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Accurate estimation of the relative concentrations of chromophores in a spectroscopic photoacoustic (sPA) image can reveal immense structural, functional, and molecular information about physiological processes. However, due to nonlinearities and ill-posedness inherent to sPA imaging, concentration estimation is intractable. The Spectroscopic Photoacoustic Optical Inversion Autoencoder (SPOI-AE) aims to address the sPA optical inversion and spectral unmixing problems without assuming linearity. Herein, SPOI-AE was trained and tested on textit{in vivo} mouse lymph node sPA images with unknown ground truth chromophore concentrations. SPOI-AE better reconstructs input sPA pixels than conventional algorithms while providing biologically coherent estimates for optical parameters, chromophore concentrations, and the percent oxygen saturation of tissue. SPOI-AE's unmixing accuracy was validated using a simulated mouse lymph node phantom ground truth.

Background: Several studies show that large language models (LLMs) struggle with phenotype-driven gene prioritization for rare diseases. These studies typically use Human Phenotype Ontology (HPO) terms to prompt foundation models like GPT and LLaMA to predict candidate genes. However, in real-world settings, foundation models are not optimized for domain-specific tasks like clinical diagnosis, yet inputs are unstructured clinical notes rather than standardized terms. How LLMs can be instructed to predict candidate genes or disease diagnosis from unstructured clinical notes remains a major challenge.

Methods: We introduce RAG-driven CoT and CoT-driven RAG, two methods that combine Chain-of-Thought (CoT) and Retrieval Augmented Generation (RAG) to analyze clinical notes. A five-question CoT protocol mimics expert reasoning, while RAG retrieves data from sources like HPO and OMIM (Online Mendelian Inheritance in Man). We evaluated these approaches on rare disease datasets, including 5,980 Phenopacket-derived notes, 255 literature-based narratives, and 220 in-house clinical notes from Childrens Hospital of Philadelphia.

Results: We found that recent foundations models, including Llama 3.3-70B-Instruct and DeepSeek-R1-Distill-Llama-70B, outperformed earlier versions such as Llama 2 and GPT-3.5. We also showed that RAG-driven CoT and CoT-driven RAG both outperform foundation models in candidate gene prioritization from clinical notes; in particular, both methods with DeepSeek backbone resulted in a top-10 gene accuracy of over 40% on Phenopacket-derived clinical notes. RAG-driven CoT works better for high-quality notes, where early retrieval can anchor the subsequent reasoning steps in domain-specific evidence, while CoT-driven RAG has advantage when processing lengthy and noisy notes.

Single-cell RNA sequencing (scRNA-seq) data exhibit strong and reproducible statistical structure. This has motivated the development of large-scale foundation models, such as TranscriptFormer, that use transformer-based architectures to learn a generative model for gene expression by embedding genes into a latent vector space. These embeddings have been used to obtain state-of-the-art (SOTA) performance on downstream tasks such as cell-type classification, disease-state prediction, and cross-species learning. Here, we ask whether similar performance can be achieved without utilizing computationally intensive deep learning-based representations. Using simple, interpretable pipelines that rely on careful normalization and linear methods, we obtain SOTA or near SOTA performance across multiple benchmarks commonly used to evaluate single-cell foundation models, including outperforming foundation models on out-of-distribution tasks involving novel cell types and organisms absent from the training data. Our findings highlight the need for rigorous benchmarking and suggest that the biology of cell identity can be captured by simple linear representations of single cell gene expression data.

Accurate and timely identification of hospital outbreak clusters is crucial for preventing the spread of infections that have epidemic potential. While assessing pathogen similarity through whole genome sequencing (WGS) is considered the gold standard for outbreak detection, its high cost and lengthy turnaround time preclude routine implementation in clinical laboratories. We explore the utility of two rapid and cost-effective alternatives to WGS, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry and antimicrobial resistance (AR) patterns. We develop a machine learning framework that extracts informative representations from MALDI-TOF spectra and AR patterns for outbreak detection and explore their fusion. Through multi-species analyses, we demonstrate that in some cases MALDI-TOF and AR have the potential to reduce reliance on WGS, enabling more accessible and rapid outbreak surveillance.

Purpose of review: Imaging-derived fractional flow reserve (FFR) is rapidly evolving beyond conventional computational fluid dynamics (CFD)-based pipelines toward machine learning (ML), deep learning (DL), and physics-informed approaches that enable fast, wire-free, and scalable functional assessment of coronary stenosis. This review synthesizes recent advances in CT- and angiography-based FFR, with particular emphasis on emerging physics-informed neural networks and neural operators (PINNs and PINOs) and key considerations for their clinical translation.

Recent findings: ML/DL approaches have markedly improved automation and computational speed, enabling prediction of pressure and FFR from anatomical descriptors or angiographic contrast dynamics. However, their real-world performance and generalizability can remain variable and sensitive to domain shift, due to multi-center heterogeneity, interpretability challenges, and differences in acquisition protocols and image quality. Physics-informed learning introduces conservation structure and boundary-condition consistency into model training, improving generalizability and reducing dependence on dense supervision while maintaining rapid inference. Recent evaluation trends increasingly highlight deployment-oriented metrics, including calibration, uncertainty quantification, and quality-control gatekeeping, as essential for safe clinical use.

Summary: The field is converging toward imaging-derived FFR methods that are faster, more automated, and more reliable. While ML/DL offers substantial efficiency gains, physics-informed frameworks such as PINNs and PINOs may provide a more robust balance between speed and physical consistency. Prospective multi-center validation and standardized evaluation will be critical to support broad and safe clinical adoption.

Understanding the dynamic nature of brain connectivity is critical for elucidating neural processing, behavior, and brain disorders. Traditional approaches such as sliding-window correlation (SWC) characterize time-varying undirected associations but do not resolve directional interactions, limiting inference about time-resolved information flow in brain networks. We introduce sliding-window prediction correlation (SWpC), which embeds a directional linear time-invariant (LTI) model within each sliding window to estimate time-varying directed functional connectivity (FC). SWpC yields two complementary descriptors of directed interactions: a strength measure (prediction correlation) and a duration measure (window-wise duration of information transfer). Using concurrent local field potential (LFP) and fMRI BOLD recordings from rat somatosensory cortices, we demonstrate stable directionality estimates in both LFP band-limited power and BOLD. Using Human Connectome Project (HCP) motor task fMRI, SWpC detects significant task-evoked changes in directed FC strength and duration and shows higher sensitivity than SWC for identifying task-evoked connectivity differences. Finally, in post-concussion vestibular dysfunction (PCVD), SWpC reveals reproducible vestibular-multisensory brain-state shifts and improves healthy-control vs subacute patient (HC-ST) discrimination using state-derived features. Together, these results show that SWpC provides biologically interpretable, time-resolved directed connectivity patterns across multimodal validation and clinical application settings, supporting both basic and translational neuroscience.

Three-dimensional (3D) ultrasound promises various medical applications for abdominal, obstetrics, and cardiovascular imaging. However, ultrasound matrix arrays have extremely high element counts limiting their field of view (FOV). This work seeks to demonstrate an increased field-of-view using a reduced element count array design. The approach is to increase the element size and use advanced beamformers to maintain image quality. The delay and sum (DAS), Null Subtraction Imaging (NSI), directional coherence factor (DCF), and Minimum Variance (MV) beamformers were compared. K-wave simulations of the 3D point-spread functions (PSF) of NSI, DCF, and MV display reduced side lobes and narrowed main lobes compared to DAS. Experiments were conducted using a multiplexed 1024-element matrix array on a Verasonics 256 system. Elements were electronically coupled to imitate a larger pitch and element size. Then, a virtual large aperture was created by using a positioning system to collect data in sections with the matrix array. High-quality images were obtained using a coupling factor of two, doubling the FOV while maintaining the same element count in the virtual large aperture as the original matrix array. The NSI beamformer demonstrated the best resolution performance in simulations and on the large aperture, maintaining the same resolution as uncoupled DAS for coupling factors up to 4. Our results demonstrate how larger matrix arrays could be constructed with larger elements, with resolution maintained by advanced beamformers.

Several applications of medical ultrasound can benefit from a larger imaging field of view (FOV). This study is aimed at increasing the FOV of linear array probes by increasing the element size rather than the element count. To investigate larger FOV, this study used coupled elements to imitate a larger element size. The effects of coupling on array beam patterns are examined with Fourier transforms of elements. The effects of coupling on resolution, contrast, and speckle signal-to-noise ratio are examined through phantom images and in-vivo images of a rabbit tumor reconstructed with plane-wave compounding. Furthermore, a positioning system was used to acquire data from a virtual large aperture with 120 mm FOV and 128 elements, collected in sections with a single probe. This study also investigates the Null Subtraction Imaging (NSI), Sign Coherence Factor (SCF), and Minimum Variance (MV) beamformers for regaining resolution lost by an increased F-number with large elements. The MV beamformer, while the most computationally expensive, was best for improving resolution without increasing speckle variance, decreasing Full-Width at Half-Max (FWHM) estimates of wire targets from 0.78 mm with DAS on a 2.5 wavelength element size to 0.54 mm with MV on a 5 wavelength element size.

Distinguishing causal relationships from statistical correlations remains a fundamental challenge in clinical research, limiting the translation of observational findings into interventional treatment guidelines. Here we apply causal machine learning to establish causal effects of radiation dose parameters on mandibular osteoradionecrosis (ORN) in 931 head and neck cancer patients treated with volumetric-modulated arc therapy. Using generalized random forests, we demonstrate that all examined dosimetric factors exhibit significant positive causal effects on ORN development (average treatment effects: 0.092-0.141). Integration with explainable machine learning reveals substantial treatment effect heterogeneity, with patients aged 50-60 years showing the strongest causal dose-response relationships (conditional average treatment effects up to 0.229), while patients over 70 years demonstrate minimal effects. These results suggest that age-stratified treatment optimization and personalized treatment planning for the dosimetric factors could reduce ORN risk. Our findings demonstrate that causal inference methods can transform clinical retrospective radiotherapy data into personalized treatment recommendations, providing a methodological framework applicable to toxicity prediction across oncology and other clinical domains where treatment decisions depend on complex dose-response relationships.

Functional MRI is a neuroimaging technique that analyzes the functional activity of the brain by measuring blood-oxygen-level-dependent signals throughout the brain. The derived functional features can be used for investigating brain alterations in neurological and psychiatric disorders. In this work, we employed a hypergraph to model high-order functional relations across brain regions, introducing algebraic connectivity $\left(a\left(𝒢\right)\right)$ for estimating the hyperedge weights. The hypergraph structure was derived from healthy controls to build a common topology across individuals. The considered cohort for subsequent analyses included subjects covering the Alzheimer's disease (AD) continuum, encompassing both mild cognitive impairment and AD patients. Statistical analysis and three classification tasks: HC vs AD, MCI vs AD, and HC vs MCI, were performed to assess differences across the three groups and the potential of the hyperedge weights as functional features. Furthermore, a mediation analysis was performed to evaluate the reliability of the $a\left(𝒢\right)$ values, representing functional information as the mediator between tau-PET levels, a key biomarker of AD, and cognitive scores. The proposed approach identified a larger number of hyperedges statistically different across groups compared to state-of-the-art methods. The $a\left(𝒢\right)$ hyperedge weights also demonstrated a higher discriminative power in all three binary classifications. Finally, two hyperedges belonging to salience/ventral attention and somatomotor networks showed a partial mediation effect between the tau biomarker and cognitive decline. These results suggested that $a\left(𝒢\right)$ can be an effective approach for extracting the hyperedge weights, including important functional information that resides in the brain areas forming the hyperedges.