyond facilitating novel clinical trial endpoints to evaluate treatment efficacy, they enable objective, real-world monitoring to advance personalized patient care.
Artificial intelligence is increasingly integrated into radiotherapy workflows, yet it remains vulnerable to out-of-distribution image data that can introduce unexpected behavior in clinical tasks. Deep learning (DL)-based anomaly detection for pelvic magnetic resonance imaging (MRI) remains limited and transparent evaluation for full automation is lacking. This study aimed to develop two self-supervised anomaly-detection framework variations in radiotherapy for pelvic and brain MRI.A two-stage self-supervised DL-framework was trained separately for pelvic and brain MRI utilizing three public datasets. The first stage compressed normal image data into discrete representations, and a second stage modeled the representation distribution. Anomaly-evidence was obtained by combining perceptual image differences with token-surprisal scores via negative log-likelihood estimation. Automated detection was evaluated for two anatomical cohorts: pelvis, encompassing both synthetic global anomalies and real clinical anomalies, and brain, comprising clinically annotated anomalies. Performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). For each cohort, a subset of normal images was reserved for analysis. Promising exploratory performance across evaluation cohorts was obtained. AUCs were 0.97 (95% CI 0.96-0.99) for synthetic pelvic anomalies, 0.95 (95% CI 0.90-1.00) for clinical pelvic anomalies, and 0.81 (95% CI 0.74-0.87) for brain anomalies. Qualitative heatmap analysis showed spatial agreement between detected anomalies and reference annotations. The framework variations showed promising anomaly detection performance across pelvic and brain MRI, supporting its potential for automated MRI quality control in radiotherapy. Heatmap-based visualization further improved interpretability by spatially localizing detected anomalies.
Background and purpose: Intensity-modulated proton therapy (IMPT) enables conformal dose delivery for head and neck (H&N) cancers. However, its sensitivity to inter-fractional anatomical changes motivates online adaptations, where rapid and accurate Monte Carlo (MC) dose calculation remains a major bottleneck. Low-statistics MC simulations reduce computation time but introduce noise. This study aimed to develop a diffusion-transformer framework to recover high-statistics dose distributions from noisy MC simulations. Materials and methods: A diffusion-transformer-based dose denoising framework was developed. Eighty H&N patients were used for training and additional 10 H&N patients and 30 patients with lung, breast, and prostate cancers (10 per site) were used for evaluation. Noisy and high-statistics dose maps were generated using MCsquare. The model was trained using noisy dose maps and CT images as inputs and high-statistics dose maps as ground truth, with mean squared error, residual, regional mean absolute error (MAE), and dose-volume histogram (DVH) losses. Performance was evaluated using MAE, 3D gamma passing rates, and DVH indices. Results: Mean whole-body MAE ranged from 0.08 +/- 0.06 to 0.20 +/- 0.11 Gy (Relative Biological Effectiveness, RBE) (RBE = 1.1) across test cohorts. Mean whole-body 3 %/2 mm gamma passing rates ranged from 95.8 +/- 0.8 % to 97.6 +/- 0.9 %. DVH indices from high-statistics and predicted dose distributions showed close agreement for clinical target volumes and organs of interest. Conclusions: The diffusion-transformer-based framework denoised low-statistics MC dose distributions. Despite being trained on H&N data, the model generalized to lung, breast, and prostate cohorts without retraining.
Cone beam computed tomography (CBCT) is widely used for image guided and adaptive radiotherapy, but scatter, noise, reconstruction artifacts, and inaccurate Hounsfield units limit its quantitative use. Recent diffusion approaches for CBCT to CT synthesis remain largely image driven, with limited use of the underlying acquisition physics. We propose EPC-RawDC, a conditional 3D latent diffusion framework that combines volumetric generative modeling with two complementary constraints derived from the same scanner specific CBCT forward model. First, geometry equivariant projection constraint exploits the rotational equivariance of the CBCT forward operator by supervising the synthesized CT through correspondingly transformed reference projections. Second, raw data consistency uses noisy projection measurements of the individual acquisition as scan specific supervision during training. The framework was evaluated on two independent clinical cohorts with distinct scanner geometries and projection sources. For JUST, the physics constraints used measured clinical raw CBCT projections acquired with an Elekta system, whereas for SynthRAD2025 the projection data were simulated from the reference CT using a Varian geometry with Poisson photon statistics. EPC-RawDC achieved an SSIM of 0.97 in both cohorts and improved PSNR over DDPM by 2.66 dB on SynthRAD2025 and 2.10 dB on JUST, while reducing mean MAE by 20.3% and 19.0%, respectively. On SynthRAD2025, projection consistency and equivariant errors were reduced by 55.0% and 41.4% relative to DDPM. These results demonstrate that combining a volumetric diffusion prior with scanner geometry and scan specific projection measurements improves quantitative CBCT to CT synthesis across both simulated and measured projection domains. Code available after publication at https://github.com/ALZAHRAALTALIB/EPC-RawDC.
Macromolecular pool fraction (MPF) is a quantitative imaging biomarker sensitive to myelin integrity and other changes in tissue macromolecular content, but specialized acquisitions and reconstruction methods limit its use in large-scale studies. We present a physics-guided, self-supervised deep learning framework for retrospectively estimating MPF directly from conventional clinical brain MRI ($T_1$-weighted, $T_2$-weighted, and fluid-attenuated inversion recovery [FLAIR]) without paired quantitative reference scans. The framework embeds an analytical two-pool magnetization transfer signal model that related sequence-averaged radiofrequency transmit power to apparent longitudinal relaxation. To accommodate heterogeneous clinical protocols, the network conditions intermediate features on acquisition parameters via adaptive instance normalization. It was trained and evaluated on a multisite, multivendor, multiprotocol dataset of 7,705 MRI sessions (3 T). Across 1,237 test sessions, mean MPF was $0.182 \pm 0.007$ in white matter and $0.144 \pm 0.009$ in gray matter, with limited variation across vendor-by-protocol groups (between-group coefficient of variation: 2.65% and 5.63%, respectively). In 70 sessions with demyelinating-disease labels, MPF was 35.6% lower in segmented lesions than in normal-appearing white matter. MPF maps from two different clinical protocols acquired in a healthy volunteer showed a mean voxel-wise absolute percentage difference of 7.7% and a concordance correlation coefficient of $0.888$, indicating good cross-protocol consistency. These results suggest that magnetization transfer-informed self-supervised learning enables stable MPF mapping from conventional clinical MRI, providing a scalable approach to investigate demyelinating pathology in both existing imaging archives and prospectively acquired conventional clinical scans without dedicated qMT acquisitions.