Gene network inference from single-cell omics data and domain knowledge for constructing COVID-19-specific ICAM1-associated pathways.

Introduction: Intercellular adhesion molecule 1 (ICAM-1) is a critical molecule responsible for interactions between cells. Previous studies have suggested that ICAM-1 triggers cell-to-cell transmission of HIV-1 or HTLV-1, that SARS-CoV-2 shares several features with these viruses via interactions between cells, and that SARS-CoV-2 cell-to-cell transmission is associated with COVID-19 severity. From these previous arguments, it is assumed that ICAM-1 can be related to SARS-CoV-2 cell-to-cell transmission in COVID-19 patients. Indeed, the time-dependent change of the ICAM-1 expression level has been detected in COVID-19 patients. However, signaling pathways that consist of ICAM-1 and other molecules interacting with ICAM-1 are not identified in COVID-19. For example, the current COVID-19 Disease Map has no entry for those pathways. Therefore, discovering unknown ICAM1-associated pathways will be indispensable for clarifying the mechanism of COVID-19. Materials and methods: This study builds ICAM1-associated pathways by gene network inference from single-cell omics data and multiple knowledge bases. First, single-cell omics data analysis extracts coexpressed genes with significant differences in expression levels with spurious correlations removed. Second, knowledge bases validate the models. Finally, mapping the models onto existing pathways identifies new ICAM1-associated pathways. Results: Comparison of the obtained pathways between different cell types and time points reproduces the known pathways and indicates the following two unknown pathways: (1) upstream pathway that includes proteins in the non-canonical NF-κB pathway and (2) downstream pathway that contains integrins and cytoskeleton or motor proteins for cell transformation. Discussion: In this way, data-driven and knowledge-based approaches are integrated into gene network inference for ICAM1-associated pathway construction. The results can contribute to repairing and completing the COVID-19 Disease Map, thereby improving our understanding of the mechanism of COVID-19.

Acute mitral regurgitation after non-ischemic papillary muscle rupture: A case report.

Papillary muscle rupture (PMR) is a life-threatening cardiac emergency that is generally associated with inadequate myocardial perfusion after acute myocardial infarction. Nonischemic spontaneous PMR occurs less frequently and is mostly caused by myocarditis, infections, or trauma. We report a patient with spontaneous PMR resulting in severe mitral regurgitation with refractory heart failure showing no specific causes but deterioration of the mitral leaflet and papillary muscle. The integration of pathologic and echocardiographic findings describes the details of the disease. .

Explainable Model Fusion for Customer Journey Mapping.

Due to advances in computing power and internet technology, various industrial sectors are adopting IT infrastructure and artificial intelligence (AI) technologies. Recently, data-driven predictions have attracted interest in high-stakes decision-making. Despite this, advanced AI methods are less often used for such tasks. This is because AI technology is a black box for the social systems it is meant to support; trustworthiness and fairness have not yet been established. Meanwhile in the field of marketing, strategic decision-making is a high-stakes problem that has a significant impact on business trends. For global marketing, with its diverse cultures and market environments, future decision-making is likely to focus on building consensus on the formulation of the problem itself rather than on solutions for achieving the goal. There are two important and conflicting facts: the fact that the core of domestic strategic decision-making comes down to the formulation of the problem itself, and the fact that it is difficult to realize AI technology that can achieve problem formulation. How can we resolve this difficulty with current technology? This is the main challenge for the realization of high-level human-AI systems in the marketing field. Thus, we propose customer journey mapping (CJM) automation through model-level data fusion, a process for the practical problem formulation known as explainable alignment. Using domain-specific requirements and observations as inputs, the system automatically outputs a CJM. Explainable alignment corresponds with both human and AI perspectives and in formulating the problem, thereby improving strategic decision-making in marketing. Following preprocessing to make latent variables and their dynamics transparent with latent Dirichlet allocation and a variational autoencoder, a post-hoc explanation is implemented in which a hidden Markov model and learning from an interpretation transition are combined with a long short-term memory architecture that learns sequential data between touchpoints for extracting attitude rules for CJM. Finally, we realize the application of human-AI systems to strategic decision-making in marketing with actual logs in over-the-top media services, in which the dynamic behavior of customers for CJM can be automatically extracted.

Comparative pathological findings between coronary bare-metal stent implantation and balloon angioplasty over 16 years.

A 68-year old man underwent bare metal stent (BMS; Palmaz-Shatz stent) implantation in the distal right coronary artery (RCA; #4PL) and balloon angioplasity (BA) in the proximal left circumflex coronary artery (LCX; #11) for stable angina. After 5 years after initial stent implantation, de novo lesion located in mid RCA was treated by BMS (NIR stent) implantation additionally. After 16 years from first BMS implantation, the patient died from heart failure due to cardiac amyloidosis, and pathologic examination was performed for the specimen of stented RCA segment and LCX BA segment. An autopsy demonstrated that the lesions of stented site at RCA and BA site LCX were histopathologically different. In the stented segment, severe luminal stenosis is observed due to marked proliferation of the neointima in all stented sites. In addition, neovascularization and spotty calcification with mild lymphocyte infiltration were observed especially around the struts. In contrast, at the BA site of the proximal LCX lesion, in the neointima, the smooth muscle cells were rather atrophic and abundant collagen fibers were evident in the intercellular spaces, which showed very stable findings. Compared with these BMS implanted portions, the site of BA was associated with a trend for smaller late lumen loss. These findings suggested that in the stented site, chronic inflammatory reaction to the stent struts could evoke continuous proliferation of neointima resulting in severe late lumen loss. .

Modeling viral dynamics in SARS-CoV-2 infection based on differential equations and numerical analysis.

Computational modeling and simulation of viral dynamics would explain the pathogenesis for any virus. Such computational attempts have been successfully made to predict and control HIV-1 or hepatitis B virus. However, the dynamics for SARS-CoV-2 has not been adequately investigated. The purpose of this research is to propose different SARS-CoV-2 dynamics models based on differential equations and numerical analysis towards distilling the models to explain the mechanism of SARS-CoV-2 pathogenesis. The proposed four models formalize the dynamical system of SARS-CoV-2 infection, which consists of host cells and viral particles. These models undergo numerical analysis, including sensitivity analysis and stability analysis. Based on the sensitivity indices of the four models' parameters, the four models are simplified into two models. In advance of the following calibration experiments, the eigenvalues of the Jacobian matrices of these two models are calculated, thereby guaranteeing that any solutions are stable. Then, the calibration experiments fit the simulated data sequences of the two models to two observed data sequences, SARS-CoV-2 viral load in mild cases and that in severe cases. Comparing the estimated parameters in mild cases and severe cases indicates that cell-to-cell transmission would significantly correlate to the COVID-19 severity. These experiments for modeling and simulation provide plausible computational models for the SARS-CoV-2 dynamics, leading to further investigation for identifying the essential factors in severe cases.

Pathological evaluation 18 years after bare-metal stent implantation in the superficial femoral artery.

Bare-metal stents (BMSs) have been generally applied for the treatment of peripheral artery disease in patients with femoropopliteal disease. However, very long-term pathological findings after BMS implantation have not been elucidated to date. We experienced an autopsy case in which we performed a pathological evaluation 18 years after BMS implantation in the right superficial femoral artery. The BMS was totally occluded and filled with remarkable neointima formation. Neointima was mainly composed of a lot of rather atrophic smooth muscles and intercellular spaces containing dense collagenous fibers. Furthermore, regional fatty infiltration was also observed, but inflammatory cell infiltration, such as macrophages and lymphocytes, was not recognized obviously even around the struts. Judging from the pathological findings, the main mechanism of the very long-term in-stent restenosis in the patients with femoropopliteal disease was continuous proliferation of smooth muscle cells that led to the totally occlusive disease. This observation leads us to speculate that continuous elution of an anti-proliferating drug over a longer duration, at least beyond 1 year, would be effective to prevent chronic-phase restenosis. Further development of devices that can be used in the femoropopliteal artery is needed in light of this speculation. .

Very late intrastent thrombotic occlusion caused by neoatherosclerosis after bare-metal stent implantation in the superficial femoral artery: Insight from histopathological findings.

A 58-year-old male with gangrene in his left 1st digit due to critical limb ischemia had undergone endovascular therapy for chronic total occlusion of the left superficial femoral artery using bare-metal stents (BMSs). Angiography revealed in-stent occlusion of the BMS site when he was referred to our hospital with a recurrent ulcer at 7 years after stent implantation. As catheter-directed thrombolysis with urokinase was not effective, surgical thrombectomy was performed. His ankle-brachial index improved, and the ulcer was completely healed after thrombectomy. Pathological evaluation of the retrieved thrombi showed that it consisted of a massive erythrocyte, abundant fibrin precipitation, and fragments of atherosclerotic plaques, such as foamy macrophages and ghost images thought to be cholesterol crystals. These findings suggested that the neoatherosclerotic changes in the neointima gradually occurred in the stented segment, and neointimal disruption potentially caused the intrastent thrombotic occlusion. .

Clinical impact of pathology-proven etiology of severely stenotic aortic valves on mid-term outcomes in patients undergoing surgical aortic valve replacement.

BACKGROUND: The use of transcatheter or surgical aortic valve replacement (AVR) for severe aortic stenosis (AS) has considerably increased in recent years. However, the association between AS etiology and mid-term clinical outcomes after surgical AVR has not been fully investigated. METHODS AND RESULTS: We retrospectively included 201 patients (mean age, 75 years; 43%, men) who underwent surgical AVR for severe native AS (aortic valve area ≤1.0 cm2 on preoperative transthoracic echocardiography examination). The following valve etiologies were postoperatively identified on pathological examination: post-inflammatory (n = 28), congenital (n = 35), and calcific/degenerative (n = 138). The median follow-up interval was 4.1 years following surgical AVR. Of the 201 patients, 27% were asymptomatic, 40% had a history of heart failure, and 11% underwent previous heart surgery. The cumulative incidence of cardiac events (all-cause death, aortic valve deterioration requiring repeated AVR, and hospitalization for heart failure) and combined adverse events, which included non-fatal stroke, unplanned coronary revascularization, pacemaker implantation, and gastrointestinal bleeding along with cardiac events, was significantly higher in the calcific/degenerative group (p = 0.02 and p = 0.02, respectively). In multivariate analysis adjusted for age, sex, renal function, heart failure, atrial fibrillation, concomitant surgical procedures, and EuroSCORE II, AS etiology was independently associated with an increased risk of combined adverse events (congenital vs. post-inflammatory: hazard ratio [HR], 4.13; p = 0.02 and calcific/degenerative vs. post-inflammatory: HR, 5.69; p = 0.002). CONCLUSIONS: Pathology-proven AS etiology could aid in predicting the mid-term outcomes after surgical AVR, supporting the importance of accurate identification of severe AS etiology with or without postoperative pathological examination.

Two rare cases of congenital aortic stenosis showing a discrepancy between preoperative imaging diagnosis, intraoperative findings, and histopathological diagnosis.

Unicuspid aortic valve (UAV) is an extremely rare congenital heart valve abnormality while bicuspid valve (BAV) has been reported as one of the most common cardiac anomalies. With a UAV usually showing similar presentations to a BAV, such as aortic regurgitation or aortic stenosis (AS), it is challenging to differentiate them from each other in clinical settings. Despite some features shared between both valve disorders, there can be a clinical significance in distinguishing UAV from BAV for the management of patients with these heart anomalies. Herein, we describe two cases where patients with hemodynamically severe AS were diagnosed with BAV and UAV, respectively based on preoperative examinations and intraoperative findings, but subsequent pathological examinations confirmed the opposite diagnosis in both cases. .

Assessing the resilience of stochastic dynamic systems under partial observability.

Resilience is a property of major interest for the design and analysis of generic complex systems. A system is resilient if it can adjust in response to disruptive shocks, and still provide the services it was designed for, without interruptions. In this work, we adapt a formal definition of resilience for constraint-based systems to a probabilistic framework derived from hidden Markov models. This allows us to more realistically model the stochastic evolution and partial observability of many complex real-world environments. Within this framework, we propose an efficient and exact algorithm for the inference queries required to construct generic property checking. We show that the time complexity of this algorithm is on par with other state-of-the-art inference queries for similar frameworks (that is, linear with respect to the time horizon). We also provide considerations on the specific complexity of the probabilistic checking of resilience and its connected properties, with particular focus on resistance. To demonstrate the flexibility of our approach and to evaluate its performance, we examine it in four qualitative and quantitative example scenarios: (1) disaster management and damage assessment; (2) macroeconomics; (3) self-aware, reconfigurable computing for aerospace applications; and (4) connectivity maintenance in robotic swarms.

Short versus prolonged dual antiplatelet therapy duration after bare-metal stent implantation: 2-month landmark analysis from the CREDO-Kyoto registry cohort-2.

One-month duration of dual antiplatelet therapy (DAPT) has widely been adopted after bare-metal stent (BMS) implantation in the real clinical practice. However, it has not been adequately addressed yet whether DAPT for only 1-month could provide sufficient protection from ischemic events beyond 1-month after BMS implantation. We assessed the effects of short DAPT relative to prolonged DAPT on clinical outcomes with the landmark analysis at 2 month after BMS implantation. Among 13,058 consecutive patients enrolled in the CREDO-Kyoto registry cohort-2, this study population consisted of 4905 patients treated with BMS only in whom the information on the status of antiplatelet therapy was available at 2 month after stent implantation [single-antiplatelet therapy (SAPT) group: N = 2575 (acute myocardial infarction (AMI): N = 1257, and non-AMI: N = 1318), and DAPT group: N = 2330 (AMI: N = 1304, and non-AMI: N = 1026)]. Cumulative 3-year incidence of the primary outcome measure (a composite of cardiovascular death, myocardial infarction, stroke, definite stent thrombosis, and GUSTO moderate/severe bleeding) was not significantly different between the SAPT and DAPT groups (9.8 versus 10.6 %, P = 0.34). After adjusting confounders, the risk of SAPT relative to DAPT for the primary outcome measure remained insignificant in the entire cohort (HR 0.97, 95 % CI 0.79-1.19, P = 0.77), and in both AMI and non-AMI strata without any significant interaction between clinical presentation (AMI versus non-AMI) and the effect of SAPT relative to DAPT (P interaction = 0.56). In conclusion, short DAPT <2 month after BMS implantation was as safe as prolonged DAPT ≥2-month in both AMI and non-AMI patients.

Pathology of Neointimal Calcification in Very Late Restenosis After Bare Metal Stent Implantation for Superficial Femoral Artery.

A 60-year-old man, who had claudication in his right limb due to total occlusion of the right superficial femoral artery, received bare metal stents. Although the bare metal stents in the superficial femoral artery did not show restenosis 5 years after stent implantation, angiography revealed significant in-stent restenosis when he developed right critical limb ischemia at 8 years post implantation. Ballooning for in-stent lesions did not result in full expansion. His right limb was amputated above the knee due to progressive limb ischemia. In the pathological findings in the superficial femoral artery, marked calcification was observed in the entire circumference of the luminal surface of the neointima. However, lipid core formation was not identified in the neointima. Although several cracks following balloon angioplasty were observed at the superficial calcified layers, injury to neointimal tissue such as compression was not observed. The neointima exhibited heavy calcification in the very late phase of in-stent restenosis after bare metal stent implantation in superficial femoral artery. Therefore, balloon angioplasty in the very late phase of in-stent restenosis potentially results in underexpansion.

Histological Evaluation of a Self-Expanding Stent-Graft 23 Months After Implantation in the Superficial Femoral Artery.

PURPOSE: To report histological examination of a Viabahn stent-graft implanted in the superficial femoral artery (SFA) for nearly 2 years. CASE REPORT: A 78-year-old man with peripheral artery disease was treated successfully with a 6.0×250-mm Viabahn self-expanding stent-graft in the right SFA, relieving his lower limb claudication. The patient died suddenly due to acute myocardial infarction 23 months later. Histological evaluation of the stent-graft implantation site revealed moderate neointimal proliferation at both proximal and distal edges of the device. In the middle part of the stent, significant macrophages and multinucleated foreign body giant cells had accumulated, although the stent was entirely patent. Furthermore, no endothelial cell coverage was found. CONCLUSION: Judging from these features, it might be necessary to continue dual antiplatelet therapy after stent-graft implantation over the long term to prevent thrombosis and subsequent restenosis or reocclusion.

Nardilysin is a promising biomarker for the early diagnosis of acute coronary syndrome.

BACKGROUND: Biomarkers for detection of transient myocardial ischemia in patients with unstable angina (UA) or for very early diagnosis of acute myocardial infarction (AMI) are not currently available. METHODS AND RESULTS: We performed two sequential screenings of autoantibodies elevated shortly after the onset of acute coronary syndrome (ACS), and focused on metalloendopeptidase nardilysin (NRDC) among 19 identified candidate antigens. In a retrospective analysis among 93 ACS and 117 non-ACS patients, the serum level of NRDC was significantly increased in patients with ACS compared with that in patients with non-ACS (2073.5±189.8pg/ml versus 775.7±63.4pg/ml, P<0.0001). The area under the curve of NRDC for the diagnosis of ACS was 0.822 by the receiver operating characteristic curves analysis. In the time course analysis in 43 consecutive ACS patients (AMI: N=35 and UA: N=8), serum concentration of NRDC was significantly increased even in UA patients with a peak serum NRDC levels reached at admission both in AMI and UA patients. In a mouse model of AMI, we found an acute increase in serum NRDC and reduced NRDC expression in ischemic regions shortly after coronary artery ligation. NRDC expression was also reduced in infarcted regions in human autopsy samples from AMI patients. Moreover, the short treatment of primary culture of rat cardiomyocytes with H2O2 or A23187 induced NRDC secretion without cell toxicity. CONCLUSION: NRDC is a promising biomarker for the early detection of ACS, even in UA patients without elevation of necrosis markers.

Analyzing resilience properties in oscillatory biological systems using parametric model checking.

Automated verification of living organism models allows us to gain previously unknown knowledge about underlying biological processes. In this paper we show how parametric time model checking can be applied to define the time behavior of biological oscillatory systems more precisely. In particular, we focus on the resilience properties of such systems. This notion was introduced to understand the behavior of biological systems (e.g. the mammalian circadian rhythm) that are reactive and adaptive enough to endorse major changes in their environment (e.g. jet-lags, day-night alternating work-time). We formalize these properties through parametric TCTL and investigate the influence of environmental conditions changes on the resilience of living organisms under the uncertainty in parameters. In particular, we discuss the influence of various perturbations, e.g. artificial jet-lag or components knock-out on the parameters controlling the oscillatory behavior. This analysis is crucial when it comes to model elicitation for dynamic biological systems. We demonstrate the applicability of this technique using a simplified model of circadian clock and discuss its results with regard to other previous studies based on hybrid modeling.