Early Clinical Results From the Japanese Prospective Multicenter Study to Evaluate Zenith Alpha Abdominal Stent Graft for Abdominal Aortic Aneurysm (JUSTICE) Registry Demonstrate Acceptable Limb Patency at 12 Months.

PURPOSE: Recent reports of the Zenith Alpha abdominal endovascular graft (Zenith Alpha AAA, Cook, Inc., Bloomington, Indiana) have demonstrated an unexpectedly high incidence of limb graft occlusion (LGO). The purpose of this study was to prospectively evaluate the performance of the Zenith AAA in Japan, with a specific focus on LGO. MATERIALS AND METHODS: All endovascular aneurysm repairs (EVARs) for abdominal aortic aneurysms performed using the Zenith Alpha AAA from July 2020 to October 2021 in 23 Japanese hospitals were prospectively evaluated. All computed tomographic images were analyzed in the core laboratory. Late complications were defined as any aneurysm-related events occurring >30 days after EVAR, including aneurysm sac enlargement of >5 mm and any reinterventions performed. Endoleaks without sac enlargement or reintervention were excluded as late complications. RESULTS: During the study period, 147 EVARs were performed using the Zenith Alpha AAA. The mean patient age was 76.5±7.7 years, 84.4% of patients were male, and the mean aneurysm diameter was 52.4±9.2 mm. Instruction-for-use violations were observed in 76 patients (51.7%), primarily associated with a severely angulated proximal neck (>60°). There were six intraoperative complications and 62 additional intraoperative treatments reported, most of which involved preemptive coil embolization of the inferior mesenteric artery (37 cases). Technical success, defined as the absence of type 1 or 3 endoleaks on final angiography, was achieved in 99.3% of patients. At 12 months, there was only one case of type 1/3 endoleak (0.8%) and one aneurysm sac enlargement exceeding 5 mm (0.8%); however, a high incidence of type 2 endoleaks was observed in 35.2% of patients, and aneurysm sac regression exceeding 5 mm was achieved in 30.1% of patients. Nine late complications were observed, and the rate of freedom from late complications at 12 months was 93.5%, encompassing four LGOs and one limb graft stenosis (3.4%). CONCLUSIONS: In contrast to recent reports, our Japanese multicenter prospective study demonstrated satisfactory early clinical results, including an acceptable LGO rate, for the low-profile Zenith Alpha AAA. Long-term follow-ups will be performed to confirm the persistence of these outcomes. CLINICAL IMPACT: This study prospectively evaluated the performance of 147 Zenith Alpha AAAs used for endovascular aneurysm repair with core-lab adjudication focusing especially on limb graft occlusion (LGO). At 12 months, aneurysm sac regression exceeding 5 mm was achieved in 30.1% of patients, and there was only one type 1/3 endoleak, one aneurysm sac enlargement (>5 mm), and nine late complications including five LGOs (3.4%), resulting in rate of freedom from late complications at 93.5%. Satisfactory early clinical results, including an acceptable rate of LGO can be achieved, particularly with cautious usage of the Zenith Alpha Spiral-Z Endovascular Leg." 5mm), and nine late complications including five LGOs (3.4%), resulting in rate of freedom from late complications at 93.5%. Satisfactory early clinical results, including an acceptable rate of LGO can be achieved, particularly with cautious usage of the Zenith Alpha Spiral-Z Endovascular Leg.

Mid-term outcomes of right ventricular papillary muscle approximation for severe functional tricuspid regurgitation.

OBJECTIVES: Recurrence of tricuspid regurgitation (TR) after tricuspid annuloplasty can occur in cases where a dilated right ventricle exists and subsequent leaflet tethering follows. We previously reported a new technique of the right ventricular papillary muscle approximation (RV-PMA) for functional TR associated with leaflet tethering. The objective of this study is to elucidate the mid-term outcomes and evaluate the durability of RV-PMA. METHODS: Between January 2014 and March 2023, we applied RV-PMA in 20 patients of advanced functional TR with severe leaflet tethering. The indication of the technique was severe TR with leaflet tethering height >8 mm, and/or a right ventricular end-diastolic diameter >45 mm. The patients were followed up with echocardiography before discharge and at annual interval thereafter. RESULTS: There was no perioperative mortality. In the echocardiography performed before discharge, TR was decreased to mild or less in 85%, and a significant improvement in right ventricular end-diastolic diameter and tethering height were achieved (53-45 mm and 11.1-4.4 mm, respectively). Furthermore, during the median 3-year follow-up period, TR was kept controlled mild or less in 80% of the cases. CONCLUSIONS: RV-PMA is considered to be a safe, effective and durable technique as an additional approach for tricuspid annuloplasty.

Transitions of Activities of Daily Living Status among Inpatients with Subacute Stroke: A Latent Class Approach.

Objectives: This study investigated the transition patterns of activities of daily living (ADL) status based on the Functional Independence Measure (FIM) motor and cognitive items in patients who experienced subacute stroke. Methods: In this single-site, retrospective investigation, 1592 FIM samples were collected during the hospitalization of 373 stroke patients who were admitted between April 2018 and March 2020. FIM item levels were transformed from seven to three (FIM1-2, Complete Dependence; FIM3-5, Modified Dependence; FIM6-7, Independence). FIM samples were classified by latent class modeling into six latent ADL states based on the independence levels of FIM motor and cognitive items. We created an ADL status transition diagram based on the FIM sample's probability of belonging to each status at different hospitalization timepoints. Results: Transition diagrams for each ADL status at admission revealed distinct patterns. In two ADL statuses for which patients required full assistance in FIM motor items, the patients remained motor-dependent without achieving independence on discharge. In contrast, patients in transition from the other four ADL statuses largely achieved independence in motor items by the time of discharge. The time required to reach higher ADL status varied according to the initial ADL status at admission; the slowest improvement was observed in statuses initially classified as needing the most assistance, whereas many patients achieved transition within 3 months from admission. Conclusions: Based on the characteristics of patient ADL status and timing of its changes, the classification of ADL status and visualization of ADL transition can contribute to improved treatment.

Segmentation of beating embryonic heart structures from 4-D OCT images using deep learning.

Optical coherence tomography (OCT) has been used to investigate heart development because of its capability to image both structure and function of beating embryonic hearts. Cardiac structure segmentation is a prerequisite for the quantification of embryonic heart motion and function using OCT. Since manual segmentation is time-consuming and labor-intensive, an automatic method is needed to facilitate high-throughput studies. The purpose of this study is to develop an image-processing pipeline to facilitate the segmentation of beating embryonic heart structures from a 4-D OCT dataset. Sequential OCT images were obtained at multiple planes of a beating quail embryonic heart and reassembled to a 4-D dataset using image-based retrospective gating. Multiple image volumes at different time points were selected as key-volumes, and their cardiac structures including myocardium, cardiac jelly, and lumen, were manually labeled. Registration-based data augmentation was used to synthesize additional labeled image volumes by learning transformations between key-volumes and other unlabeled volumes. The synthesized labeled images were then used to train a fully convolutional network (U-Net) for heart structure segmentation. The proposed deep learning-based pipeline achieved high segmentation accuracy with only two labeled image volumes and reduced the time cost of segmenting one 4-D OCT dataset from a week to two hours. Using this method, one could carry out cohort studies that quantify complex cardiac motion and function in developing hearts.

Stent-Graft Placement for Radiation-Induced Abdominal Aortic Stenosis after Renal Autotransplantation.

Renovascular hypertension (RVH) is a common cause of secondary hypertension. However, there have been no reports on RVH due to radiation-induced abdominal aorta stenosis after renal autotransplantation. A 27-year-old woman with a history of neuroblastoma treated by radiation therapy and RVH treated with renal autotransplantation presented with hypertension and dyspnea. At age 19, she had experienced hypertensive heart failure due to RVH from radiation-induced left renal artery stenosis and had undergone renal autotransplantation involving the extraction of her left kidney. Her systolic blood pressure (BP) was well-controlled but had increased progressively. She was diagnosed with hypertensive heart failure and admitted to hospital. Although her dyspnea soon subsided after treatment, her BP remained high. Renal artery ultrasound revealed no obvious stenosis. The ankle brachial pressure index (ABI) showed a significant bilateral decrease to 0.71/0.71 (right/left) from 0.94/0.95 eight years before. Magnetic resonance angiography and aortic angiography revealed severe stenosis in the abdominal aorta, and the systolic pressure gradient of intra-aortic blood flow, distal and proximal to a stenotic lesion, was 58 mmHg. These arterial stenoses in the irradiated area were highly suggestive of radiation-induced vasculopathy. She finally underwent an endovascular VIABAHN VBX balloon-expandable stent-graft placement for this radiation-induced abdominal aorta stenosis, which resolved the pressure gradient. After the procedure, her ABI improved to 0.91/0.88 and her BP was well-controlled. This is the first case of successful stent-graft placement for RVH after renal autotransplantation due to radiation-induced abdominal aorta stenosis as a consequence of neuroblastoma.

Modification of pulmonary endarterectomy to prevent neurologic adverse events.

PURPOSE: Neurologic adverse events (NAEs) are a major complication after pulmonary endarterectomy (PEA) performed under periods of deep hypothermic circulatory arrest (HCA) for chronic thromboembolic pulmonary hypertension. We modified the PEA strategy to prevent NAEs and evaluated the effectiveness of these modifications. METHODS: We reviewed the surgical outcomes of 87 patients divided into the following three groups based on the surgical strategy used: group S (n = 49), periods of deep HCA with alpha-stat strategy; group M1 (n = 19), deep HCA with modifications of slower cooling and rewarming rates and the pH-stat strategy for cooling: and group M2 (n = 13), multiple short periods of moderate HCA. RESULTS: PEA provided significant improvement of pulmonary hemodynamics in each group. Sixteen (29%) of the 49 group S patients suffered NAEs, associated with total circulatory arrest time (cutoff, 57 min) and Jamieson type I disease. The Group M1 and M2 patients did not suffer NAEs, although the group M1 patients had prolonged cardiopulmonary bypass (CPB) and more frequent respiratory failure. CONCLUSIONS: NAEs were common after PEA performed under periods of deep HCA. The modified surgical strategy could decrease the risk of NAEs but increase the risk of respiratory failure. Multiple short periods of moderate HCA may be useful for patients at risk of NAEs.

Diagnosis of Atrial Fibrillation Using Machine Learning With Wearable Devices After Cardiac Surgery: Algorithm Development Study.

BACKGROUND: Some attempts have been made to detect atrial fibrillation (AF) with a wearable device equipped with photoelectric volumetric pulse wave technology, and it is expected to be applied under real clinical conditions. OBJECTIVE: This study is the second part of a 2-phase study aimed at developing a method for immediate detection of paroxysmal AF, using a wearable device with built-in photoplethysmography (PPG). The objective of this study is to develop an algorithm to immediately diagnose AF by an Apple Watch equipped with a PPG sensor that is worn by patients undergoing cardiac surgery and to use machine learning on the pulse data output from the device. METHODS: A total of 80 patients who underwent cardiac surgery at a single institution between June 2020 and March 2021 were monitored for postoperative AF, using a telemetry-monitored electrocardiogram (ECG) and an Apple Watch. AF was diagnosed by qualified physicians from telemetry-monitored ECGs and 12-lead ECGs; a diagnostic algorithm was developed using machine learning on the pulse rate data output from the Apple Watch. RESULTS: One of the 80 patients was excluded from the analysis due to redness caused by wearing the Apple Watch. Of 79 patients, 27 (34.2%) developed AF, and 199 events of AF including brief AF were observed. Of them, 18 events of AF lasting longer than 1 hour were observed, and cross-correlation analysis showed that pulse rate measured by Apple Watch was strongly correlated (cross-correlation functions [CCF]: 0.6-0.8) with 8 events and very strongly correlated (CCF>0.8) with 3 events. The diagnostic accuracy by machine learning was 0.9416 (sensitivity 0.909 and specificity 0.838 at the point closest to the top left) for the area under the receiver operating characteristic curve. CONCLUSIONS: We were able to safely monitor pulse rate in patients who wore an Apple Watch after cardiac surgery. Although the pulse rate measured by the PPG sensor does not follow the heart rate recorded by telemetry-monitored ECGs in some parts, which may reduce the accuracy of AF diagnosis by machine learning, we have shown the possibility of clinical application of using only the pulse rate collected by the PPG sensor for the early detection of AF.

Late open conversion after endovascular treatment for the coarctation of aorta in adult due to restenosis with thrombus.

A 22-year-old man was referred to our hospital for rib notching found on a radiograph and hypertension. Computed tomography revealed coarctation of the descending aortic isthmus. Because he refused open surgery, endovascular treatment was performed. The 2-year follow-up computed tomography scan showed infolding of the stent graft and thrombus formation. He had presented with intermittent claudication; therefore, graft interposition was performed. Endovascular surgery plays an important role in the treatment of coarctation of the aorta. However, insufficient dilatation can lead to restenosis accompanied by thrombus formation, and excess ballooning can cause aortic wall injury. Careful performance of the procedure and close postoperative follow-up are essential.

Development of an adenovirus-mediated reporter assay system to detect a low concentration of retinoic acid in MCF-7 cells.

Retinoic acid, an active form of vitamin A, plays very important roles in mammalian embryogenesis. The concentration of retinoic acid is extremely low and strictly regulated by enzymes of cytochrome P450 (CYP) family, CYP26s (CYP26A1, CYP26B1 and CYP26C1) in the cells. Therefore, it is thought that changes in CYP26s activities due to exposure to a wide variety of drugs and chemicals exhibit teratogenicity. In this study, to easily detect the changes in retinoic acid level, we constructed an adenovirus-mediated reporter assay system using the promoter region of the CYP26A1 gene and inserting retinoic acid response element (RARE) and retinoid X response element (RXRE) into the downstream of the luciferase gene of reporter plasmid, which highly increased the response to retinoic acid. Reporter activity significantly increased in a concentration-dependent manner with retinoic acid; this increase was also observed at least after treatment with a very low concentration of 1 nM retinoic acid. This increase was suppressed by the accelerated metabolism of retinoic acid due to the overexpression of CYP26A1; however, this suppression was almost completely suspended by treatment with talarozole, a CYP26 inhibitor. In conclusion, the reporter assay system constructed using the induction of CYP26A1 expression is a risk assessment system that responds to extremely low concentrations of retinoic acid and is useful for assessing the excess vitamin A mediated teratogenicity caused by various chemicals at the cellular level.

Functional Independence Measure Subtypes among Inpatients with Subacute Stroke: Classification via Latent Class Analysis.

Objectives: Using Functional Independence Measure (FIM) records, this study used latent class analysis (LCA) to clarify the structure of activities of daily living (ADL) status in patients following stroke. Methods: In this retrospective, single-center study, we extracted the medical records of patients with stroke who were admitted to a rehabilitation hospital in Japan between April 2018 and March 2020. LCA was used to determine classes of ADL status based on response patterns in FIM items converted from the original seven levels to three levels: Complete Dependence, FIM1-2; Modified Dependence, FIM3-5; Independence, FIM6-7. We compared the length of stay and discharge destinations among subgroups of patients with different ADL status at admission. Results: From 373 patients, 1592 FIM records were analyzed. These were classified into six ADL status classes based on "Complete Dependence," "Modified Dependence," and "Independence" in the motor and cognitive domains. Significant differences were observed among the six admission ADL subgroups for the length of stay (median values in patient subgroups based on admission ADL status: 126, 146, 90, 65, 44, and 29 days in the Motor Complete/Cognitive Complete, Motor Complete/Cognitive Modified, Motor Modified/Cognitive Modified, Motor Modified/Cognitive Independent, Motor Independent/Cognitive Modified, and Motor Independent/Cognitive Independent groups, respectively) and discharge destinations (patients discharged home: 27%, 62%, 81%, 92%, 95%, and 98%, respectively, and to acute care hospitals: 18%, 14%, 8%, 8%, 2%, and 2%, respectively). Conclusions: LCA successfully stratified ADL status in patients with stroke undergoing rehabilitation and may aid in determining an appropriate treatment regimen.

Differential immunostaining patterns of transient receptor potential (TRP) ion channels in the rat nodose ganglion.

Vagal afferents regulate numerous physiological functions including arterial blood pressure, heart rate, breathing, and nociception. Cell bodies of vagal afferents reside in the inferior vagal (nodose) ganglia and their stimulation by various means is being considered as a way to regulate cardiorespiratory responses and control pain sensations. Stimulation of the nodose by exposure to infrared light is recently being considered as a precise way to elicit responses. These responses would likely involve the activity of temperature-sensitive membrane-bound channels. While papers have been published to track the expression of these transient receptor potential ion channels (TRPs), further studies are warranted to determine the in situ expression of the endogenous TRP proteins in the nodose ganglia to fully understand their pattern of expression, subcellular locations, and functions in this animal model. TRP ion channels are a superfamily of Na+ /Ca2+ -channels whose members are temperature- and/or mechano-sensitive and therefore represent a potential set of proteins that will be activated directly or indirectly by infrared light. Here, we report the spatial localization of six TRP channels, TRPV1, TRPV4, TRPM3, TRPM8, TRPA1, and TRPC1, from nodose ganglia taken from juvenile male Sprague-Dawley rats. The channels were detected using immunohistology with fluorescent tags on cryosections and imaged using confocal microscopy. All six TRP channels were detected with different levels of intensity in neuronal cell bodies and some were also detected in axonal fibers and blood vessels. The TRP receptors differed in their prevalence, in their patterns of expression, and in subcellular expression/localization. More specifically, TRPV1, TRPV4, TRPA1, TRPM8, TRPC1, and TRPM3 were found in vagal afferent cell bodies with a wide range of immunostaining intensity from neuron to neuron. Immunostaining for TRPV1, TRPV4, and TRPA1 appeared as fine particles scattered throughout the cytoplasm of the cell body. Intense TRPV1 immunostaining was also evident in a subset of axonal fibers. TRPM8 and TRPC1 were expressed in courser particles suggesting different subcellular compartments than for TRPV1. The localization of TRPM3 differed markedly from the other TRP channels with an immunostaining pattern that was localized to the periphery of a subset of cell bodies, whereas a scattering or no immunostaining was detected within the bulk of the cytoplasm. TRPV4 and TRPC1 were also expressed on the walls of blood vessels. The finding that all six TRP channels (representing four subfamilies) were present in the nodose ganglia provides the basis for studies designed to understand the roles of these channels in sensory transmission within vagal afferent fibers and in the responses elicited by exposure of nodose ganglia to infrared light and other stimuli. Depending on the location and functionality of the TRP channels, they may regulate the flux of Na+ /Ca2+ -across the membranes of cell bodies and axons of sensory afferents, efferent (motor) fibers coursing through the ganglia, and in vascular smooth muscle.

Assessment of coding-based frailty algorithms for long-term outcome prediction among older people in community settings: a cohort study from the Shizuoka Kokuho Database.

OBJECTIVES: To assess the applicability of Electronic Frailty Index (eFI) and Hospital Frailty Risk Score (HFRS) algorithms to Japanese administrative claims data and to evaluate their association with long-term outcomes. STUDY DESIGN AND SETTING: A cohort study using a regional government administrative healthcare and long-term care (LTC) claims database in Japan 2014-18. PARTICIPANTS: Plan enrollees aged ≥50 years. METHODS: We applied the two algorithms to the cohort and assessed the scores' distributions alongside enrollees' 4-year mortality and initiation of government-supported LTC. Using Cox regression and Fine-Gray models, we evaluated the association between frailty scores and outcomes as well as the models' discriminatory ability. RESULTS: Among 827,744 enrollees, 42.8% were categorised by eFI as fit, 31.2% mild, 17.5% moderate and 8.5% severe. For HFRS, 73.0% were low, 24.3% intermediate and 2.7% high risk; 35 of 36 predictors for eFI, and 92 of 109 codes originally used for HFRS were available in the Japanese system. Relative to the lowest frailty group, the highest frailty group had hazard ratios [95% confidence interval (CI)] of 2.09 (1.98-2.21) for mortality and 2.45 (2.28-2.63) for LTC for eFI; those for HFRS were 3.79 (3.56-4.03) and 3.31 (2.87-3.82), respectively. The area under the receiver operating characteristics curves for the unadjusted model at 48 months was 0.68 for death and 0.68 for LTC for eFI, and 0.73 and 0.70, respectively, for HFRS. CONCLUSIONS: The frailty algorithms were applicable to the Japanese system and could contribute to the identifications of enrollees at risk of long-term mortality or LTC use.

Celiac Artery Dissection and Retroperitoneal Hemorrhage in Median Arcuate Ligament Syndrome Treated With a Stent and Transcatheter Arterial Embolization: Preprocedural 4-Dimensional Computed Tomography Angiography Assessment.

A 61-year-old man presented with retroperitoneal hemorrhage caused by an aneurysm rupture of the pancreaticoduodenal arcade (PDA), and acute celiac artery dissection distal to celiac axis stenosis. Owing to the gradual growth of the false lumen, we planned to deploy a stent to the celiac artery dissection and embolize the PDA aneurysm. Prior to stent placement, we assessed the acute celiac artery dissection distal to the stenosis using four-dimensional computed tomography (CT) angiography through expiration/inspiration/expiration cycle. We diagnosed median arcuate ligament syndrome considering that the celiac axis showed a hooked narrowing at end-expiration, and the compression decreased at end-inspiration. Additionally, the true lumen distal to the stretched axis dilated in the inspiration phase. Therefore, we could advance a catheter into the true lumen during inspiration and successfully deploy a stent. Subsequently, laparoscopic median arcuate ligament release was performed after the stent deployment. A postoperative CT scan showed good patency in the stent, with disappearance of the blood filling the false lumen and with reduced celiac axis stenosis.

Do Community Social Capital and Built Environment Associate With Homebound in Older Adults? The JAGES Niigata Study.

BACKGROUND: Homebound status is one of the most important risk factors associated with functional decline and long-term care in older adults. Studies show that neighborhood built environment and community social capital may be related to homebound status. This study aimed to clarify the association between homebound status for community-dwelling older adults and community environment-including social capital and neighborhood built environment-in rural and urban areas. METHODS: We surveyed people aged 65 years and older residing in three municipalities of Niigata Prefecture, Japan, who were not certified as requiring long-term care. The dependent variable was homebound status; explanatory variables were community-level social capital and neighborhood built environment. Covariates were age, sex, household, marital status, socioeconomic status, instrumental activities of daily living, the Geriatric Depression Scale-15, self-rated health, number of diseases under care, and individual social capital. The association between community social capital or neighborhood built environment and homebound status, stratified by rural/urban areas, was investigated using multilevel logistic regression analysis. RESULTS: Among older adults (n = 18,099), the homebound status prevalence rate was 6.9% in rural areas and 4.2% in urban areas. The multilevel analysis showed that, in rural areas, fewer older adults were homebound in communities with higher civic participation and with suitable parks or pavements for walking and exercising. However, no significant association was found between community social capital or neighborhood built environment and homebound status for urban older adults. CONCLUSION: Community social capital and neighborhood built environment were significantly associated with homebound status in older adults in rural areas.

Determinant analysis and developing evaluation indicators of grade of execution score of double axel jump in figure skating.

A figure skating jump score is determined by the sum of the base value based on the difficulty and grade of execution (GOE) that indicates the performance quality. Therefore, performing a high-quality jump to obtain a high GOE is essential to win a competition. However, the relationship between the GOE and kinematic parameters remains unclear. We analysed the horizontal distance, vertical height, and landing speed of double axel jumps in the Ladies' Short Program at the 2019 World Championships. The highest GOE group had significantly larger horizontal distances than the middle and lower groups, while the landing speed and vertical height were not significantly different. A principal component regression analysis was conducted to clarify the contrast between the three variables affecting the GOE. The results showed that greater horizontal distance and landing speed compared to vertical height (component 1) and greater horizontal distance compared to landing speed (component 3) contributed to higher GOE. We divided skaters into four clusters using these two components and provided general GOE acquisition strategies for each cluster. Finally, to apply our results to the industry, we proposed two new evaluation indicators which are highly correlated with the two components and easy to interpret.

Automated endocardial cushion segmentation and cellularization quantification in developing hearts using optical coherence tomography.

Of all congenital heart defects (CHDs), anomalies in heart valves and septa are among the most common and contribute about fifty percent to the total burden of CHDs. Progenitors to heart valves and septa are endocardial cushions formed in looping hearts through a multi-step process that includes localized expansion of cardiac jelly, endothelial-to-mesenchymal transition, cell migration and proliferation. To characterize the development of endocardial cushions, previous studies manually measured cushion size or cushion cell density from images obtained using histology, immunohistochemistry, or optical coherence tomography (OCT). Manual methods are time-consuming and labor-intensive, impeding their applications in cohort studies that require large sample sizes. This study presents an automated strategy to rapidly characterize the anatomy of endocardial cushions from OCT images. A two-step deep learning technique was used to detect the location of the heart and segment endocardial cushions. The acellular and cellular cushion regions were then segregated by K-means clustering. The proposed method can quantify cushion development by measuring the cushion volume and cellularized fraction, and also map 3D spatial organization of the acellular and cellular cushion regions. The application of this method to study the developing looping hearts allowed us to discover a spatial asymmetry of the acellular cardiac jelly in endocardial cushions during these critical stages, which has not been reported before.

Identification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.

Drug-induced liver injury (DILI) is one of major causes of discontinuing drug development and withdrawing drugs from the market. In this study, we investigated chemical properties associated with DILI using in silico methods, to identify a physicochemical property useful for DILI screening at the early stages of drug development. Total of 652 drugs, including 432 DILI-positive drugs (DILI drugs) and 220 DILI-negative drugs (no-DILI drugs) were selected from Liver Toxicity Knowledge Base of US Food and Drug Administration. Decision tree models were constructed using 2,473 descriptors as explanatory variables. In the final model, the descriptor AMW, representing average molecular weight, was found to be at the first node and showed the highest importance value. With AMW alone, 276 DILI drugs (64%) and 156 no-DILI drugs (71%) were correctly classified. Discrimination with AMW was then performed using therapeutic category information. The performance of discrimination depended on the category and significantly high performance (>0.8 balanced accuracy) was obtained in some categories. Taken together, the present results suggest AMW as a novel descriptor useful for detecting drugs with DILI risk. The information presented may be valuable for the safety assessment of drug candidates at the early stage of drug development.