Early Detection of Adverse Drug Reaction Signals by Association Rule Mining Using Large-Scale Administrative Claims Data

INTRODUCTION: Adverse drug reactions (ADRs) are a leading cause of mortality worldwide and should be detected promptly to reduce health risks to patients. A data-mining approach using large-scale medical records might be a useful method for the early detection of ADRs. Many studies have analyzed medical records to detect ADRs; however, most of them have focused on a narrow range of ADRs, limiting their usefulness. OBJECTIVE: This study aimed to identify methods for the early detection of a wide range of ADR signals. METHODS: First, to evaluate the performance in signal detection of ADRs by data-mining, we attempted to create a gold standard based on clinical evidence. Second, association rule mining (ARM) was applied to patient symptoms and medications registered in claims data, followed by evaluating ADR signal detection performance. RESULTS: We created a new gold standard consisting of 92 positive and 88 negative controls. In the assessment of ARM using claims data, the areas under the receiver-operating characteristic curve and the precision-recall curve were 0.80 and 0.83, respectively. If the detection criteria were defined as lift > 1, conviction > 1, and p-value < 0.05, ARM could identify 156 signals, of which 90 were true positive controls (sensitivity: 0.98, specificity: 0.25). Evaluation of the capability of ARM with short periods of data revealed that ARM could detect a greater number of positive controls than the conventional analysis method. CONCLUSIONS: ARM of claims data may be effective in the early detection of a wide range of ADR signals

Palmitate induces reactive oxygen species production and β-cell dysfunction by activating nicotinamide adenine dinucleotide phosphate oxidase through Src signaling.

[Aims/Introduction]Chronic hyperlipidemia impairs pancreatic β-cell function, referred to as lipotoxicity. We have reported an important role of endogenous reactive oxygen species (ROS) overproduction by activation of Src, a non-receptor tyrosine kinase, in impaired glucose-induced insulin secretion (GIIS) from diabetic rat islets. In the present study, we investigated the role of ROS production by Src signaling in palmitate-induced dysfunction of β-cells. [Materials and Methods]After rat insulinoma INS-1D cells were exposed to 0.6 mmol/L palmitate for 24 h (palmitate exposure); GIIS, ROS production and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity were examined with or without exposure to10 μmol/L 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a Src inhibitior, for 30 or 60 min. [Results]Exposure to PP2 recovered impaired GIIS and decreased ROS overproduction as a result of palmitate exposure. Palmitate exposure increased activity of NOX and protein levels of NOX2, a pathological ROS source in β-cells. Palmitate exposure increased the protein level of p47phox, a regulatory protein of NOX2, in membrane fraction compared with control, which was reduced by PP2. Transfection of small interfering ribonucleic acid of p47phox suppressed the augmented p47phox protein level in membrane fraction, decreased augmented ROS production and increased impaired GΙIS by palmitate exposure. In addition, exposure to PP2 ameliorated impaired GIIS and decreased ROS production in isolated islets of KK-Ay mice, an obese diabetic model with hyperlipidemia. [Conclusions]Activation of NOX through Src signaling plays an important role in ROS overproduction and impaired GΙIS caused by chronic exposure to palmitate, suggesting a lipotoxic mechanism of β-cell dysfunction of obese mice

AN ESTIMATION OF THERMODYNAMIC AND TRANSPORT PROPERTIES OF CRYOGENIC HYDROGEN USING CLASSICAL MOLECULAR SIMULATION

ABSTRACT In this paper, we estimated the thermodynamic and transport properties of cryogenic hydrogen using classical molecular simulation to clarify the limit of classical method on the estimation of those properties of cryogenic hydrogen. Three empirical potentials, the Lennard-Jones (LJ) potential, twocenter Lennard-Jones (2CLJ) potential, and modified Buckingham (exp-6) potential, and an ab initio potential model derived by the molecular orbital (MO) calculation were applied. Molecular dynamics (MD) simulations were performed across a wide density-temperature range. Using these data, the equation of state (EOS) was obtained by Kataoka&quot;s method, and these were compared with NIST (National Institute of Standards and Technology) data according to the principle of corresponding states. Moreover, we investigated transport coefficients (viscosity coefficient, diffusion coefficient and thermal conductivity) using time correlation function. As a result, it was confirmed that the potential model has a large effect on the estimated thermodynamic and transport properties of cryogenic hydrogen. On the other hand, from the viewpoint of the principle of corresponding states, we obtained the same results from the empirical potential models as from the ab initio potential, showing that the potential model has only a small effect on the reduced EOS: the classical MD results could not reproduce the NIST data in the high-density region. This difference is thought to arise from the quantum effect in actual liquid hydrogen. INTRODUCTION Currently liquid hydrogen is used as fuel for fuel cells and propellant for liquid rocket engines and the demand for liquid hydrogen is increasing. Therefore, it is very important to accurately ascertain the thermal flow phenomena which occur in the liquid hydrogen for safety and efficient use. Especially, in the case of analysis of nanoscale phenomena, molecular simulation is a powerful method. In recent years, studies that clarify the thermodynamic and transport properties of liquid hydrogen using molecular simulation [1-4] have attracted attention. It is possible to calculate macroscopic thermodynamic properties from the microscopic information using an intermolecular interaction. However there is a problem in the molecular simulation of liquid hydrogen. It is how to treat lowtemperature quantum effect. The rotational characteristic temperature of hydrogen is higher than those of other liquids, and the thermal de Broglie wavelength is on the same order as the molecular diameter of hydrogen. Therefore, it is not possible to simply apply the classical method to simulations of liquid hydrogen. Clearly, the non-classical approach for approximating quantum effects should be applied for such a system. It is especially desired in physics and chemistry to reproduce the time evolution of quantum many-body system, such as liquid hydrogen. Accordingly many studies of such simulations have been conducted and new methods have been propose

Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonists-induced orofacial dyskinesia

ジスキネジア新治療法の発見 --副作用を減らす併用薬から新しい創薬標的へ--. 京都大学プレスリリース. 2021-04-16.Antipsychotics often cause tardive dyskinesia, an adverse symptom of involuntary hyperkinetic movements. Analysis of the U.S. Food and Drug Administration Adverse Event Reporting System and JMDC insurance claims revealed that acetaminophen prevents the dyskinesia induced by dopamine D₂ receptor antagonists. In vivo experiments further showed that a 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) in rats, an effect that was inhibited by oral acetaminophen treatment or intracerebroventricular injection of N-(4-hydroxyphenyl)-arachidonylamide (AM404), an acetaminophen metabolite that acts as an activator of the transient receptor potential vanilloid 1 (TRPV1). In mice, haloperidol-induced VCMs were also mitigated by treatment with AM404 applied to the dorsal striatum, but not in TRPV1-deficient mice. Acetaminophen prevented the haloperidol-induced decrease in the number of c-Fos⁺/preproenkephalin⁺ striatal neurons in wild-type mice but not in TRPV1-deficient mice. Finally, chemogenetic stimulation of indirect-pathway medium spiny neurons in the dorsal striatum decreased haloperidol-induced VCMs. These results suggest that acetaminophen activates the indirect pathway neurons by activating TRPV1 channels via AM404

Primary Synovial Sarcoma of the Kidney

The case was a 40-year-old female. She visited a local doctor with a chief complaint of right side abdominal pain. A right kidney tumor measuring 10 cm in diameter was observed in an abdominal Computed Tomography (CT) scan. Based on the CT image, the possibility of angiomiolipoma (AML) could not be ruled out, but a high maximum standardized uptake value (SUVmax) of 7.8 was observed in a Positron Emission Tomography CT (PET-CT) scan and there was a possibility of malignancy. We therefore performed a transperitoneal right radial nephrectomy. Although adhesion of the tumor to the duodenum and the inferior vena cava was observed, it was possible to perform an excision. The tumor accounted for a large proportion of the excised kidney; the surrounding areas had taken on a cyst-like structure, and the interior comprised grayish brittle tissue exhibiting solid growth. Histologically, gland-like and cyst-like structures composed of cylindrical cuboidal cells and mainly characterized by the solid growth of short fusiform-shaped and oval-shaped basophilic cells were observed, and we believed it was a synovial sarcoma. There were no malignant findings in the adrenal gland. There have been approximately 30 reported cases around the world of synovial sarcoma that developed in the kidney, and we herein report this case with bibliographic considerations

骨盤底筋訓練による出産後尿失禁症状の消失例と非消失例の比較検討 : MR画像による骨盤底の形態学的評価

骨盤底筋訓練（訓練）の前後における骨盤底の支持構造の変化を、MR画像（MRI）を用いて失禁症状の消失群8例と非消失群3例の間で形態学的に比較検討した。分娩後4 か月以降継続する尿失禁には、膀胱頚部や尿道を支持する骨盤底筋群のダメージが大きいことを考慮する必要がある。T2強調横断像では、肛門中心部を通る横断面における左右肛門挙筋の内側の距離が訓練前・後とも非消失群が消失群より有意に長かった。したがって、この計測値が尿失禁の重症度の指標になる可能性が示唆された。また、非消失群は訓練により尿失禁量が改善したが症状が消失しなかった。遅筋用訓練の実施回数が10セットでは治療効果が少ないことが示唆された