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

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

AIR-COOLED MAGNETIC ALLOY CAVITY FOR J-PARC DOUBLED REP.-RATE SCENARIO

Abstract The upgrade project of the J-PARC MR (Main Ring) based on doubled repetition-rate scenario is in progress to deliver the beam power of 750 kW. The present RF section will be occupied by 9 sets of new magnetic alloy, FT3L, cavities using the direct water cooling scheme. The direct water cooling is the efficient scheme to cool the magnetic alloy core although it requires dedicated high-quality cooling water which does not contain copper oxide and copper ions because copper ions may cause the severe corrosion damage on the magnetic alloy cores. These cavities will be used for the fundamental RF for acceleration which requires high duty operation. The second harmonic RF is necessary to increase the bunch length. This allows to enlarge the beam current because it relaxes the space charge effects during the injection. Thanks to the high impedance FT3L and low duty operation of the second harmonic RF, the power loss in the second harmonic RF system becomes moderate. The air cooled cavity is designed to fit in any locations in the MR where the dedicated high-quality water is not available. This paper reports the design of the second RF system, technical issues to produce the magnetic alloy cores to fit the air cooling, and construction of the system

PERFORMANCE OF MULTI-HARMONIC RF FEEDFORWARD SYSTEM FOR BEAM LOADING COMPENSATION IN THE J-PARC RCS

Abstract The beam loading compensation is a key part for acceleration of high intensity proton beams in the J-PARC RCS. In the wide-band MA-loaded RF cavity, the wake voltage consists of not only the accelerating harmonic component but also the higher harmonics. The higher harmonic components cause the RF bucket distortion. We employ the RF feedforward method to compensate the multi-harmonic beam loading. The full-digital feedforward system is developed, which compensates the first three harmonic components of the beam loading. We present the results of the beam test with a high intensity proton beam (2.5 × 10 13 ppp). The impedance seen by the beam is greatly reduced, the impedance of the fundamental accelerating harmonic is reduced to less than 25 Ω in a full accelerating cycle, while the shunt resistance of the cavity is in the order of 800 Ω. The performance of the feedforward system is promising for achievement of the design beam power, 1 MW, in the future

Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion

不快感を誘発するセロトニン神経を発見 --セロトニン神経の多様性が明らかに--. 京都大学プレスリリース. 2022-12-23.Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli

Tim4- and MerTK-mediated engulfment of apoptotic cells by mouse resident peritoneal macrophages.

Apoptotic cells are swiftly engulfed by macrophages to prevent the release of noxious materials from dying cells. Apoptotic cells expose phosphatidylserine (PtdSer) on their surface, and macrophages engulf them by recognizing PtdSer using specific receptors and opsonins. Here, we found that mouse resident peritoneal macrophages expressing Tim4 and MerTK are highly efficient at engulfing apoptotic cells. Neutralizing antibodies against either Tim4 or MerTK inhibited the macrophage engulfment of apoptotic cells. Tim4-null macrophages exhibited reduced binding and engulfment of apoptotic cells, whereas MerTK-null macrophages retained the ability to bind apoptotic cells but failed to engulf them. The incubation of wild-type peritoneal macrophages with apoptotic cells induced the rapid tyrosine phosphorylation of MerTK, which was not observed with Tim4-null macrophages. When mouse Ba/F3 cells were transformed with Tim4, apoptotic cells bound to the transformants but were not engulfed. Transformation of Ba/F3 cells with MerTK had no effect on the binding or engulfment of apoptotic cells; however, Tim4/MerTK transformants exhibited strong engulfment activity. Taken together, these results indicate that the engulfment of apoptotic cells by resident peritoneal macrophages proceeds in two steps: binding to Tim4, a PtdSer receptor, followed by MerTK-mediated cell engulfment

Hypothalamic expression and moonlight-independent changes of Cry3 and Per4 implicate their roles in lunar clock oscillators of the lunar-responsive Goldlined spinefoot.

Lunar cycle-associated physiology has been found in a wide variety of organisms. Studies suggest the presence of a circalunar clock in some animals, but the location of the lunar clock is unclear. We previously found lunar-associated expression of transcripts for Cryptochrome3 gene (SgCry3) in the brain of a lunar phase-responsive fish, the Goldlined spinefoot (Siganus guttatus). Then we proposed a photoperiodic model for the lunar phase response, in which SgCry3 might function as a phase-specific light response gene and/or an oscillatory factor in unidentified circalunar clock. In this study, we have developed an anti-SgCRY3 antibody to identify SgCRY3-immunoreactive cells in the brain. We found immunoreactions in the subependymal cells located in the mediobasal region of the diencephalon, a crucial site for photoperiodic seasonal responses in birds. For further assessment of the lunar-responding mechanism and the circalunar clock, we investigated mRNA levels of Cry3 as well as those of the other clock(-related) genes, Period (Per2 and Per4), in S. guttatus reared under nocturnal moonlight interruption or natural conditions. Not only SgCry3 but SgPer4 mRNA levels showed lunar phase-dependent variations in the diencephalon without depending on light condition during the night. These results suggest that the expressions of SgCry3 and SgPer4 are not directly regulated by moonlight stimulation but endogenously mediated in the brain, and implicate that circadian clock(-related) genes may be involved in the circalunar clock locating within the mediobasal region of the diencephalon

Utility of TEMPS-A in differentiation between major depressive disorder, bipolar I disorder, and bipolar II disorder.

BACKGROUND:The association between temperament characteristics and mood disorders has gained much attention in recent years. The Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A) is a self-rating scale measuring 5 affective temperament dimensions. In this study, we aimed to clarify whether each affective temperament of TEMPS-A is a differentiating factor between major depressive disorder (MDD), bipolar I disorder (BD-I), and bipolar II disorder (BD-II), and analyzed the utility of TEMPS-A in their differential diagnosis in a clinical setting. METHODS:A total of 346 patients (MDD, n = 176; BD-II, n = 112; BD-I, n = 58) filled out TEMPS-A. To assess the patients' mood state at the time of temperament assessment, Patient Health Questionnaire-9 (PHQ-9) and Young Mania Rating Scale (YMRS) were also conducted. RESULTS:Multivariate logistic regression analysis demonstrated that cyclothymic and anxious temperament scores were significant factors differentiating the diagnosis of BD-I and BD-II from the diagnosis of MDD, and hyperthymic temperament score was a specific factor for the differential diagnosis of BD-I versus the diagnosis of BD-II. LIMITATIONS:All of the patients included in our study received treatment in large general hospitals. Because the nature of the present study was cross-sectional, some MDD subjects in this study might have unrecognized BD-I/BD-II. CONCLUSIONS:Cyclothymic and anxious temperament scores assessed by TEMPS-A might enable differentiation between MDD and BD, and hyperthymic temperament score on TEMPS-A might be useful in distinguishing between BD-I and BD-II

A novel C-domain-dependent inhibition of the rainbow trout CMP-sialic acid synthetase activity by CMP-deaminoneuraminic acid

International audienceThe CMP-sialic acid synthetase (CSS) activates free sialic acid (Sia) to CMP-Sia using CTP, and is prerequisite for the sialylation of cell surface glycoconjugates. The vertebrate CSS consists of two domains, a catalytic N-domain and a non-catalytic C-domain. Although the C-domain is not required for the CSS enzyme to synthesize CMP-Sia, its involvement in the catalytic activity remains unknown. First, the real-time monitoring of CSS-catalyzed reaction was performed by P NMR using the rainbow trout CSS (rtCSS). While a rtCSS lacking the C-domain (rtCSS-N) similarly activated both deaminoneuraminic acid (Kdn) and N-acetylneuraminic acid (Neu5Ac), the full-length rtCSS (rtCSS-FL) did not activate Kdn as efficiently as Neu5Ac. These results suggest that the C-domain of rtCSS affects the enzymatic activity, when Kdn was used as a substrate. Second, the enzymatic activity of rtCSS-FL and rtCSS-N was measured under various concentrations of CMP-Kdn. Inhibition by CMP-Kdn was observed only for rtCSS-FL, but not for rtCSS-N, suggesting that the inhibition was C-domain-dependent. Third, the inhibitory effect of CMP-Kdn was also investigated using the mouse CSS (mCSS). However, no inhibition was observed with mCSS even at high concentrations of CMP-Kdn. Taken together, the data demonstrated that the C-domain is involved in the CMP-Kdn-dependent inhibition of rtCSS, which is a novel regulation of the Sia metabolism in rainbow trout