Aneurysmal bone cyst (ABC) is a locally destructive benign tumour-like condition of the bones with blood-filled cystic cavities. The talus is an extremely rare site for an ABC, with <20 reported cases till 2012 based on a PubMed database search. Aneurysmal bone cyst recurrence in the talus after curettage and bone grafting is extremely rare. To the best of our knowledge, no detailed reports of resection and adjuvant therapy with artificial bone packing of recurrent ABC of the talus have been published. We report a case of ABC in the talus of a 9-year-old boy. As the initial surgery consisted of only lesion resection and artificial bone (beta-tricalcium phosphate [TCP]) packing, local recurrence was diagnosed. Reoperation was performed 5 months after the initial surgery. The recurrent lesion was resected using a curette, and the bone cavity septum was shaved with a high-speed burr. Phenol-ethanol ablation was used as an adjuvant with artificial bone (beta-TCP) packing to prevent recurrence. No local recurrence was observed 36 months after the reoperation. This extremely rare case of resection and adjuvant therapy with artificial bone packing of recurrent ABC of the talus highlights the need for careful observation to assess the progression of ankle joint osteoarthrosis.

Intrathecal baclofen therapy can substantially improve symptoms in patients with severe spasticity owing to traumatic spinal cord injury, multiple sclerosis, cerebral paresis, or tethered cord syndrome. Problems associated with intrathecal catheters include migration, laceration, occlusion, or disconnection. Several case reports have described the management of catheter fragments. To the best of our knowledge, this is the first detailed report of the insertion of a new catheter. A 64-year-old Japanese man with spinal myoclonus was undergoing intrathecal baclofen therapy; his spasticity was well controlled with intrathecal baclofen therapy but worsened 13 years after pump implantation. Imaging revealed spinal catheter breakage, and the catheter was retained in the spinal canal. We inserted a new catheter through a different intervertebral space without removing the original catheter. Postoperatively, the spasticity remained well controlled with intrathecal baclofen therapy. This is the first detailed report on the insertion of a new catheter for intrathecal baclofen therapy at a different intervertebral space from the catheter breakage, without removal of the old intrathecal catheter.

Mitochondrial toxicity has been implicated in the development of various toxicities, including hepatotoxicity. Therefore, mitochondrial toxicity has become a major screening factor in the early discovery phase of drug development. Several models have been developed to predict mitochondrial toxicity based on chemical structures. However, they only provide a binary classification of positive or negative results and do not provide the substructures that contribute to a positive decision. Therefore, we developed an artificial intelligence (AI) model to predict mitochondrial toxicity and visualize structural alerts. To construct the model, we used the open-source software library kMoL, which employs a graph neural network approach that allows learning from chemical structure data. We also utilized the integrated gradient method, which enables the visualization of substructures that contribute to positive results. The dataset used to construct the AI model exhibited a significant imbalance, with significantly more negative than positive data. To address this, we employed the bagging method, which resulted in a model with high predictive performance, as evidenced by an F1 score of 0.839. This model can also be used to visualize substructures that contribute to mitochondrial toxicity using the integrated gradient method. Our AI model predicts mitochondrial toxicity based on chemical structures and may contribute to screening mitochondrial toxicity in the early stages of drug discovery.

BackgroundIntrathecal baclofen therapy can substantially improve symptoms in most patients with severe spasticity due to traumatic spinal cord injury, multiple sclerosis, or cerebral paresis. To the best of our knowledge, decompression surgeries at the intrathecal catheter insertion site in patients with a preexisting intrathecal pump for drug delivery have not been reported.Case presentationWe report the case of a 61-year-old Japanese man with lumbar spinal stenosis who underwent intrathecal baclofen therapy. We performed decompression for lumbar spinal stenosis at the intrathecal catheter insertion site during intrathecal baclofen therapy. The yellow ligament was removed by partial resection of the lamina under a microscope to avoid damage to the intrathecal catheter. The dura mater was distended. No obvious cerebrospinal fluid leakage was observed. Postoperatively, lumbar spinal stenosis symptoms improved, and spasticity remained well controlled with intrathecal baclofen therapy.ConclusionsThis is the first reported case of lumbar spinal stenosis decompression at an intrathecal catheter insertion site during intrathecal baclofen therapy. Preoperative preparation is necessary, as the intrathecal catheter may be replaced during surgery. We performed surgery without removing or replacing the intrathecal catheter, taking care not to damage the spinal cord by migrating the intrathecal catheter.

The interaction between sunlight and drugs can lead to phototoxicity in patients who have received such drugs. Phototoxicity assessment is a regulatory requirement globally and one of the main toxicity screening steps in the early stages of drug discovery. An in silico-in vitro approach has been utilized mainly for toxicology assessments at these stages. Although several quantitative structure-activity relationship (QSAR) models for phototoxicity have been developed, in silico technology to evaluate phototoxicity has not been well established. In this study, we attempted to develop an artificial intelligence (AI) model to predict the in vitro Neutral Red Uptake Phototoxicity Test results from a chemical struc-ture and its derived information. To accomplish this, we utilized an open-source software library, kMoL. kMoL employs a graph convolutional neural networks (GCN) approach, which allows it to learn the data for the specified chemical structure. kMoL also utilizes the integrated gradient (IG) method, enabling it to visually display the substructures contributing to any positive results. To construct this AI model, we used only the chemical structure as a basis, then added the descriptors and the HOMO-LUMO gap, which was obtained from quantum chemical calculations. As a result, the assortment of chemical structures and the HOMO-LUMO gap produced an AI model with high discrimination performance, and an F1 score of 0.857. Additionally, our AI model could visualize the substructures involved in phototoxicity using the IG method. Our AI model can be applied as a toxicity screening method and could enhance productivity in drug development.

[This corrects the article DOI: 10.1371/journal.pone.0201956.].

BACKGROUND:Simultaneous bilateral hip fractures without major trauma in the elderly are rare and usually symmetrical. To the best of our knowledge, only two cases of bilateral simultaneous asymmetric hip fracture in the elderly without major trauma have been reported.CASE PRESENTATION:We present the case of a 90-year-old Japanese man with simultaneous bilateral asymmetric hip fractures with trochanteric fracture on the right side and greater trochanteric fracture on the left side. He complained of dyspnea at midnight and was referred to our emergency department. He was admitted to the internal medicine department for bacterial pneumonia treatment. On the 8th day of hospitalization, he was referred to our orthopedic surgery department for hip pain and was found to have fractures of both hips. Computed tomography findings showed that the left femoral neck fracture was an old fracture, while the left greater trochanteric fracture and the right trochanteric fracture were fresh fractures. He was surgically treated through open reduction and internal fixation with an intramedullary nail on the right and hemiarthroplasty on the left in supine position, performed during the same surgical sessions on the 12th day of hospitalization.CONCLUSIONS:We report a new form of simultaneous bilateral asymmetric hip fracture in the elderly. The fracture types of the case were femoral trochanteric fracture and greater trochanteric fracture of the femur, which were different from the fracture types in the previously reported two cases. Clinicians should be aware of the possibility of simultaneous bilateral hip fractures, especially in the elderly.

This study aimed to investigate the relationship between endothelial nitric oxide synthase Glu(298)Asp gene polymorphism and hemorheological parameters. Red blood cell (RBC) deformability, aggregation were measured using an ectacytometry, whole blood, plasma viscosities were determined by a viscometer. Restriction fragment length polymorphism was used to detect polymorphism. Plasma nitrite, nitrate concentrations were determined by Griess method. The genotype distribution of the control group was as follows: 50 (67.5%) GG, 21 (28.4%) GT, 3 (4.1%) TT. A 48 (57.8%) of the patients with CAD had GG, 28 (33.7%) GT, 7 (8.5%) of them TT genotype. RBC aggregation index of CAD patients with G allele was higher and t½ lower compared to controls carrying the same allele. The amplitude of RBC aggregation of healthy subjects with T allele, who are under increased cardiovascular risk was lower compared to control subjects with G allele. The results of this study indicate that, alterations in RBC aggregation seem to be a consequence of CAD, more than being a preexisting cause. Additionally, some compensatory mechanisms by causing decrements in RBC aggregation, may help regulation of circulation in healthy individuals with high cardiovascular risk.

The principal physics results obtained in stellarator experiments are described together with the fundamental physics basis and the history. The stellarator is an alternative and promising concept of magnetic confinement fusion with certain advantages relative to the tokamak. A toroidal plasma current is not a prerequisite in stellarators unlike in tokamaks, since the confining magnetic field is generated only by external coils. This advantage greatly facilitates the requirements for a fusion reactor, such as stable steady-state-operation. Although the stellarator was invented earlier than the tokamak, the expansion of its parameter range, including the device scale, has lagged behind that of the tokamak because of the complexity of the three-dimensional magnetic configuration. However, recent progress in large stellarators, such as LHD and W7-X, is remarkable and encouraging.

Primary extradural spinal melanoma is a very rare lesion. Here, we report a thoracic extradural malignant melanoma in a 77-year-old male. MRI showed a dorsal spinal extradural tumour at the T6-T8 level. The tumour showed hyperintensity on T1W imaging and mixed hypointensity and hyperintensity on T2W imaging. Gadolinium-enhanced MRI showed high enhancement on the lesion. Information on imaging findings for extradural spinal melanoma appears very limited. We discuss the MRI findings from this case, which can be considered typical of extradural spinal melanoma and review the literature.

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.

In drug development, Drug-Induced Liver Injury (DILI) is a significant cause of discontinuation of development, and safety evaluation and management technology at early development stage are highly required. In recent years, toxicity prediction by in silico analysis is expected, and the machine learning research using omics data has attracted attention. However, the lack of explanation of machine learning is a problem. In order to make an appropriate safety assessment, it is necessary to clarify the mechanism of the toxicity (toxic course). In this study, we focus on the toxic course and propose an ontological model of the liver toxicity, which systematizes toxicity knowledge based on a consistent viewpoint. In application research, we introduce a prototype of a knowledge system for supporting toxicity mechanism interpretation. Based on the ontology, this system provides information flexibly according to the user's purpose by using semantic technologies. The system provides a graph visualization function in which nodes correspond to concepts and edges correspond to interactions between concepts. In such a visualization function, a toxic course map shows causal relationships of the toxic process. We illustrate examples of application to safety assessment and management by combining ontological and data-driven methodologies. Our ontological engineering solution contributes to converting from data to higher-order knowledge and making the data explainable in both human and computer understandable manner. We believe that our approach can be expected as a fundamental technology and will be useful for a wide range of applications in interdisciplinary areas.

Elucidating the mechanism of toxicity is crucial in drug safety evaluations. We focus on toxic processes and developed a toxic process ontology, designated TXPO. Here, we outline the TXPO, which systematizes toxic processes within the liver in a consistent manner. The TXPO makes processes explicit across granularity using a functional decomposition tree. Concerning the course of toxic processes, we present a framework of causal relationships between processes from latent to toxicity manifestation. In applied work, we introduce a prototype of TOXPILOT, a toxic process interpretable knowledge system. TOXPILOT provides visualization maps of the toxic course, which facilitates capturing the comprehensive picture for understanding toxicity mechanisms. Our ontological approach will help develop new knowledge regarding drug safety evaluations.

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.

Although microendoscopy-assisted lumbar discectomy for lateral or extraforaminal lumbar disc herniations via the lateral approach has previously been reported, microendoscopy-assisted lumbar discectomy for central or paramedian disc herniations via the lateral approach has not been reported.

Diethyl ether (ether) had been widely used in Japan for anesthesia, despite its explosive properties and toxicity to both humans and animals. We also had used ether as an anesthetic for euthanizing rats for research in the Toxicogenomics Project (TGP). Because the use of ether for these purposes will likely cease, it is required to select an alternative anesthetic which is validated for consistency with existing TGP data acquired under ether anesthesia. We therefore compared two alternative anesthetic candidates, isoflurane and pentobarbital, with ether in terms of hematological findings, serum biochemical parameters, and gene expressions. As a result, few differences among the three agents were observed. In hematological and serum biochemistry analysis, no significant changes were found. In gene expression analysis, four known genes were extracted as differentially expressed genes in the liver of rats anesthetized with ether, isoflurane, or pentobarbital. However, no significant relationships were detected using gene ontology, pathway, or gene enrichment analyses by DAVID and TargetMine. Surprisingly, although it was expected that the lung would be affected by administration via inhalation, only one differentially expressed gene was extracted in the lung. Taken together, our data indicate that there are no significant differences among ether, isoflurane, and pentobarbital with respect to effects on hematological parameters, serum biochemistry parameters, and gene expression. Based on its smallest affect to existing data and its safety profile for humans and animals, we suggest isoflurane as a suitable alternative anesthetic for use in rat euthanasia in toxicogenomics analysis.