BACKGROUND AND OBJECTIVES: Discovering causal associations between variables is one of the main goals of clinical trials, with the ultimate aim of identifying the causes of specific health status. Prior knowledge of causal paths could help ensure patients do not develop the resultant conditions. In recent years, thanks to the enormous amount of health data stored with the support of digital tools, attempts have been made to employ Machine Learning to infer causality. Those methodologies suffer from some deficiencies in controlling cofounders when analysing causality, as well as providing causal rules general enough to be useful in healthcare practice. Conversely, this work presents and evaluates CauRuler, a new approach to deal with causality from association rules. The proposed approach uses a pruning strategy to reduce the association rule set, which does not compromise the causality learning capability of the algorithm. This behaviour makes the algorithm suitable for exploiting large health databases with thousands of patients and medical instances. CauRuler can control a larger number of confounders than other proposals, bringing robustness to causal analysis and avoiding the identification of spurious associations. Additionally, the method generalizes causality using anti-monotone properties to obtain complex and general causal paths. The method can target correct causal associations in complex medical databases with retrospective data. METHOD: CauRuler extends association rule mining with an irredundancy property so that the set of rules learnt is reduced in size and generalized. General association rules, conformed by fewer items, enable controlling more confounding variables to verify, with more statistical evidence on available data, if they represent causal paths in patient disease trajectories. RESULTS: CauRuler has been tested on a complex real medical database (3,5 M visits to the primary care services between 2019 and 2020, and controlling over 15.000 different variables including diagnoses and demographic and other clinical patient data). The reduction of the rule set achieved by the pruning strategy goes from 7.732 to 2.240 rules, from which 46 have been found to have causality relationships in the patient trajectories, and generalized to 14 rules tested as true causal relationships thanks to the confounding analysis. These rules have been validated by clinicians with the support of a graphical map. The obtained causal paths control in average of 906 confounder variables, retrieving robust results. CONCLUSIONS: Causal relationships enable predicting causal paths between health conditions according to patient trajectories. Knowing these causal paths is crucial for understanding and preventing the appearance or worsening of diseases in patients. CauRuler, with high demanding thresholds, has proven its efficiency and effectiveness in targeting previously known causal associations between diagnoses, reaching consensus in the medical community. Softening these thresholds should help target interesting general causal paths.

Single-Cell RNA sequencing (scRNA-seq) has provided unprecedented opportunities for exploring gene expression and thus uncovering regulatory relationships between genes at the single-cell level. However, scRNA-seq relies on isolating cells from tissues. Therefore, the spatial context of the regulatory processes is lost. A recent technological innovation, spatial transcriptomics, allows for the measurement of gene expression while preserving spatial information. An initial step in the spatial transcriptomic analysis is to identify the cell type, which requires a careful selection of cell-specific marker genes. For this purpose, currently, scRNA-seq data is used to select a limited number of marker genes from among all genes that distinguish cell types from each other. This study proposes scMAGS (single-cell MArker Gene Selection), a novel method for marker gene selection from scRNA-seq data for spatial transcriptomics studies. scMAGS uses a filtering step in which the candidate genes are identified before the marker gene selection step. For the selection of marker genes, cluster validity indices, the Silhouette index, or the Calinski-Harabasz index (for large datasets) are utilized. Experimental results showed that, in comparison to the existing methods, scMAGS is scalable, fast, and accurate. Even for large datasets with millions of cells, scMAGS could find the required number of marker genes in a reasonable amount of time with fewer memory requirements. scMAGS is made freely available at https://github.com/doganlab/scmags and can be downloaded from the Python Package Directory (PyPI) software repository with the command pip install scmags.

Automatic breast ultrasound image segmentation helps radiologists to improve the accuracy of breast cancer diagnosis. In recent years, the convolutional neural networks (CNNs) have achieved great success in medical image analysis. However, it exhibits limitations in modeling long-range relations, which is unfavorable for ultrasound images with speckle noise and shadows, resulting in decreased accuracy of breast lesion segmentation. Transformer can obtain sufficient global information, but it is deficient in acquiring local details and needs to be pre-trained on large-scale datasets. In this paper, we propose a Hybrid CNN-Transformer network (HCTNet) for boosting the breast lesion segmentation in ultrasound images. In the encoder of HCTNet, Transformer Encoder Blocks (TEBlocks) are designed to learn the global contextual information, which are combined with CNNs to extract features. In the decoder of HCTNet, a Spatial-wise Cross Attention (SCA) module is developed based on the spatial attention mechanism, which reduces the semantic discrepancy with the encoder. Moreover, residual connection is used between decoder blocks to make the generated features more discriminative by aggregating contextual feature maps at different semantic scales. Extensive experiments on three public breast ultrasound datasets demonstrate that HCTNet outperforms other medical image segmentation methods and the recent semantic segmentation methods on breast ultrasound lesion segmentation.

Cardiac disease is the leading cause of death in the US. Accurate heart disease detection is critical to timely medical treatment to save patients' lives. Routine use of the electrocardiogram (ECG) is the most common method for physicians to assess the cardiac electrical activities and detect possible abnormal conditions. Fully utilizing the ECG data for reliable heart disease detection depends on developing effective analytical models. In this paper, we propose a two-level hierarchical deep learning framework with Generative Adversarial Network (GAN) for ECG signal analysis. The first-level model is composed of a Memory-Augmented Deep AutoEncoder with GAN (MadeGAN), which aims to differentiate abnormal signals from normal ECGs for anomaly detection. The second-level learning aims at robust multi-class classification for different arrhythmia identification, which is achieved by integrating the transfer learning technique to transfer knowledge from the first-level learning with the multi-branching architecture to handle the data-lacking and imbalanced data issues. We evaluate the performance of the proposed framework using real-world ECG data from the MIT-BIH arrhythmia database. Experimental results show that our proposed model outperforms existing methods that are commonly used in current practice.

The recent developments in communication and information ease people's lives to sit in one place and access any information from anywhere. However, the longevity of sitting and sitting in different postures raises the issues of spinal curvature. It necessitates a physical examination to identify the spinal illness in its early stages. This article aims to develop an intelligent monitoring framework for detecting and monitoring spinal curvature syndrome problems based on Software Defined Radio Frequency (SDRF) sensing and verify its feasibility for diagnosing actual patients. The proposed SDRF-based system identifies irregular spinal curvature syndrome and offers feedback signals when an incorrect posture is identified. We design the system using wireless university software-defined radio peripheral (USRP) kits to transmit and receive RF signals and record the wireless channel state information (WCSI) for kyphosis, Lordosis, and scoliosis spinal disorders. The statistical measures are extracted from the WCSI and apply machine learning algorithms to identify and classify the type of disorders. We record and test the system using 11 subjects with the spinal disorders kyphosis, Lordosis, and scoliosis. We acquire the WCSI, extract various statistical measures in terms of time and frequency domain features, and evaluate machine learning classifiers to identify and classify the spinal disorder. The performance comparison of the machine learning algorithms showed overall and each spinal curvature disorder recognition accuracy of more than 99%.

It has been indicated that leukemic stem cells (LSCs), a subset of leukaemia cells, are responsible for therapy resistance and relapse in acute myeloid leukaemia (AML). Therefore, the current study aimed to discover an LSC biomarker in AML patients and identify a natural compound that may target the same. By performing the different gene expression analyses, we identified 12 up-regulated and 192 down-regulated genes in LSCs of AML compared to normal bone marrow-derived HSCs. Further STRING interaction, GO enrichment and KEGG pathway analysis were carried out to top hub genes. Wilms' tumour-1 (WT1) transcription factor was pointed out as the top hub gene and a potential biomarker for LSCs in AML. For the targeted inhibition of WT1, we performed screening and stimulation of potential natural compounds. The results revealed Gallic acid (GA) and Chlorogenic acid (CA) as promising WT1 inhibitors. In-vitro validation of cytotoxic effects of both GA and CA on THP-1 and HL-60 cell lines suggested that both these compounds inhibited cell proliferation. Still, GA has a more cytotoxic effect compared to CA. Next, we performed cell cycle analysis and apoptosis analysis and found that both compounds arrested cells in G0/G1 phase and induced apoptosis in both cell lines. Surprisingly, a significant decrease in colony formation and cell migration was also observed. However, GA gave more promising results in all cellular assays than CA. Furthermore, we studied the mRNA expression of WT1 and BCL2, which are transcriptionally activated by it. We found that GA significantly downregulated both these genes compared to CA. Our results suggested that GA is a potential inhibitor of WT1 and might be an excellent anti-LSCs natural drug for AML patients.

Deciphering information hidden in the gene expression assays for identifying disease subtypes has significant importance in precision medicine. However, computational limitations thwart this process due to the intricacy of the biological networks and the curse of dimensionality of gene expression data. Therefore, clustering in such scenarios often becomes the first choice of exploratory data analysis to identify natural structures and intrinsic patterns in the data. However, sparse and high dimensional nature of omics data prevents conventional clustering algorithms to discover subtypes that are clinically relevant and statistically significant. Hence, non-linear dimensionality reduction techniques coupled with clustering in such scenarios often becomes imperative to improve the clustering results. In this study, we present a robust pipeline to discover disease subtypes with clinical relevance. Specifically, we focus on discovering patient sub-groups that have a residual life patterns remarkably different from other sub-groups. This is significant because by refining prognosis, subtyping can reduce uncertainty in approximating patients expected outcome. The methodology present is based on robust correlation estimation, UMAP- a non-linear dimensionality reduction method and mapper- a tool from topology. Notably, we suggest a method for improving the robustness of the correlation matrix of gene expression data for improving the clustering results. The performance of the model is evaluated by applying to five cancer datasets obtained through TCGA and comparisons are performed with some state of the art methods of NEMO, RSC-OTRI and SNF with regard to log-rank test and Restricted Life Expectancy Difference. For example in GBM dataset, the minimum separation for any two discovered subtypes is 221 days which is significantly higher than the other methodologies. We also compared the results without using the robust correlation based estimate and observed that robust correlation improves separability between survival curves significantly. From the results we infer that our methodology performs better compared to other methodologies with regard to separating survival curves of patient sub-groups despite using single omics profiles of patients compared to multiple omics profiles of SNF and NEMO. Pathway over-representation analysis is performed on the final clustering results to investigate the biological underpinnings characterizing each subtype.

Cyclin-dependent kinases 1 (CDK1) has been identified as a potential target for the search for new antitumor drugs. However, no clinically effective CDK1 inhibitors are now available for cancer treatment. Therefore, this study aimed to offer potential CDK1 inhibitors using de novo drug generation, molecular docking, and molecular dynamics (MD) simulation studies. We first utilized the BREED algorithm (a de novo drug generation approach) to produce a novel library of small molecules targeting CDK1. To initially obtain novel potential CDK1 inhibitors with favorable physicochemical properties and excellent druggability, we performed a virtual rule-based rational drug screening on our generated library and found ten initial hits. Then, the molecular interactions and dynamic stability of these ten initial hits and CDK1 complexes during their all-atom MD simulations (total 18 μs) and binding pose metadynamics simulations were investigated, resulting in five final hits. Furthermore, another MD simulation (total 2.1 μs) with different force fields demonstrated the binding ability of the five hits to CDK1. It was found that these five hits, CBMA001 (ΔG = -29.88 kcal/mol), CBMA002 (ΔG = -34.89 kcal/mol), CBMA004 (ΔG = -32.47 kcal/mol), CBMA007 (ΔG = -31.16 kcal/mol), and CBMA008 (ΔG = -34.78 kcal/mol) possessed much greater binding affinity to CDK1 than positive compound Flavopiridol (FLP, ΔG = -25.38 kcal/mol). Finally, CBMA002 and CBMA004 were identified as excellent selective CDK1 inhibitors in silico. Together, this study provides a workflow for rational drug design and two promising selective CDK1 inhibitors that deserve further investigation.

Machine learning (ML) methods are used in cheminformatics processes to predict the activity of an unknown drug and thus discover new potential antibacterial drugs. This article conducts a bibliometric study to analyse the contributions of leading authors, universities/organisations and countries in terms of productivity, citations and bibliographic linkage. A sample of 1596 Scopus documents for the period 2006-2022 is the basis of the study. In order to develop the analysis, bibliometrix R-Tool and VOSviewer software were used. We determined essential topics related to the application of ML in the field of antibacterial development (Computer model in antibacterial drug design, and Learning algorithms and systems for forecasting). We identified obsolete and saturated areas of research. At the same time, we proposed emerging topics according to the various analyses carried out on the corpus of published scientific literature (Title, abstract and keywords). Finally, the applied methodology contributed to building a broader and more specific "big picture" of ML research in antibacterial studies for the focus of future projects.

Colorectal cancer (CRC) is a severe health concern that results from a cocktail of genetic, epigenetic, and environmental abnormalities. Because it is the second most lethal malignancy in the world and the third-most common malignant tumor, but the treatment is unavailable. The goal of the current study was to use bioinformatics and systems biology techniques to determine the pharmacological mechanism underlying putative important genes and linked pathways in early-onset CRC. Computer-aided methods were used to uncover similar biological targets and signaling pathways associated with CRC, along with bioinformatics and network pharmacology techniques to assess the effects of enzastaurin on CRC. The KEGG and gene ontology (GO) pathway analysis revealed several significant pathways including in positive regulation of protein phosphorylation, negative regulation of the apoptotic process, nucleus, nucleoplasm, protein tyrosine kinase activity, PI3K-Akt signaling pathway, pathways in cancer, focal adhesion, HIF-1 signaling pathway, and Rap1 signaling pathway. Later, the hub protein module identified from the protein-protein interactions (PPIs) network, molecular docking and molecular dynamics simulation represented that enzastaurin showed strong binding interaction with two hub proteins including CASP3 (-8.6 kcal/mol), and MCL1 (-8.6 kcal/mol), which were strongly implicated in CRC management than other the five hub proteins. Moreover, the pharmacokinetic features of enzastaurin revealed that it is an effective therapeutic agent with minimal adverse effects. Enzastaurin may inhibit the potential biological targets that are thought to be responsible for the advancement of CRC and this study suggests a potential novel therapeutic target for CRC.

Explainable Artificial Intelligence (XAI) makes AI understandable to the human user particularly when the model is complex and opaque. Local Interpretable Model-agnostic Explanations (LIME) has an image explainer package that is used to explain deep learning models. The image explainer of LIME needs some parameters to be manually tuned by the expert in advance, including the number of top features to be seen and the number of superpixels in the segmented input image. This parameter tuning is a time-consuming task. Hence, with the aim of developing an image explainer that automizes image segmentation, this paper proposes Ensemble-based Genetic Algorithm Explainer (EGAE) for melanoma cancer detection that automatically detects and presents the informative sections of the image to the user. EGAE has three phases. First, the sparsity of chromosomes in GAs is determined heuristically. Then, multiple GAs are executed consecutively. However, the difference between these GAs are in different number of superpixels in the input image that result in different chromosome lengths. Finally, the results of GAs are ensembled using consensus and majority votings. This paper also introduces how Euclidean distance can be used to calculate the distance between the actual explanation (delineated by experts) and the calculated explanation (computed by the explainer) for accuracy measurement. Experimental results on a melanoma dataset show that EGAE automatically detects informative lesions, and it also improves the accuracy of explanation in comparison with LIME efficiently. The python codes for EGAE, the ground truths delineated by clinicians, and the melanoma detection dataset are available at https://github.com/KhaosResearch/EGAE.

These days, the ratio of cancer diseases among patients has been growing day by day. Recently, many cancer cases have been reported in different clinical hospitals. Many machine learning algorithms have been suggested in the literature to predict cancer diseases with the same class types based on trained and test data. However, there are many research rooms available for further research. In this paper, the studies look into the different types of cancer by analyzing, classifying, and processing the multi-omics dataset in a fog cloud network. Based on SARSA on-policy and multi-omics workload learning, made possible by reinforcement learning, the study made new hybrid cancer detection schemes. It consists of different layers, such as clinical data collection via laboratories and tool processes (biopsy, colonoscopy, and mammography) at the distributed omics-based clinics in the network. The study considers the different cancer classes such as carcinomas, sarcomas, leukemias, and lymphomas with their types in work and processes them using the multi-omics distributed clinics in work. In order to solve the problem, the study presents omics cancer workload reinforcement learning state action reward state action "SARSA" (OCWLS) schemes, which are made up of an on-policy learning scheme on different parameters like states, actions, timestamps, reward, accuracy, and processing time constraints. The goal is to process multiple cancer classes and workload feature matching while reducing the time it takes to process in clinical hospitals that are spread out. Simulation results show that OCWLS is better than other machine learning methods regarding+ processing time, extracting features from multiple classes of cancer, and matching in the system.

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase expressed following exposure to pro-inflammatory stimuli. The mPGES-1 enzyme represents a new target for the therapeutic treatment of acute and chronic inflammatory disorders and cancer. In the present study, compounds from the ZINC15 database with an indole scaffold were docked at the mPGES-1 binding site using Glide (high-throughput virtual screening [HTVS], standard precision [SP] and extra precision [XP]), and the stabilities of the complexes were determined by molecular simulation studies. Following HTVS, the top 10% compounds were retained and further screened by SP. Again, the top 10% of these compounds were retained. Finally, the Glide XP scores of the compounds were determined, 20% were analyzed, and the Prime MM-GBSA total free binding energies of the compounds were calculated. The molecular simulations (100 ns) of the reference ligand, LVJ, and the two best-scoring compounds were performed with the Desmond program to analyze the dynamics of the target protein-ligand complexes. In human lung cells treated with the hit compounds, cell viability by colorimetric method and PGE2 levels by immunoassay method were determined. These in vitro experiments demonstrated that the two indole-containing hit compounds are potential novel inhibitors of mPGES-1 and are, therefore, potential therapeutic agents for cancer/inflammation therapies. Moreover, the compounds are promising lead mPGES-1 inhibitors for novel molecule design.

Tumor burden assessment by magnetic resonance imaging (MRI) is central to the evaluation of treatment response for glioblastoma. This assessment is, however, complex to perform and associated with high variability due to the high heterogeneity and complexity of the disease. In this work, we tackle this issue and propose a deep learning pipeline for the fully automated end-to-end analysis of glioblastoma patients. Our approach simultaneously identifies tumor sub-regions, including the enhancing tumor, peritumoral edema and surgical cavity in the first step, and then calculates the volumetric and bidimensional measurements that follow the current Response Assessment in Neuro-Oncology (RANO) criteria. Also, we introduce a rigorous manual annotation process which was followed to delineate the tumor sub-regions by the human experts, and to capture their segmentation confidences that are later used while training deep learning models. The results of our extensive experimental study performed over 760 pre-operative and 504 post-operative adult patients with glioma obtained from the public database (acquired at 19 sites in years 2021-2020) and from a clinical treatment trial (47 and 69 sites for pre-/post-operative patients, 2009-2011) and backed up with thorough quantitative, qualitative and statistical analysis revealed that our pipeline performs accurate segmentation of pre- and post-operative MRIs in a fraction of the manual delineation time (up to 20 times faster than humans). Volumetric measurements were in strong agreement with experts with the Intraclass Correlation Coefficient (ICC): 0.959, 0.703, 0.960 for ET, ED, and cavity. Similarly, automated RANO compared favorably with experienced readers (ICC: 0.681 and 0.866) producing consistent and accurate results. Additionally, we showed that RANO measurements are not always sufficient to quantify tumor burden. The high performance of the automated tumor burden measurement highlights the potential of the tool for considerably improving and simplifying radiological evaluation of glioblastoma in clinical trials and clinical practice.

Grasping good understanding of the weight-bearing spatial structure of the spine of a human subject in a standing position is critical for the treatment of spinal disorders. Such disorders are commonly diagnosed via 2D X-ray imaging of the human subject in a standing position. However, 3D reconstruction techniques based on bi-planar X-ray imaging can enable better exploration and analysis of the spinal structure. In particular, compared to earlier deformable modeling approaches, the recently-developed deep-learning-based 3D reconstruction methods exhibit higher efficiency and generalizability. But these methods usually employ simple architectures with 2D encoders and 3D decoders. Thus, these methods have several drawbacks, namely, the existence of a semantic gap between dimensionally-inconsistent feature maps, the difficulty of jointly handling multi-view inputs, and the information source limitations for the decoding process. In order to better assist clinicians and tackle these problems, we propose a novel convolutional neural network framework, which we call BX2S-Net, to effectively achieve 3D spine reconstruction based on bi-planar X-ray images. In particular, a dimensionally-consistent encoder-decoder architecture is designed in conjunction with a dimensionality enhancement method in order to reduce the semantic gap between feature maps and achieve information fusion for multi-view inputs. A feature-guided progressive decoding process is developed on the decoder side, where a full-scale feature attention guidance (FFAG) module is introduced to efficiently aggregate image features and guide the decoding process at each level. In addition, a class augmentation method and a spatially-weighted cross-entropy loss function are used for network training with improved reconstruction quality for the vertebral edge region. The experimental results demonstrate the effectiveness of our model in reconstructing high-quality 3D spinal structures from bi-planar X-ray images. The code is available at https://github.com/NBU-CVMI/bx2s-net.

BACKGROUND: IPAF (ICE-protease Activating Factor) is a nucleotide-binding/leucine-rich repeat (NLR) protein known as the cysteine-associated recruitment domain 12 (CARD12). Previous studies only discuss the role of IPAF inflammasomes in specific tumors. The role of IPAF inflammasomes in pan-cancer is still unclear. Therefore, we performed a comprehensive analysis of IPAF inflammasome in 33 tumors. METHODS: We used databases like The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) from the UCSC XENA (http://xena.ucsc.edu/) to retrieve and analyze gene expression. The influence of IPAF inflammasome on the prognosis of tumor patients was analyzed using univariate Cox regression analysis and Kaplan-Meier survival analysis. Furthermore, we conducted the following analysis: Single-sample gene set enrichment analysis, single-cell level functional state analysis, single-cell sequencing, immune cell infiltration analysis, and tumor immune dysfunction and exclusion (TIDE) score. RESULTS: First, the differential expression of IPAF inflammasome-related genes (IPAF-RGs) in 33 tumors were analyzed. The results revealed that IPAF-RGs were significantly and differentially expressed in eight tumors. The prognostic significance of IPAF inflammasome scores was different in different tumors. A positive correlation was observed between IPAF inflammasomes scores and CD8+ T cells in most tumors. Further analysis revealed that IPAF inflammasome might affect tumor immunity mainly by mediating effector T cell recruitment via the expression of chemokines such as CXCL9, CXCL10, and CCL5. The analysis of TIDE and IPAF inflammasome scores revealed a significant negative correlation between IPAF inflammasome and TIDE scores in 11 tumors. CONCLUSION: A pan-cancer analysis of IPAF inflammasome in various tumors was performed. The results highlight the potential value of IPAF inflammasome in response to immunotherapy in patients and provide a new direction for future immunotherapy.

BACKGROUND: In addition to the nutritional benefits of Cucumis melo L., herbalists in Pakistan and India employ seeds to treat various ailments. This study aimed to determine the regulatory role of C. melo seeds in calcium-mediated smooth muscle contraction. METHODS: We identified and quantified the phytochemicals of C. melo with LC ESI-MS/MS and HPLC, then conducted in vitro and in vivo tests to confirm the involvement in smooth muscle relaxation. Then, diarrhea-predominant irritable bowel syndrome gene datasets from NCBI GEO were acquired, DEGs and WGCNA followed by functional enrichment analysis. Next, molecular docking of key genes was performed. RESULTS: The quantification of C. melo seeds revealed concentrations of rutin, kaempferol, and quercetin were 702.38 μg/g, 686.29 μg/g, and 658.41 μg/g, respectively. In vitro experiments revealed that C. melo seeds had a dose-dependent relaxant effect for potassium chloride (80 mM)-induced spastic contraction and exhibited calcium antagonistic response in calcium dose-response curves. In in vivo studies, Cm.EtOH exhibited antidiarrheal, antiperistaltic, and antisecretory effects. The functional enrichment of WGCNA and DEGs IBS-associated pathogenic genes, including those involved in calcium-mediated signaling, MAPK cascade, and inflammatory responses. MAPK1 and PIK3CG were identified as key genes with greater binding affinity with rutin, quercitrin, and kaempferol in molecular docking. CONCLUSIONS: The bronchodilator and antidiarrheal effects of C. melo were produced by altering the regulatory genes of calcium-mediated smooth contraction.

The ongoing COVID-19 pandemic is leading to the discovery of hundreds of novel SARS-CoV-2 variants daily. While most variants do not impact the course of the pandemic, some variants pose an increased risk when the acquired mutations allow better evasion of antibody neutralisation or increased transmissibility. Early detection of such high-risk variants (HRVs) is paramount for the proper management of the pandemic. However, experimental assays to determine immune evasion and transmissibility characteristics of new variants are resource-intensive and time-consuming, potentially leading to delays in appropriate responses by decision makers. Presented herein is a novel in silico approach combining spike (S) protein structure modelling and large protein transformer language models on S protein sequences to accurately rank SARS-CoV-2 variants for immune escape and fitness potential. Both metrics were experimentally validated using in vitro pseudovirus-based neutralisation test and binding assays and were subsequently combined to explore the changing landscape of the pandemic and to create an automated Early Warning System (EWS) capable of evaluating new variants in minutes and risk-monitoring variant lineages in near real-time. The system accurately pinpoints the putatively dangerous variants by selecting on average less than 0.3% of the novel variants each week. The EWS flagged all 16 variants designated by the World Health Organization (WHO) as variants of interest (VOIs) if applicable or variants of concern (VOCs) otherwise with an average lead time of more than one and a half months ahead of their designation as such.

The COVID-19 pandemic has caused millions of cases and deaths and the AI-related scientific community, after being involved with detecting COVID-19 signs in medical images, has been now directing the efforts towards the development of methods that can predict the progression of the disease. This task is multimodal by its very nature and, recently, baseline results achieved on the publicly available AIforCOVID dataset have shown that chest X-ray scans and clinical information are useful to identify patients at risk of severe outcomes. While deep learning has shown superior performance in several medical fields, in most of the cases it considers unimodal data only. In this respect, when, which and how to fuse the different modalities is an open challenge in multimodal deep learning. To cope with these three questions here we present a novel approach optimizing the setup of a multimodal end-to-end model. It exploits Pareto multi-objective optimization working with a performance metric and the diversity score of multiple candidate unimodal neural networks to be fused. We test our method on the AIforCOVID dataset, attaining state-of-the-art results, not only outperforming the baseline performance but also being robust to external validation. Moreover, exploiting XAI algorithms we figure out a hierarchy among the modalities and we extract the features' intra-modality importance, enriching the trust on the predictions made by the model.

Deep learning architecture with convolutional neural network achieves outstanding success in the field of computer vision. Where U-Net has made a great breakthrough in biomedical image segmentation and has been widely applied in a wide range of practical scenarios. However, the equal design of every downsampling layer in the encoder part and simply stacked convolutions do not allow U-Net to extract sufficient information of features from different depths. The increasing complexity of medical images brings new challenges to the existing methods. In this paper, we propose a deeper and more compact split-attention u-shape network, which efficiently utilises low-level and high-level semantic information based on two frameworks: primary feature conservation and compact split-attention block. We evaluate the proposed model on CVC-ClinicDB, 2018 Data Science Bowl, ISIC-2018, SegPC-2021 and BraTS-2021 datasets. As a result, our proposed model displays better performance than other state-of-the-art methods in terms of the mean intersection over union and dice coefficient. More significantly, the proposed model demonstrates excellent segmentation performance on challenging images. The code for our work and more technical details can be found at https://github.com/xq141839/DCSAU-Net.

The spatial architecture of the tumour microenvironment and phenotypic heterogeneity of tumour cells have been shown to be associated with cancer prognosis and clinical outcomes, including survival. Recent advances in highly multiplexed imaging, including imaging mass cytometry (IMC), capture spatially resolved, high-dimensional maps that quantify dozens of disease-relevant biomarkers at single-cell resolution, that contain potential to inform patient-specific prognosis. Existing automated methods for predicting survival, on the other hand, typically do not leverage spatial phenotype information captured at the single-cell level. Furthermore, there is no end-to-end method designed to leverage the rich information in whole IMC images and all marker channels, and aggregate this information with clinical data in a complementary manner to predict survival with enhanced accuracy. To that end, we present a deep multimodal graph-based network (DMGN) with two modules: (1) a multimodal graph-based module that considers relationships between spatial phenotype information in all image regions and all clinical variables adaptively, and (2) a clinical embedding module that automatically generates embeddings specialised for each clinical variable to enhance multimodal aggregation. We demonstrate that our modules are consistently effective at improving survival prediction performance using two public breast cancer datasets, and that our new approach can outperform state-of-the-art methods in survival prediction.

BACKGROUND: Motor learning experiments are typically performed in laboratory environments, which can be time-consuming and require dedicated equipment/personnel, thus limiting the ability to gather data from large samples. To address this problem, some researchers have transitioned to unsupervised online experiments, showing advantages in participant recruitment without losing validity. However, most online platforms require coding experience or time-consuming setups to create and run experiments, limiting their usage across the field. METHOD: To tackle this issue, an open-source web-based platform was developed (https://experiments.neurro-lab.engin.umich.edu/) to create, run, and manage procedural skill learning experiments without coding or setup requirements. The feasibility of the platform and the comparability of the results between supervised (n = 17) and unsupervised (n = 24) were tested in 41 naive right-handed participants using an established sequential finger tapping task. The study also tested if a previously reported rapid form of offline consolidation (i.e., microscale learning) in procedural skill learning could be replicated with the developed platform and evaluated the extent of interlimb transfer associated with the finger tapping task. RESULTS: The results indicated that the performance metrics were comparable between the supervised and unsupervised groups (all p's > 0.05). The learning curves, mean tapping speeds, and micro-scale learning were similar to previous studies. Training led to significant improvements in mean tapping speed (2.22 ± 1.48 keypresses/s, p < 0.001) and a significant interlimb transfer of learning (1.22 ± 1.43 keypresses/s, p < 0.05). CONCLUSIONS: The results show that the presented platform may serve as a valuable tool for conducting online procedural skill-learning experiments.

Plant pests and diseases play a significant role in reducing the quality of agricultural products. As one of the most important plant pathogens, pests like Mediterranean fruit fly cause significant damage to crops and thus annually farmers face a lot of loss in their products. Therefore, the use of modern and non-destructive methods such as machine vision systems and deep learning for early detection of pests in agricultural products is of particular importance. In this study, citrus fruit images were taken in three stages: 1) before pest infestation, 2) beginning of fruit infestation, and 3) eight days after the second stage, in natural light conditions (7000-11,000 lux). A total of 1519 images were prepared for all classes. To classify the images, 70% of the images were used for the network training stage, 10% and 20% of the images were used for the validation and testing stages. Four pre-trained CNN models, namely ResNet-50, GoogleNet, VGG-16 and AlexNet as well as the SGDm, RMSProp and Adam optimization algorithms were used to identify and classify healthy fruit and fruit infected with the Mediterranean fly. The results of evaluating the models in the pest outbreak stage showed that the VGG-16 model with the help of SGDm algorithm had the best efficiency with the highest detection accuracy and F1 of 98.33% and 98.36%, respectively. The evaluation of the third stage showed that the AlexNet model with the help of SGDm algorithm had the best result with the highest detection accuracy and F1 of 99.33% and 99.34%, respectively. AlexNet model using SGDm optimization algorithm had the shortest network training time (323 s). The results of this study showed that convolutional neural network method and machine vision system can be effective in controlling and managing pests in orchards and other agricultural products.

Mortality prediction is crucial to evaluate the severity of illness and assist in improving the prognosis of patients. In clinical settings, one way is to analyze the multivariate time series (MTSs) of patients based on their medical data, such as heart rates and invasive mean arterial blood pressure. However, this suffers from sparse, irregularly sampled, and incomplete data issues. These issues can compromise the performance of follow-up MTS-based analytic applications. Plenty of existing methods try to deal with such irregular MTSs with missing values by capturing the temporal dependencies within a time series, yet in-depth research on modeling inter-MTS couplings remains rare and lacks model interpretability. To this end, we propose a bidirectional time and multi-feature attention coupled network (BiT-MAC) to capture the temporal dependencies (i.e., intra-time series coupling) and the hidden relationships among variables (i.e., inter-time series coupling) with a bidirectional recurrent neural network and multi-head attention, respectively. The resulting intra- and inter-time series coupling representations are then fused to estimate the missing values for a more robust MTS-based prediction. We evaluate BiT-MAC by applying it to the missing-data corrupted mortality prediction on two real-world clinical datasets, i.e., PhysioNet'2012 and COVID-19. Extensive experiments demonstrate the superiority of BiT-MAC over cutting-edge models, verifying the great value of the deep and hidden relations captured by MTSs. The interpretability of features is further demonstrated through a case study.

The Computer-aided Diagnosis or Detection (CAD) approach for skin lesion analysis is an emerging field of research that has the potential to alleviate the burden and cost of skin cancer screening. Researchers have recently indicated increasing interest in developing such CAD systems, with the intention of providing a user-friendly tool to dermatologists to reduce the challenges encountered or associated with manual inspection. This article aims to provide a comprehensive literature survey and review of a total of 594 publications (356 for skin lesion segmentation and 238 for skin lesion classification) published between 2011 and 2022. These articles are analyzed and summarized in a number of different ways to contribute vital information regarding the methods for the development of CAD systems. These ways include: relevant and essential definitions and theories, input data (dataset utilization, preprocessing, augmentations, and fixing imbalance problems), method configuration (techniques, architectures, module frameworks, and losses), training tactics (hyperparameter settings), and evaluation criteria. We intend to investigate a variety of performance-enhancing approaches, including ensemble and post-processing. We also discuss these dimensions to reveal their current trends based on utilization frequencies. In addition, we highlight the primary difficulties associated with evaluating skin lesion segmentation and classification systems using minimal datasets, as well as the potential solutions to these difficulties. Findings, recommendations, and trends are disclosed to inform future research on developing an automated and robust CAD system for skin lesion analysis.

Medical imaging technology provides a good understanding of human tissue structure. MRI provides high-resolution soft tissue information, and CT provides high-quality bone density information. By creating CT-MRI fusion images of complex diagnostic situations, experts can develop diagnoses and treatment plans more quickly and precisely. We propose a dual-path CT-MRI image fusion model based on multi-axial gated MLP to create high-quality CT-MRI fusion images. The model employs the feature fusion module SFT-block to effectively integrate detailed Local-Path information guided by global Global-Path information. The fusion is completed through triple constraints, namely global constraints, local constraints, and overall constraints. We design a multi-axial gated MLP module (Ag-MLP). The multi-axial structure maintains the computational complexity linear and increases MLP's inductive bias, allowing MLP to work in shallower or pixel-level small dataset tasks. Ag-MLP and CNN are combined in the network so that the model has both globality and locality. In addition, we design a loss calculation method based on image patches that adaptively generates weights for each patch based on image pixel intensity. The details of the image are efficiently increased when patch-loss is used. Numerous studies demonstrate that the results of our model are superior to those of the latest mainstream fusion model, which are more in accordance with actual clinical diagnostic standards. The ablation studies successfully validate the performance of the model's constituent parts. It is worth mentioning that the model can also be excellently generalized to other modal image fusion tasks.

AIM: COVID-19 has revealed the need for fast and reliable methods to assist clinicians in diagnosing the disease. This article presents a model that applies explainable artificial intelligence (XAI) methods based on machine learning techniques on COVID-19 metagenomic next-generation sequencing (mNGS) samples. METHODS: In the data set used in the study, there are 15,979 gene expressions of 234 patients with COVID-19 negative 141 (60.3%) and COVID-19 positive 93 (39.7%). The least absolute shrinkage and selection operator (LASSO) method was applied to select genes associated with COVID-19. Support Vector Machine - Synthetic Minority Oversampling Technique (SVM-SMOTE) method was used to handle the class imbalance problem. Logistics regression (LR), SVM, random forest (RF), and extreme gradient boosting (XGBoost) methods were constructed to predict COVID-19. An explainable approach based on local interpretable model-agnostic explanations (LIME) and SHAPley Additive exPlanations (SHAP) methods was applied to determine COVID-19- associated biomarker candidate genes and improve the final model's interpretability. RESULTS: For the diagnosis of COVID-19, the XGBoost (accuracy: 0.930) model outperformed the RF (accuracy: 0.912), SVM (accuracy: 0.877), and LR (accuracy: 0.912) models. As a result of the SHAP, the three most important genes associated with COVID-19 were IFI27, LGR6, and FAM83A. The results of LIME showed that especially the high level of IFI27 gene expression contributed to increasing the probability of positive class. CONCLUSIONS: The proposed model (XGBoost) was able to predict COVID-19 successfully. The results show that machine learning combined with LIME and SHAP can explain the biomarker prediction for COVID-19 and provide clinicians with an intuitive understanding and interpretability of the impact of risk factors in the model.