Herbal prescriptions are a cornerstone of Traditional Chinese Medicine (TCM), bridging diagnostic reasoning and therapeutic interventions. Existing herbal prescription recommendation (HPR) methods often rely on structured inputs or multi-stage pipelines, limiting their applicability to real-world clinical scenarios. To address this, we propose MKE-DAN (Medical Knowledge Enhanced Dual-level Alignment Network), a novel framework that directly generates herbal prescriptions from raw, unstructured medical records. By integrating a domain-specific pre-trained language model and label-wise self-attention, our model leverages intra-modal alignment to capture subtle diagnostic patterns and treatment reasoning from medical records. Additionally, cross-modal alignment with a heterogeneous graph transformer and knowledge-enhanced cross-attention ensures effective integration of structured knowledge with medical records for accurate and interpretable herb recommendations. Using TCM-9K, a large-scale dataset of clinical records paired with expert-verified prescriptions, and the CCL2025-800 dataset for external validation, experimental results demonstrate that MKEDAN achieves state-of-the-art performance, robust generalization, and strong handling of rare prescription patterns, showcasing its potential for real-world deployment in intelligent TCM systems.

Primary liver malignancies are widely recognized as the most heterogeneous and prognostically diverse cancers of the digestive system. Among these, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) emerge as the two principal histological subtypes, demonstrating significantly greater complexity in tissue morphology and cellular architecture than other common tumors. The intricate representation of features in Whole Slide Images (WSIs) encompasses abundant crucial information for liver cancer histological subtyping, regarding hierarchical pyramid structure, tumor microenvironment (TME), and geometric representation. However, recent approaches have not adequately exploited these indispensable effective descriptors, resulting in a limited understanding of histological representation and suboptimal subtyping performance. To mitigate these limitations, A hieRarchical Geometry-gUided tranSformer (ARGUS) is proposed to advance histological subtyping in liver cancer by capturing the macro-meso-micro hierarchical information within the TME. Extensive experiments on public and private cohorts demonstrate that our ARGUS achieves state-of-the-art (SOTA) performance in histological subtyping of liver cancer, which provide an effective diagnostic tool for primary liver malignancies in clinical practice. Related code will be available to public.

Automated International Classification of Diseases (ICD) coding assigns standardized codes to clinical records, playing a critical role in healthcare systems. However, existing methods struggle with semantic gaps between clinical text and ICD codes, poor performance on rare codes, and limited interpretability. We propose TraceCoder, a framework that integrates multi-source external knowledge, including UMLS, Wikipedia, and large language models (LLMs), to enrich ICD code representations and provide traceable, evidence-based predictions. A hybrid attention mechanism is introduced to model interactions among labels, clinical context, and knowledge, improving longtail code recognition and interpretability by grounding predictions in external evidence. Experiments on MIMIC-III-ICD9, MIMIC-IV-ICD9, and MIMIC-IV-ICD10 datasets demonstrate that TraceCoder achieves state-of-the-art performance, with ablation studies validating its components. TraceCoder offers a scalable, interpretable, and reliable solution for automated ICD coding, aligning with clinical needs for accuracy and traceability.

Electronic medical records (EMRs) are crucial for modern healthcare, containing rich information about patient care, diagnoses, and treatments. However, their unstructured nature, domain-specific language, and complexity pose significant challenges for automated understanding. Existing methods often treat all data equally, limiting their ability to handle rare or complex cases effectively. We present TACL (Threshold-Adaptive Curriculum Learning), a novel framework that dynamically adjusts the training process based on sample complexity. Inspired by progressive learning, TACL categorizes data into difficulty levels, focusing on simpler cases early in training and gradually addressing more complex ones. A domain-specific pre-trained language model is used for difficulty assessment, considering semantic, syntactic, and contextual features. Additionally, TACL employs an adaptive training strategy to enhance task-specific performance and ensure generalization across diverse datasets. Experimental results on multilingual datasets, including MIMICIII, MIMIC-IV, and Chinese clinical records, demonstrate TACL's effectiveness in tasks such as ICD coding, readmission prediction, and TCM syndrome differentiation. TACL improves performance on rare and complex cases, providing a scalable and robust solution for medical text understanding.

Intraoperative hypotension (IOH), a critical condition characterized by sustained arterial pressure below 65 mmHg, poses significant risks of organ damage and mortality. Despite advancements in predictive models, current methods often fall short in capturing the dynamic, multi-scale nature of physiological signals due to their reliance on fixed convolutional kernels. To address this challenge, we introduce the Adaptive Time-Shift Convolutional Neural Network (ATS-CNN), a novel approach that combines the flexibility of deformable convolutions with the temporal modeling power of LSTMs. Unlike traditional methods, ATS-CNN leverages an innovative LSTM-based offset generation mechanism to dynamically adjust convolutional sampling points, enabling precise adaptation to the non-stationary characteristics of biosignals. Through a combination of adaptive sampling, deformable 1D convolutions, and robust data augmentation techniques-including dynamic noise injection-the model achieves unparalleled robustness and predictive accuracy. Extensive internal and external validations on two large-scale real-world datasets demonstrate that ATSCNN not only sets a new benchmark in$\mathbf{I O H}$prediction but also offers a clinically interpretable framework, transforming how machine learning addresses high-stakes medical challenges. This fusion of adaptability, precision, and interpretability positions ATS-CNN as a disruptive innovation in the field of perioperative care.

MOTIVATION: Crohn's disease (CD) exhibits substantial variability in response to biological therapies such as ustekinumab (UST), a monoclonal antibody targeting interleukin-12/23. However, predicting individual treatment responses remains difficult due to the lack of reliable histopathological biomarkers and the morphological complexity of tissue. While recent deep learning methods have leveraged whole-slide images (WSIs), most lack effective mechanisms for selecting relevant regions and integrating patch-level evidence into robust patient-level predictions. Therefore, a framework that captures local histological cues and global tissue context is needed to improve prediction performance. RESULTS: We propose a novel clustering-enhanced weakly supervised learning framework to predict UST treatment response from pre-treatment WSIs of CD patients. First, patches from WSIs were encoded using a pre-trained vision foundation model, and k-means clustering was applied to identify representative morphological patterns. Discriminative patches associated with treatment outcomes were selected via a DenseNet-based classifier, with Grad-CAM used to enhance interpretability. To aggregate patch-level predictions, we adopted a multi-instance learning approach, from which whole-slide features were extracted using both patch likelihood histograms and bag-of-words representations. These features were subsequently used to train a classifier for final response prediction. Experimental results on an independent test set demonstrated that our WSI-level model achieved superior predictive performance with an AUC of 0.938 (95% CI: 0.879-0.996), sensitivity of 0.951, and specificity of 0.825, outperforming baseline patch-level models. These findings suggest that our method enables accurate, interpretable, and scalable prediction of biological therapy response in CD, potentially supporting personalized treatment strategies in clinical settings. AVAILABILITY AND IMPLEMENTATION: https://github.com/caicai2526/USTAIM.

MOTIVATION: Endometrial cancer is a prevalent gynecological malignancy that requires accurate identification of its molecular subtypes for effective diagnosis and treatment. Four molecular subtypes with different clinical outcomes have been identified: POLE mutation, mismatch repair deficient, p53 abnormal, and no specific molecular profile. However, determining these subtypes typically relies on expensive gene sequencing. To overcome this limitation, we propose a novel method that utilizes hematoxylin and eosin-stained whole slide images to predict endometrial cancer molecular subtypes. RESULTS: Our approach leverages a hierarchical foundation model as a backbone, fine-tuned from the UNI computational pathology foundation model, to extract tissue embedding from different scales. We have achieved promising results through extensive experimentation on the Fudan University Shanghai Cancer Center cohort (N = 364). Our model demonstrates a macro-average AUROC of 0.879 (95% CI, 0.853-0.904) in a five-fold cross-validation. Compared to the current state-of-the-art molecular subtypes prediction for endometrial cancer, our method outperforms in terms of predictive accuracy and computational efficiency. Moreover, our method is highly reproducible, allowing for ease of implementation and widespread adoption. This study aims to address the cost and time constraints associated with traditional gene sequencing techniques. By providing a reliable and accessible alternative to gene sequencing, our method has the potential to revolutionize the field of endometrial cancer diagnosis and improve patient outcomes. AVAILABILITY AND IMPLEMENTATION: The codes and data used for generating results in this study are available at https://github.com/HaoyuCui/hi-UNI for GitHub and https://doi.org/10.5281/zenodo.14627478 for Zenodo.

Given the intricate situation of modelling gigapixel images, the usage of multiple instance learning (MIL) framework has recently increased to support clinical practice, encompassing cancer diagnosis, subtyping, survival prediction and other tasks. In current practice, most state-of-the-art MIL proposals typically apply a frozen pre-trained CNN or a pathological foundation model for feature extraction. While this paradigm lacks the capability for sequence feature fine-tuning within the downstream-specific tasks, which hinders the continuous performance promotion in Whole Slide Images (WSIs) Analysis. To address this issue, we propose a Sequence Feature Reconstruction Transformer (SeqFRT) for optimizing feature extraction of the foundation model, which can capture more discriminative features within pathological instance sequences. The proposed model comprises three main modules: 1) an offline foundation model as the pathological feature extractor; 2) a sequence position optimization architecture which aims at refining the correlations between instances in both sequential ordering and transpositional ordering; 3) a sequence sparsity enhancement strategy is designed to reconstruct the sequence feature and extract the latent representations instead of redundant information. Extensive experiments on six benchmark datasets for three computational pathology tasks demonstrated our model’s superiority over the state-of-the-art MIL methods. The source code is available at https://github.com/caicai2526/SeqFRT-MIL.

Timely prediction and intervention for Intraoperative Hypotension (IOH), a prevalent complication associated with general anesthesia, is crucial to prevent severe postoperative outcomes. While existing machine learning methods for IOH prediction have shown promise, they face limitations such as reliance on single data sources and disregard for crucial features like the trend in Arterial Blood Pressure (ABP) waveforms. To address these challenges, this paper proposes a novel multichannel deep learning framework that combines Convolutional Neural Networks (CNN) and Transformers for automatic IOH prediction. The model leverages four types of physiological waveforms, including ABP, ElectroCardioGram (ECG), photoplethysmography (PLE), and Carbon Dioxide (CO2), to capture both local and global information, enhancing information representation. Experimental results on retrospective data of 14,140 adult patients undergoing non-cardiac surgery from VitalDB, a public data repository of vital signs taken during surgeries in 10 operating rooms at Seoul National University Hospital (from January 6, 2005 to March 1, 2014), demonstrate that the proposed model consistently outperforms other methods, achieving superior AUROC values of 0.943, 0.928, and 0.923 at 5, 10, and 15 minutes before the event, respectively. These results demonstrate the powerfulness of multi-modal data source as well as the importance of ABP waveform trends. Additionally, the incorporation of multi-task learning and the attention mechanism validates the effectiveness and superiority of our model, highlighting its potential for proactive clinical interventions and improved postoperative patient outcomes.

MOTIVATION: Differentiating 12 stages of the mouse seminiferous epithelial cycle is vital towards understanding the dynamic spermatogenesis process. However, it is challenging since two adjacent spermatogenic stages are morphologically similar. Distinguishing Stages I-III from Stages IV-V is important for histologists to understand sperm development in wildtype mice and spermatogenic defects in infertile mice. To achieve this, we propose a novel pipeline for computerized spermatogenesis staging (CSS). RESULTS: The CSS pipeline comprises four parts: (i) A seminiferous tubule segmentation model is developed to extract every single tubule; (ii) A multi-scale learning (MSL) model is developed to integrate local and global information of a seminiferous tubule to distinguish Stages I-V from Stages VI-XII; (iii) a multi-task learning (MTL) model is developed to segment the multiple testicular cells for Stages I-V without an exhaustive requirement for manual annotation; (iv) A set of 204D image-derived features is developed to discriminate Stages I-III from Stages IV-V by capturing cell-level and image-level representation. Experimental results suggest that the proposed MSL and MTL models outperform classic single-scale and single-task models when manual annotation is limited. In addition, the proposed image-derived features are discriminative between Stages I-III and Stages IV-V. In conclusion, the CSS pipeline can not only provide histologists with a solution to facilitate quantitative analysis for spermatogenesis stage identification but also help them to uncover novel computerized image-derived biomarkers. AVAILABILITY AND IMPLEMENTATION: https://github.com/jydada/CSS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cluster analysis is a data mining technique that has been widely used to exploit useful information in a great amount of data. Because of their evaluation mechanism based on an intracluster distance (ICD) function, traditional single-objective clustering algorithms are not appropriate for not-well-separated data. Specifically, they may easily result in the drop of the optimal solution accuracy on their late stages of search when dealing with the latter. To overcome the problem, in this paper a novel index reflecting the similarity of data within a cluster is presented and called intracluster cohesion (ICC). However, if a multiobjective method is used to cluster with ICD and ICC as the specified objectives, its clustering accuracy may depend on one's experience. Motivated by these, we propose an accelerated two-stage particle swarm optimization (ATPSO) in which K-means is utilized to accelerate particles' convergence during the population initialization. Its clustering process consists of two stages. First, the main objective of minimizing ICD is to execute preliminary clustering; second, ICC is optimized to promote the clustering accuracy. Extensive experiments with the help of 17 open-source clustering sets in various geometric distributions are conducted. The results show that ATPSO outperforms PSO, K -means PSO (KPSO), chaotic PSO (CPSO), and accelerated CPSO in terms of accuracy, and its efficiency is approximate to that of KPSO. Its convergence trend indicates that the adoption of the proposed ICC contributes to the clustering accuracy. Remarkably, compared with the Pareto-based multiobjective PSO, ATPSO can detect clusters more accurately and quickly through the proposed two-stage search.

In the analysis of histopathological images, both holistic (e.g., architecture features) and local appearance features demonstrate excellent performance, while their accuracy may vary dramatically when providing different inputs. This motivates us to investigate how to fuse results from these features to enhance the accuracy. Particularly, we employ content-based image retrieval approaches to discover morphologically relevant images for image-guided diagnosis, using holistic and local features, both of which are generated from the cell detection results by a stacked sparse autoencoder. Because of the dramatically different characteristics and representations of these heterogeneous features (i.e., holistic and local), their results may not agree with each other, causing difficulties for traditional fusion methods. In this paper, we employ a graph-based query-specific fusion approach where multiple retrieval results (i.e., rank lists) are integrated and reordered based on a fused graph. The proposed method is capable of combining the strengths of local or holistic features adaptively for different inputs. We evaluate our method on a challenging clinical problem, i.e., histopathological image-guided diagnosis of intraductal breast lesions, and it achieves 91.67% classification accuracy on 120 breast tissue images from 40 patients.

Automated nuclear detection is a critical step for a number of computer assisted pathology related image analysis algorithms such as for automated grading of breast cancer tissue specimens. The Nottingham Histologic Score system is highly correlated with the shape and appearance of breast cancer nuclei in histopathological images. However, automated nucleus detection is complicated by 1) the large number of nuclei and the size of high resolution digitized pathology images, and 2) the variability in size, shape, appearance, and texture of the individual nuclei. Recently there has been interest in the application of "Deep Learning" strategies for classification and analysis of big image data. Histopathology, given its size and complexity, represents an excellent use case for application of deep learning strategies. In this paper, a Stacked Sparse Autoencoder (SSAE), an instance of a deep learning strategy, is presented for efficient nuclei detection on high-resolution histopathological images of breast cancer. The SSAE learns high-level features from just pixel intensities alone in order to identify distinguishing features of nuclei. A sliding window operation is applied to each image in order to represent image patches via high-level features obtained via the auto-encoder, which are then subsequently fed to a classifier which categorizes each image patch as nuclear or non-nuclear. Across a cohort of 500 histopathological images (2200 × 2200) and approximately 3500 manually segmented individual nuclei serving as the groundtruth, SSAE was shown to have an improved F-measure 84.49% and an average area under Precision-Recall curve (AveP) 78.83%. The SSAE approach also out-performed nine other state of the art nuclear detection strategies.

The presence of lymphocytic infiltration (LI) has been correlated with nodal metastasis and tumor recurrence in HER2+breast cancer (BC), making it important to study LI. The ability to detect and quantify extent of LI could serve as an image based prognostic tool for HER2+ BC patients. Lymphocyte segmentation in H & E-stained BC histopathology images is, however, complicated due to the similarity in appearance between lymphocyte nuclei and cancer nuclei. Additional challenges include biological variability, histological artifacts, and high prevalence of overlapping objects. Although active contours are widely employed in segmentation, they are limited in their ability to segment overlapping objects. In this paper, we propose a segmentation scheme (EMaGACOR) that integrates Expectation Maximization (EM) based segmentation with a geodesic active contour (GAC). Additionally, a novel heuristic edge-path algorithm exploits the size of lymphocytes to split contours that enclose overlapping objects. For a total of 62 HER2+ breast biopsy images, EMaGACOR was found to have a detection sensitivity of over 90% and a positive predictive value of over 78%. By comparison, EMaGAC (model without overlap resolution) and GAC (Randomly initialized geodesic active contour) model yielded corresponding sensitivities of 57.4% and 26.7%, respectively. Furthermore, EMaGACOR was able to resolve over 92% of overlaps. Our scheme was found to be robust, reproducible, accurate, and could potentially be applied to other biomedical image segmentation applications.

Breast cancer is the second-most common and leading cause of cancer death among women. It has become a major health issue in the world over the past 50 years, and its incidence has increased in recent years. Early detection is an effective way to diagnose and manage breast cancer. Computer-aided detection or diagnosis (CAD) systems can play a key role in the early detection of breast cancer and can reduce the death rate among women with breast cancer. The purpose of this paper is to provide an overview of recent advances in the development of CAD systems and related techniques. We begin with a brief introduction to some basic concepts related to breast cancer detection and diagnosis. We then focus on key CAD techniques developed recently for breast cancer, including detection of calcifications, detection of masses, detection of architectural distortion, detection of bilateral asymmetry, image enhancement, and image retrieval.

In this paper, the recurrent neural networks (RNNs) with a generalized activation function class is proposed. In this proposed model, every component of the neuron's activation function belongs to a convex hull which is bounded by two odd symmetric piecewise linear functions that are convex or concave over the real space. All of the convex hulls are composed of generalized activation function classes. The novel activation function class is not only with a more flexible and more specific description of the activation functions than other function classes but it also generalizes some traditional activation function classes. The absolute exponential stability (AEST) of the RNN with a generalized activation function class is studied through three steps. The first step is to demonstrate the global exponential stability (GES) of the equilibrium point of original RNN with a generalized activation function being equivalent to that of RNN under all vertex functions of convex hull. The second step transforms the RNN under every vertex activation function into neural networks under an array of saturated linear activation functions. Because the GES of the equilibrium point of three systems are equivalent, the next stability analysis focuses on the GES of the equilibrium point of RNN system under an array of saturated linear activation functions. The last step is to study both the existence of equilibrium point and the GES of the RNN under saturated linear activation functions using the theory of M-matrix. In the end, a two-neuron RNN with a generalized activation function is constructed to show the effectiveness of our results.