Homeostasis imbalance process ontology: a study on COVID-19 infectious processes.

BACKGROUND: One significant challenge in addressing the coronavirus disease 2019 (COVID-19) pandemic is to grasp a comprehensive picture of its infectious mechanisms. We urgently need a consistent framework to capture the intricacies of its complicated viral infectious processes and diverse symptoms. RESULTS: We systematized COVID-19 infectious processes through an ontological approach and provided a unified description framework of causal relationships from the early infectious stage to severe clinical manifestations based on the homeostasis imbalance process ontology (HoIP). HoIP covers a broad range of processes in the body, ranging from normal to abnormal. Moreover, our imbalance model enabled us to distinguish viral functional demands from immune defense processes, thereby supporting the development of new drugs, and our research demonstrates how ontological reasoning contributes to the identification of patients at severe risk. CONCLUSIONS: The HoIP organises knowledge of COVID-19 infectious processes and related entities, such as molecules, drugs, and symptoms, with a consistent descriptive framework. HoIP is expected to harmonise the description of various heterogeneous processes and improve the interoperability of COVID-19 knowledge through the COVID-19 ontology harmonisation working group.

Right Ventricular Dyssynchrony in Patients With Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are characterized by elevated pulmonary arterial pressure resulting in right heart failure. Right ventricular (RV) dyssynchrony may be associated with early-stage RV dysfunction; however, the differences in RV dyssynchrony between CTEPH and PAH and the factors contributing to RV dyssynchrony remain unclear.Methods and Results: Forty-four patients (CTEPH, 26; PAH, 18) were enrolled in this study. RV dyssynchrony was assessed by determining the standard deviation of the intervals from the peak QRS to peak systolic strain for 6 segments of the RV free and septal wall by using 2-dimensional speckle-tracking echocardiography (RV-6SD). The RV-6SD, pulmonary hemodynamics, echocardiographic findings, and patient demographics in CTEPH and PAH patients were compared and their correlations with RV-6SD were investigated. CTEPH patients were older and had significantly higher pulse pressure of the pulmonary artery (PP), tricuspid valve regurgitation pressure gradient, and RV-6SD, and lower pulmonary arterial compliance (PAC), despite showing comparable pulmonary arterial pressures. Age-adjusted multiple logistic analysis showed that RV-6SD and PAC were predictors of CTEPH rather than PAH. RV-SD6 was positively correlated with PP and RV dimension and negatively correlated with PAC. CONCLUSIONS: CTEPH patients showed more evident RV dyssynchrony than PAH patients. Low PAC and a widened PP may delay RV free wall motion and cause RV dyssynchrony.

Effectiveness and safety of oral direct factor Xa inhibitors for the treatment of venous thromboembolism in patients with cancer and/or older age.

Venous thromboembolism (VTE) is a multifactorial disease. Cancer and older age are risk factors for both recurrent VTE and bleeding under anticoagulant therapy. Oral direct factor Xa inhibitors (Xa inhibitors) have been widely used to treat VTE. However, their effectiveness and safety in cancer and elderly patients have not been fully elucidated. A total of 187 consecutive patients who started Xa inhibitors for VTE therapy between September 2014 and September 2016 were recruited. Patients' demographics, changes in VTE amount, VTE recurrence, clinically relevant bleeding, and death until February 2017 were compared between 92 cancer and 95 non-cancer patients, and 57 elderly (≥ 75 years) and 130 non-elderly patients. Compared with non-cancer patients, cancer patients had a significantly higher incidence of deep vein thrombosis (DVT) in the proximal legs, superior vena cava, and upper extremities (p = 0.034), although the patients' demographics and incidence of pulmonary thromboembolism (PE) were similar between the two groups. There were no significant differences in VTE recurrence (p = 0.328) and clinically relevant bleeding (p = 0.078) between the two groups. Death occurred in 29 cancer patients, 23 of whom died of cancer, while there were no deaths among the non-cancer patients. Elderly patients had a lower body weight and creatinine clearance than non-elderly patients. No significant differences between the two groups were found in relation to PE (p = 0.544), DVT site (p = 0.054), recurrent VTE (p = 0.194), clinically relevant bleeding (p = 0.130) and death (p = 0.241). In comparisons among the four groups (elderly and non-elderly patients with and without cancer), recurrent VTE and clinically relevant bleeding were comparable (p = 0.493 and 0.227, respectively), while death was more frequent in cancer patients regardless of age (p < 0.001). The efficacy and safety of Xa inhibitors as VTE treatment were comparable between cancer and non-cancer patients, and in elderly and non-elderly patients. This suggests that Xa inhibitors may be promising drugs for VTE treatment, irrespective of age and comorbid cancer.

Deeper S Wave in Lead V5 and Broader Extent of T Wave Inversions in the Precordial Leads are Clinically Useful Electrocardiographic Parameters for Predicting Pulmonary Hypertension.

Electrocardiography (ECG) is used to screen for pulmonary hypertension (PH). However, it is unclear which parameters of ECG are the most useful for screening.ECG parameters related to right ventricular hypertrophy criteria were examined in 145 ECGs of subjects who were suspected to have PH and underwent right heart catheterization (RHC) (age 58.4 ± 17.5 years, 112 women, mean pulmonary arterial pressure [MPAP] 35.4 ± 13.3 mmHg). Based on the results of RHC, 108 subjects had PH (56 pulmonary arterial hypertension [PAH] and 52 chronic thromboembolic pulmonary hypertension [CTEPH]).Fourteen of 17 ECG parameters in the present study were significantly associated with PH on univariate analysis. On multivariable logistic regression analysis, S wave depth in lead V5 (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.10-1.47) and depth of T wave inversion in lead V4 (OR 1.21, 95% CI 1.03-1.46) were independent predictors of MPAP ≥ 25 mmHg, and the cut-off values determined by receiver operating characteristic curve analyses were 0.42 mV and -0.28 mV, respectively.In conclusion, a deeper S wave in lead V5 and the presence of a wider extent of negative T waves in the precordial leads may be clinically simple and useful ECG parameters for screening for PH.

Survey on large language model annotation of cellular senescence from figures in review articles.

This study evaluated large language models (LLMs), particularly the GPT-4 with vision (GPT-4 V) and GPT-4 Turbo, for annotating biomedical figures, focusing on cellular senescence. We assessed the ability of LLMs to categorize and annotate complex biomedical images to enhance their accuracy and efficiency. Our experiments employed prompt engineering with figures from review articles, achieving more than 70% accuracy for label extraction and approximately 80% accuracy for node-type classification. Challenges were noted in the correct annotation of the relationship between directionality and inhibitory processes, which were exacerbated as the number of nodes increased. Using figure legends was a more precise identification of sources and targets than using captions, but sometimes lacked pathway details. This study underscores the potential of LLMs in decoding biological mechanisms from text and outlines avenues for improving inhibitory relationship representations in biomedical informatics.

Prototyping an Ontological Framework for Cellular Senescence Mechanisms: A Homeostasis Imbalance Perspective.

Although cellular senescence is a key factor in organismal aging, with both positive and negative effects on individuals, its mechanisms remain largely unknown. Thus, integrating knowledge is essential to explain how cellular senescence manifests in tissue damage and age-related diseases. Here, we propose an ontological model that organizes knowledge of cellular senescence in a computer-readable form. We manually annotated and defined cellular senescence processes, molecules, anatomical structures, phenotypes, and other entities based on the Homeostasis Imbalance Process ontology (HOIP). We described the mechanisms as causal relationships of processes and modelled a homeostatic imbalance between stress and stress response in cellular senescence for a unified framework. HOIP was assessed formally, and the relationships between cellular senescence and diseases were inferred for higher-order knowledge processing. We visualized cellular senescence processes to support knowledge utilization. Our study provides a knowledge base to help elucidate mechanisms linking cellular and organismal aging.

Small Barrett's adenocarcinoma, 3 mm in size, in long-segment Barrett's esophagus detected after 4 years of follow up.

We herein report a rare case of very small Barrett's adenocarcinoma. A 65-year-old man underwent surveillance esophagogastroduodenoscopy (EGD) 3 years after endoscopic submucosal dissection (ESD) for superficial Barrett's adenocarcinoma, which revealed a very small reddish area in the mucosa, 2 mm in diameter, in long-segment Barrett's esophagus. The EGD carried out 1 year later confirmed slight enlargement of the lesion, from 2 mm to 3 mm in diameter. Macroscopic type changed from flat type to slightly depressed type. On narrow-band imaging with magnifying endoscopy, an irregular microstructure and irregular microvasculature became recognizable. It was resected by ESD and diagnosed as mucosal adenocarcinoma with a diameter of only 3 mm.

A community effort for COVID-19 Ontology Harmonization.

Ontologies have emerged to become critical to support data and knowledge representation, standardization, integration, and analysis. The SARS-CoV-2 pandemic led to the rapid proliferation of COVID-19 data, as well as the development of many COVID-19 ontologies. In the interest of supporting data interoperability, we initiated a community-based effort to harmonize COVID-19 ontologies. Our effort involves the collaborative discussion among developers of seven COVID-19 related ontologies, and the merging of four ontologies. This effort demonstrates the feasibility of harmonizing these ontologies in an interoperable framework to support integrative representation and analysis of COVID-19 related data and knowledge.

Effect of Living Environment Factors on Quality of Life in Patients With Chronic Thromboembolic Pulmonary Hypertension After Completion of Balloon Pulmonary Angioplasty　- A Cross-Sectional Study.

Background: This study investigated factors related to quality of life (QoL) in patients with chronic thromboembolic pulmonary hypertension who completed balloon pulmonary angioplasty (BPA). Methods and Results: Patient QoL and living environment after BPA were evaluated prospectively using the 5-level EQ-5D questionnaire and International Physical Activity Questionnaire Environmental Module (IPAQ-E), respectively. Patients were mailed copies of both surveys. In addition, we reviewed patient charts and collected retrospective clinical data. Relationship between the clinical data and QoL and environmental living factors were investigated. Of the 33 subjects mailed the surveys, sufficient responses were obtained from 22 (71%). Spearman's rank correlation coefficient showed that psychiatric disorders (r=-0.6865, P<0.01) and IPAQ-E Question 5 (r=0.5192, P=0.02), Question 6 (r=0.5265, P=0.02), and Question 13 (r=0.4552, P=0.04) were significantly correlated with EQ-5D scores after BPA. Conclusions: A living environment that was difficult to walk around was associated with a worse QoL. A multidisciplinary approach will be required to improve QoL even after completion of BPA treatment.

Establishment and application of information resource of mutant mice in RIKEN BioResource Research Center.

Online databases are crucial infrastructures to facilitate the wide effective and efficient use of mouse mutant resources in life sciences. The number and types of mouse resources have been rapidly growing due to the development of genetic modification technology with associated information of genomic sequence and phenotypes. Therefore, data integration technologies to improve the findability, accessibility, interoperability, and reusability of mouse strain data becomes essential for mouse strain repositories. In 2020, the RIKEN BioResource Research Center released an integrated database of bioresources including, experimental mouse strains, Arabidopsis thaliana as a laboratory plant, cell lines, microorganisms, and genetic materials using Resource Description Framework-related technologies. The integrated database shows multiple advanced features for the dissemination of bioresource information. The current version of our online catalog of mouse strains which functions as a part of the integrated database of bioresources is available from search bars on the page of the Center ( https://brc.riken.jp ) and the Experimental Animal Division ( https://mus.brc.riken.jp/ ) websites. The BioResource Research Center also released a genomic variation database of mouse strains established in Japan and Western Europe, MoG+ ( https://molossinus.brc.riken.jp/mogplus/ ), and a database for phenotype-phenotype associations across the mouse phenome using data from the International Mouse Phenotyping Platform. In this review, we describe features of current version of databases related to mouse strain resources in RIKEN BioResource Research Center and discuss future views.

Ontological approach to the knowledge systematization of a toxic process and toxic course representation framework for early drug risk management.

Various types of drug toxicity can halt the development of a drug. Because drugs are xenobiotics, they inherently have the potential to cause injury. Clarifying the mechanisms of toxicity to evaluate and manage drug safety during drug development is extremely important. However, toxicity mechanisms, especially hepatotoxic mechanisms, are very complex. The significant exposure of liver cells to drugs can cause dysfunction, cell injury, and organ failure in the liver. To clarify potential risks in drug safety management, it is necessary to systematize knowledge from a consistent viewpoint. In this study, we adopt an ontological approach. Ontology provides a controlled vocabulary for sharing and reusing of various data with a computer-friendly manner. We focus on toxic processes, especially hepatotoxic processes, and construct the toxic process ontology (TXPO). The TXPO systematizes knowledge concerning hepatotoxic courses with consistency and no ambiguity. In our application study, we developed a toxic process interpretable knowledge system (TOXPILOT) to bridge the gaps between basic science and medicine for drug safety management. Using semantic web technology, TOXPILOT supports the interpretation of toxicity mechanisms and provides visualizations of toxic courses with useful information based on ontology. Our system will contribute to various applications for drug safety evaluation and management.

Acute thrombosis of everolimus-eluting platinum chromium stent caused by impaired prasugrel metabolism due to cytochrome P450 enzyme 2B6*2 (C64T) polymorphism: a case report.

BACKGROUND: Dual antiplatelet therapy with aspirin and P2Y12 receptor inhibitor is an important option for preventing acute stent thrombosis after percutaneous coronary intervention (PCI). CASE SUMMARY: A 72-year-old man was admitted to our hospital with ST-segment elevation myocardial infarction. Emergent coronary angiography identified the occlusion in the proximal left anterior descending artery. This lesion was successfully treated by thrombus aspiration and an everolimus-eluting platinum chromium stent implantation with loading of aspirin 200 mg and prasugrel 20 mg. However, acute closure of the stent occurred 1 h after PCI. P2Y12 reaction units (PRU) measured using VerifyNow assay was 282, suggesting high platelet reactivity on prasugrel. After adding cilostazol 200 mg, recanalization was successfully obtained by thrombus aspiration and ballooning under intra-aortic balloon pump. Thereafter, PRU decreased to 266 at 4 h after PCI, and 49 the next day, implying full inhibition of platelet reactivity on prasugrel. Fortunately, no stent thrombosis has recurred since then. Genotype analysis of cytochrome P450 enzyme (CYP) demonstrated CYP2B6*1/*2 polymorphism leading to impaired metabolism of prasugrel. Based on these findings, acute stent thrombosis in the present case might have been caused by delayed expression of prasugrel effects due to CYP2B6*2 (C64T) polymorphism. DISCUSSION: In cases of stent thrombosis, we should consider the possibility of poor response to P2Y12 receptor inhibitors due to CYP polymorphism. Assessment of platelet aggregation and CYP genotype may be warranted.

Current status and future perspective of computational toxicology in drug safety assessment under ontological intellection.

For the safety assessment of pharmaceuticals, initial data management requires accurate toxicological data acquisition, which is based on regulatory safety studies according to guidelines, and computational systems have been developed under the application of Good Laboratory Practice (GLP). In addition to these regulatory toxicology studies, investigative toxicological study data for the selection of lead compound and candidate compound for clinical trials are directed to estimation by computational systems such as Quantitative Structure-Activity Relationship (QSAR) and related expert systems. Furthermore, in the "Go" or "No-Go" decision of drug development, supportive utilization of a scientifically interpretable computational toxicology system is required for human safety evaluation. A pharmaceutical safety evaluator as a related toxicologist who is facing practical decision needs not only a data-driven Artificial Intelligence (AI) system that calls for the final consequence but also an explainable AI that can provide comprehensive information necessary for evaluation and can help with decision making. Through the explication and suggestion of information on the mechanism of toxic effects to safety assessment scientists, a subsidiary partnership system for risk assessment is ultimately to be a powerful tool that can indicate project-vector with data weight for the corresponding counterparts. To bridge the gaps between big data and knowledge, multi-dimensional thinking based on philosophical ontology theory is necessary for handling heterogeneous data for integration. In this review, we will explain the current state and future perspective of computational toxicology related to drug safety assessment from the viewpoint of ontology thinking.

Pulmonary Thromboembolism Caused by Calcification in the Inferior Vena Cava of a Japanese Adult.

A 45-year-old Japanese man was referred to our hospital with chest and back pain with a duration of two days. Contrast-enhanced computed tomography (CT) showed a large calcified lesion in the inferior vena cava (IVC), thrombus with calcification in the pulmonary arteries of the left lower lobe, and an infiltrative shadow in the left lower lobe. He was diagnosed with pulmonary thromboembolism (PE) and pneumonia. Calcification in the IVC was not evident on any CT images obtained six and eight years earlier. This patient was identified to be an extremely rare case of PE associated with IVC calcification that developed during adulthood.

Balloon pulmonary angioplasty is effective for treating peripheral-type chronic thromboembolic pulmonary hypertension in elderly patients.

AIM: Balloon pulmonary angioplasty (BPA) has recently been established as an effective therapy for peripheral-type chronic thromboembolic pulmonary hypertension (CTEPH). However, the safety and effectiveness of BPA in elderly patients with CTEPH have not been clarified. METHODS: A total of 19 patients with CTEPH who underwent BPA were recruited. The patients were assigned to groups by age, <70 years (non-elderly; n = 11) and ≥70 years (elderly; n = 8). Hemodynamic parameters, right ventricular function and plasma N-terminal pro-brain natriuretic peptide were assessed before and after BPA, and complications arising after BPA were also evaluated. RESULTS: Hemodynamic parameters and right heart function did not differ significantly between the two groups at baseline. BPA significantly improved pulmonary arterial pressure, pulmonary vascular resistance and fractional area change in both groups (all P < 0.05), although the differences were comparable. No fatal complications developed, but the frequency of minor complications, such as transient hemoptysis, was higher in the elderly group than in the non-elderly group (median 0.45 [interquartile range 0.27-0.63] vs 0 [0-0.33], respectively; P = 0.021). The frequency of such complications was also higher in patients with a psychiatric disorder than in those without (0.50 [0.44-1.00] vs 0.14 [0-0.33], respectively; P = 0.006). Multivariate regression analysis identified higher age, baseline N-terminal pro-brain natriuretic peptide values and an underlying psychiatric disorder as significant predictors of complications of BPA. CONCLUSIONS: BPA is an effective treatment for peripheral-type CTEPH regardless of age; however, higher age, N-terminal pro-brain natriuretic peptide values before treatment and an underlying psychiatric disorder might be associated with minor complications. Geriatr Gerontol Int 2018; 18: 678-684.

Comparison of the effects of edoxaban, an oral direct factor Xa inhibitor, on venous thromboembolism between patients with and without cancer.

BACKGROUND: Venous thromboembolism (VTE) is a frequent and serious complication of cancer. The current guidelines in the USA and Europe recommend low-molecular weight heparin (LMWH) for the treatment of cancer-associated VTE. In Japan, LMWH is not given for the treatment of VTE; instead edoxaban, an oral direct factor Xa inhibitor, was approved for the treatment of VTE in September 2014. However, the efficacy and safety of the factor Xa inhibitor in cancer patients have not been fully elucidated. METHODS: Patients' charts were reviewed retrospectively, and 125 VTE patients (61 cancer patients) in whom edoxaban therapy was started between September 2014 and September 2016 were included in this study. Patients' demographics, changes in VTE amount, VTE recurrence, clinically relevant bleeding, and outcomes until February 2017 were examined. RESULTS: Patients' characteristics, including age, sex, weight, creatinine clearance, and duration of administration of edoxaban were comparable between cancer and non-cancer patients. No parenteral anticoagulant pretreatment before edoxaban was given in 37.5% and 55.7% of non-cancer and cancer patients, respectively. The incidence of pulmonary embolism was also similar in the two groups. The amount of thrombosis decreased ("improved") or disappeared ("normalized") in 89.6% and 94.1%, respectively, of non-cancer and cancer patients who underwent at least two imaging tests. The frequencies of recurrence of VTE and clinically relevant bleeding were not significantly different between the two groups (p=0.414 and 0.516, respectively). However, 21 cancer patients died, 17 of whom died of cancer, while none of the non-cancer patients died. CONCLUSION: The present study showed that the efficacy and safety of edoxaban for the treatment of VTE is comparable between cancer and non-cancer patients. Edoxaban may be a clinically useful therapy for VTE in Japanese cancer patients.

Disease Compass- a navigation system for disease knowledge based on ontology and linked data techniques.

BACKGROUND: Medical ontologies are expected to contribute to the effective use of medical information resources that store considerable amount of data. In this study, we focused on disease ontology because the complicated mechanisms of diseases are related to concepts across various medical domains. The authors developed a River Flow Model (RFM) of diseases, which captures diseases as the causal chains of abnormal states. It represents causes of diseases, disease progression, and downstream consequences of diseases, which is compliant with the intuition of medical experts. In this paper, we discuss a fact repository for causal chains of disease based on the disease ontology. It could be a valuable knowledge base for advanced medical information systems. METHODS: We developed the fact repository for causal chains of diseases based on our disease ontology and abnormality ontology. This section summarizes these two ontologies. It is developed as linked data so that information scientists can access it using SPARQL queries through an Resource Description Framework (RDF) model for causal chain of diseases. RESULTS: We designed the RDF model as an implementation of the RFM for the fact repository based on the ontological definitions of the RFM. 1554 diseases and 7080 abnormal states in six major clinical areas, which are extracted from the disease ontology, are published as linked data (RDF) with SPARQL endpoint (accessible API). Furthermore, the authors developed Disease Compass, a navigation system for disease knowledge. Disease Compass can browse the causal chains of a disease and obtain related information, including abnormal states, through two web services that provide general information from linked data, such as DBpedia, and 3D anatomical images. CONCLUSIONS: Disease Compass can provide a complete picture of disease-associated processes in such a way that fits with a clinician's understanding of diseases. Therefore, it supports user exploration of disease knowledge with access to pertinent information from a variety of sources.

An inhibitory epitope of human Toll-like receptor 4 resides on leucine-rich repeat 13 and is recognized by a monoclonal antibody.

Lipopolysaccharide (LPS)-induced activation of Toll-like receptor 4 (TLR4) elicits the innate immune response and can trigger septic shock if excessive. Two antibodies (HT4 and HT52) inhibit LPS-induced human TLR4 activation via novel LPS binding-independent mechanisms. The HT52 epitope resides on leucine-rich repeat 2 (LRR2) and is a feature of many inhibitory antibodies; antigen specificity of HT4 does not reside in LRR2. Here, we identified an HT4 epitope on LRR13 located close to the TLR4 dimerization interface that plays a role in NFκB activation. HT4 and HT52 mutually enhanced TLR4 inhibition. LRR13 is a novel inhibitory epitope and may be useful for developing anti-TLR4 antibodies. Combination therapy with LRR2 and LRR13 may effectively inhibit TLR4 activation.

The Histological Features of a Myocardial Biopsy Specimen in a Patient in the Acute Phase of Reversible Catecholamine-induced Cardiomyopathy due to Pheochromocytoma.

A 63-year-old Japanese woman with an adrenal tumor was transferred to our hospital due to cardiogenic shock. Right and left ventriculography showed severe hypokinesis of the middle segment and the apex in both ventricles, and an endomyocardial biopsy demonstrated a small number of necrotic myocytes and cellular infiltration. She was diagnosed with pheochromocytoma and quickly recovered after treatment with an α-blocker. The functional disability of both the right and left ventricles with less myocardial damage due to an excessive level of catecholamine seemed to be related to the early recovery the present patient with catecholamine-induced cardiomyopathy due to pheochromocytoma.

Leucine-rich repeat 2 of human Toll-like receptor 4 contains the binding site for inhibitory monoclonal antibodies.

Excessive activation of Toll-like receptor 4 (TLR4)/MD-2 by lipopolysaccharide (LPS) causes septic shock. We previously produced an inhibitory antibody, HT52, against LPS-induced human TLR4 activation independently of LPS binding of MD-2. Consistent with the hypothesis that HT52 recognizes the epitopes inherent to inhibitory antibodies, we generated an HT52-crossblockable antibody and revealed the relationship between its inhibitory activity and the anti-TLR4 antibody epitope. Leucine-rich repeat 2 was identified as an inhibitory epitope, and Phe(75), Ser(76) and Pro(79) as antigenic determinants. These findings provide a way to design therapeutic antibodies targeted to TLR4 that are distinct from LPS analog antagonists targeting MD-2.