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BACKGROUND/AIM Chemotherapy for acute leukemia includes agents known to cause hepatotoxicity. This study evaluated the role of monoammonium glycyrrhizinate for the prevention of hepatotoxicity after the first methotrexate-containing intrathecal chemotherapy (ITC) in children and adolescents with leukemia. PATIENTS AND METHODS Patients with newly diagnosed acute leukemia (age 0-18 years) who received ITC during the first week of induction therapy at our hospital between April 2016 and March 2021 were enrolled. Intravenous monoammonium glycyrrhizinate (IVMG) was defined as the intravenous administration of monoammonium glycyrrhizinate initiated on the day before or the day of the first ITC. RESULTS Overall, 39 of 118 patients (33%) developed grade 3-4 hepatotoxicity. The inverse probability of treatment weighting logistic regression model showed that IVMG was not associated with the development of grade 3-4 hepatotoxicity (OR=1.9, 95%CI=0.808-4.468). CONCLUSION IVMG did not protect against the development of grade 3-4 hepatotoxicity after the first methotrexate-containing ITC for leukemia.

FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular- signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single in vivo agent using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO-7475/ABT-199 was even more potent in reducing leukemic burden and prolonging the survival of mice in both model systems. These results suggest that the ONO-7475/ABT-199 combination may be effective for AML therapy.

Introduction Tuberculin skin test (TST) has been used to diagnose tuberculosis (TB) and latent tuberculosis infection (LTBI). However, in Bacillus Calmette-Guerin (BCG) vaccinated patients, TST tends to produce false-positive results. According to the previous vaccination schedule, Japanese people were mandated to receive up to three doses of BCG-vaccine. The vaccination schedule was changed in 2003 and as per the new schedule, only infants are administered a dose of BCG vaccine. Our hypothesis is that this change can lead to a reduction in the cross-reaction to TST. Methods We evaluated the TST results obtained from 1097 recruits from six defense camps and 667 recruits from an air base. These TST data were divided into two groups according to the date of birth: a new group and an old group according to the BCG immunization schedule. We then analyzed positive and negative reaction of TST and erythema sizes. Results We confirmed that the change in BCG-vaccination schedule significantly decreased TST false-positive reaction (Pmeta = 1.4 × 10−18; risk ratio = 0.83; 95% confidence interval: 0.80–0.87) and erythema size (Pmeta = 1.1 × 10−4; mean difference = 6.6 mm; 95% confidence interval: 3.2 mm–9.9 mm). Conclusions We showed the reduction in BCG cross-reaction to TST, in the new BCG vaccination schedule group, compared to the old group, we also have extracted information on the improvement in the specificity of TST for LTBI and TB diagnosis, which resulted from BCG schedule change.

Kitchen elbow sign (KE-Sign) is a skin abnormality on the extensor side of the elbow and forearm that is often observed in patients with adult spinal deformity (ASD). The significance of KE-Sign in surgical cases was investigated. Overall, 114 patients with ASD treated with long spinal fusion were reviewed and divided into KE-Sign positive and negative groups. The preoperative and 1-year follow-up evaluations included radiographic parameters [C7 sagittal vertical axis (SVA), pelvic incidence (PI) and lumbar lordosis (LL)], the Oswestry Disability Index (ODI), visual analogue scales (VASs) for low back pain, leg pain, and satisfaction, and Short Form 36 questionnaire (SF-36). Multi-regression analysis was performed to identify patient satisfaction predictors and improvement in the ODI as dependent variables and preoperative background factors as independent variables. Preoperative characteristics showed no significant difference between both groups. Improvement in the ODI and VAS for satisfaction were significantly superior in the KE-Sign positive group. In multiple regression analysis, KE-Sign and preoperative ODI were significantly associated with improvement in the ODI; age, KE-Sign, preoperative low back pain VAS, and leg pain VAS were significantly associated with satisfaction. KE-Sign can be a predictor of better surgical outcomes in ASD patients.

Recently, the number of adult spinal deformity surgeries including sacroiliac joint fixation (SIJF) by using an S2 alar iliac screw or iliac screw has increased to avoid the distal junctional failure. However, we occasionally experienced patients who suffered from hip pain after a long instrumented spinal fusion. We hypothesized that long spinal fusion surgery including SIJF influenced the hip joint as an adjacent joint. The aim of this paper was to evaluate the association between spinal deformity surgery including SIJF and radiographic progression of hip osteoarthritis (OA). This study was retrospective cohort study. In total, 118 patients who underwent spinal fusion surgery at single center from January 2013 to August 2018 were included. We measured joint space width (JSW) at central space of the hip joint. We defined reduction of more than 0.5 mm/year in JSW as hip OA progression. The patients were divided into two groups depending on either a progression of hip osteoarthritis (Group P), or no progression (Group N). The number of patients in Group P and Group N was 47 and 71, respectively. Factor that was statistically significant for hip OA was SIJF (p = 0.0065, odds ratio = 7.1, 95% confidence interval = 1.6–31.6). There were no other significant differences by the multiple logistic regression analysis. This study identified spinal fixation surgery that includes SIJF as a predictor for radiographic progression of hip OA over 12 months. We should pay attention to hip joint lesions after adult spinal deformity surgery, including SIJF.

Background Airway complications are the most serious complications after anterior cervical decompression and fusion (ACDF) and can have devastating consequences if their detection and intervention are delayed. Plain radiography is useful for predicting the risk of dyspnea by permitting the comparison of the prevertebral soft tissue (PST) thickness before and after surgery. However, it entails frequent radiation exposure and is inconvenient. Therefore, we aimed to overcome these problems by using ultrasonography to evaluate the PST and upper airway after ACDF and investigate the compatibility between X-ray and ultrasonography for PST evaluation. Methods We included 11 radiculopathy/myelopathy patients who underwent ACDF involving C5/6, C6/7, or both segments. The condition of the PST and upper airway was evaluated over 14 days. The Bland–Altman method was used to evaluate the degree of agreement between the PST values obtained using radiography versus ultrasonography. The Pearson correlation coefficient was used to determine the relationship between the PST measurement methods. Single-level and double-level ACDF were performed in 8 and 3 cases, respectively. Results PST and upper airway thickness peaked on postoperative day 3, with no airway complications. The Bland–Altman bias was within the prespecified clinically nonsignificant range: 0.13 ± 0.36 mm (95% confidence interval 0.04–0.22 mm). Ultrasonography effectively captured post-ACDF changes in the PST and upper airway thickness and detected airway edema. Conclusions Ultrasonography can help in the continuous assessment of the PST and the upper airway as it is simple and has no risk of radiation exposure risk. Therefore, ultrasonography is more clinically useful to evaluate the PST than radiography from the viewpoint of invasiveness and convenience.

OBJECTIVEVarious surgical treatments have been reported for vertebral pseudarthrosis after osteoporotic vertebral fracture (OVF). However, the outcomes are not always good. The authors now have some experience with combined anterior-posterior short-segment spinal fusion (1 level above and 1 level below the fracture) using a wide-foot-plate expandable cage. Here, they report their surgical outcomes with this procedure.METHODSBetween June 2016 and August 2018, 16 consecutive patients (4 male and 12 female; mean age 75.1 years) underwent short-segment spinal fusion for vertebral pseudarthrosis or delayed collapse after OVF. The mean observation period was 20.1 months. The level of the fractured vertebra was T12 in 4 patients, L1 in 3, L2 in 4, L3 in 3, and L4 in 2. Clinical outcomes were assessed using the lumbar Japanese Orthopaedic Association (JOA) scale and 100-mm visual analog scale for low-back pain. Local kyphotic angle, intervertebral height, bone union rate, and instrumentation-related adverse events were investigated as imaging outcomes. The data were analyzed using the Wilcoxon signed-rank test.RESULTSThe mean operating time was 334.3 minutes (range 256–517 minutes), and the mean blood loss was 424.9 ml (range 30–1320 ml). The only perioperative complication was a superficial infection of the posterior wound that was cured by irrigation. The lumbar JOA score and visual analog scale value improved from 11.2 and 58.8 mm preoperatively to 20.6 and 18.6 mm postoperatively, respectively. The mean local kyphotic angle and mean intervertebral height were 22.6° and 28.0 mm, respectively, before surgery, −1.5° and 40.5 mm immediately after surgery, and 7.0° and 37.1 mm at the final observation. Significant improvement was observed in both parameters immediately after surgery and at the final observation when compared with the preoperative values. Intraoperative endplate injury occurred in 8 cases, and progression of cage subsidence of 5 mm or more was observed in 2 of these cases. Proximal junctional kyphosis was observed in 2 cases. There were no cases of screw loosening. No cases required reoperation due to instrument-related adverse events. Bone union was observed in all 14 cases that had CT evaluation.CONCLUSIONSThis short-segment fusion procedure is relatively minimally invasive, and local reconstruction and bone fusion have been achieved. This procedure is considered to be attempted for the surgical treatment of osteoporotic vertebral pseudarthrosis after OVF.

An effective method for monitoring the progress of rice wine fermentation (saccharification, glycolysis system, ethanol fermentation, and the TCA cycle) is required owing to the decreasing human resources in rice wine brewing and dramatically increasing export quantity of rice wine. This study aimed to develop an anion-exclusion/size-exclusion/reversed-phase chromatographic (AEC/SEC/RPC) separation protocol for the simultaneous determination of sugars, ethanol, inorganic, and organic acids for the effective monitoring of rice wine fermentation processes. Optimal chromatographic resolutions were obtained by the combination of a polymer-based size-exclusion column and H+-form weakly acidic cation-exchange resin column with a 20.0 mM phthalic acid eluent. The optimized AEC/SEC/RPC separation system determined 16 different species during rice wine fermentation in a single analysis. The developed AEC/SEC/RPC method demonstrated the below useful advantages for (1) evaluating the progress of rice wine fermentation; (2) evaluating the activity of brewing yeast from the behaviors of glucose, phosphate, and ethanol concentration; and (3) obtaining good correlation between the developed and official methods for monitoring glucose and ethanol. Consequently, several beneficial information was obtained for the process control of rice wine brewing by the developed method.

Background Baloxavir marboxil (baloxavir) is a new anti-influenza virus agent that is comparable to oseltamivir phosphate (oseltamivir). Since the efficacy of baloxavir in preventing household transmission of influenza is not well established, we compared the secondary household influenza virus transmission rates between patients on baloxavir vs oseltamivir. Methods Between October 2018 and March 2019, we enrolled index patients (diagnosed with influenza and treated with baloxavir or oseltamivir) and household members. The secondary attack rate of household members was compared between index patients treated with baloxavir vs oseltamivir. Risk factors of household transmission were determined using multivariate logistic analyses. Results In total, 169 index patients with influenza type A were enrolled. The median age was 27.0 (interquartile range; 11–57) years. The number of index patients treated with baloxavir and oseltamivir was 49 and 120, respectively. The secondary attack rate was 9.0% (95% confidence interval [CI]: 4.6–15.6) in the baloxavir group and 13.5% (95% CI: 9.8–17.9) in the oseltamivir group. In the multivariate analysis, independent risk factors were 0–6 years of age (odds ratio [OR] 2.78, 95% CI: 1.33–5.82, p p = 0.22). Conclusion The household secondary attack rate of influenza was comparable in patients treated with baloxavir vs oseltamivir. Therefore, baloxavir can be used as an alternative therapy to oseltamivir in reducing household transmission of influenza. Trial registration Patients in this study were retrospectively registered. https://www.tosei.or.jp/clinical/pdf/2_influenza.pdf.

We developed a new reinforcement technique, the Gorget-like Cuddling (GOCU) suture, to prevent suture line bleeding during aortic surgery. After continuous aortic anastomosis with thick outer felt, an additional 2-0 Ticron (Medtronic, Minneapolis, MN) suture is placed distal from the first suture line. This GOCU suture directly holds the needle holes. Wall tension on the anastomosis can also be reduced to prevent longitudinal dilatation of the aorta. This technique can contribute to hemostasis for a fragile aortic wall in cases like acute aortic dissection.

Purpose In order to detect cancer therapeutics-related cardiac dysfunction (CTRCD) early, we identified which drugs were to be monitored using signal detection and the package insert, and created and applied a protocol to address this. Methods Adverse event data recorded in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and January 2018 were used. Among small molecule tyrosine kinase inhibitors that are not described in the serious side-effects section of the package insert despite signal detection, tyrosine kinase inhibitors with severe side-effects in the background of cases reported by JADER database were selected to be monitored in clinical practice. We applied our findings clinically by creating a protocol to detect CTRCD early. All cases at Tosei General Hospital where the target tyrosine kinase inhibitors were administered from when they were first released in November 2019 were included. We compared the results from before and after we began the protocol to clarify its effects. Results We found that CTRCD was not described in the serious side-effect section of the package inserts for Bosutinib, Alectinib, and Osimertinib even though CTRCD signals were detected for them. Therefore, it is possible that we may have previously overlooked CTRCD. When we applied our protocol using Osimertinib as the target drug, we were able to detect CTRCD early in 5/21 (24%) patients. Conclusions It was clarified that the drug identification method used in this study for early detection of adverse events leads to early detection of adverse events when applied clinically.

Purpose:Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non–small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475.Experimental Design:We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR-mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs.Results:ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI–tolerant cells. In the cell line–derived xenograft models of AXL-overexpressing EGFR-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib.Conclusions:These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.

Monitoring of several sets of neuroblastoma-associated mRNAs (NB-mRNAs) by real-time quantitative PCR (qPCR) can be used to evaluate minimal residual disease in NB patients. Droplet digital PCR (ddPCR) is an adaption of qPCR that potentially provides simpler and more reproducible detection of low levels of mRNAs. However, whether minimal residual disease in NB patients can be monitored by ddPCR using a set of NB-mRNAs is not yet tested. In this study, 208 bone marrow (BM) and 67 peripheral blood samples were retrospectively collected from 20 high-risk NB patients with clinical disease evaluation at two Japanese centers between 2011 and 2018, and level of each NB-mRNA (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was determined by ddPCR. Level of 7NB-mRNAs (defined as the combined signature of each NB-mRNA) was higher in BM than peripheral blood, but correlated significantly with each other. In accordance with disease burden, it varied with disease status (remission, stable, or progression) and collection time point (diagnosis, treatment, post-treatment, or relapse). In 73 post-treatment BM samples, it was significantly higher in 17 relapsed/regrown samples than in 56 nonrelapsed/nonregrown samples. Furthermore, ddPCR had a better prognostic value than qPCR in detecting 7NB-mRNAs in the same 73 post-treatment BM samples. This study suggests that ddPCR detection of 7NB-mRNAs is significantly associated with tumor relapse/regrowth in high-risk NB patients.

Manual polishing has been commonly applied as finishing process for metal molds with complicated-shape, but it takes a long time to achieve required surface roughness. Thus, high-efficient polishing method and surface smoothing in micro-areas are required for precise molds. Therefore, the reduction method of surface roughness for metal mold was experimentally investigated by controlling the pulse duration and the waveform in microsecond pulsed Nd:YAG laser irradiation of 532 nm wavelength, which can achieve stable absorption of laser energy even for difficult-to-weld materials with high reflectance. The maximum height roughness can be reduced from 4.0 μm to 1.0 μm by setting an appropriate pulse duration. Excessive heat input generates the edge at the circumference of laser irradiated area due to the movement of molten material. However, control of pulse duration enables the reduction of edge formation. Shorter pulse duration from 2.0 μs to 4.5 μs can perform a wider range of power density without edge formation, compared with longer pulse duration. The range of power density without edge formation can be increased by controlling the temporal input power, which can improve the process controllability of surface smoothing of mold material.

Background Dural arteriovenous fistulas (DAVF) complicate intracranial hemorrhages that are secondary to cortical venous reflux (CVR). Clinicians usually pay attention to CVR but not to other uncommon etiologies in hemorrhagic cases. Here, we report the rare case of a ruptured pial feeder aneurysm arising from the posterior inferior cerebellar artery (PICA) that was successfully treated with endovascular surgery. Case description An 81-year-old man was transferred to the emergency department of our hospital because of sudden onset of vertigo and vomiting. Head computed tomography showed a hyperdense area of up to 2.6 cm in the cerebellar vermis, intraventricular hemorrhage in the fourth ventricle, and subarachnoid hemorrhage in the cerebellopontine cistern. Digital subtraction angiography (DSA) showed a torcular DAVF. CVR was observed in the bilateral cerebellar veins (Borden type 3, Cognard type 4). DSA revealed a small aneurysm in the vermian branch of the left PICA feeding the DAVF. Because the aneurysm was arising from the vermian branch itself, we decided to occlude it with 12.5% N-butyl-2-cyanoacrylate. The vermian branch harboring the aneurysm was successfully obliterated. Rebleeding did not occur postoperatively. Conclusions The CVR is a common etiology of intracranial hemorrhage caused by DAVF. However, clinicians should be aware that the pial feeder may also contribute to hemorrhagic complications. Our case illustrates the significance of the existence of the pial feeder in hemorrhagic DAVF and the potential contribution of an aneurysm arising from the pial feeder to the etiology. Care should be taken not to overlook the pial feeder on radiologic imaging, and appropriate surgical management should be performed to prevent rupture.

Background Although there are reports on the effectiveness of microendoscopic laminotomy using a spinal endoscope as decompression surgery for lumbar spinal stenosis, predicting the improvement of low back pain (LBP) still poses a challenge, and no clear index has been established. This study aimed to investigate whether microendoscopic laminotomy for lumbar spinal stenosis improves low back pain and determine the preoperative predictors of residual LBP. Methods In this single-center retrospective study, we examined 202 consecutive patients who underwent microendoscopic laminotomy for lumbar spinal stenosis with a preoperative visual analog scale (VAS) score for LBP of ≥40 mm. The lumbar spine Japanese Orthopaedic Association (JOA), and VAS scores for LBP, leg pain (LP), and leg numbness (LN) were examined before and at 1 year after surgery. Patients with a 1-year postoperative LBP-VAS of ≥25 mm composed the residual LBP group. The preoperative predictive factors associated with postoperative residual LBP were analyzed. Results JOA scores improved from 14.1 preoperatively to 20.2 postoperatively (p p p p p = 0.005), preoperative VAS for LBP ≥ 70 mm (OR, 2.19; 95% CI, 1.17–4.08; p = 0.014), and female sex (OR, 1.98; 95% CI, 1.09–3.89; p = 0.047) were preoperative predictors of residual LBP. Conclusion Microendoscopic decompression surgery had an ameliorating effect on LBP in lumbar spinal stenosis. Modic type 1 change, preoperative VAS for LBP, and female sex were predictors of postoperative residual LBP, which may be a useful index for surgical procedure selection.

All the botulinum type A neurotoxins available for clinical use are of the A1 subtype. We developed a subtype A2 low-molecular-weight (150 kD (kilo Dalton)) neurotoxin (A2NTX) with less spread and faster entry into the motor nerve terminal than A1 in vitro and in vivo. Preliminary clinical studies showed that its efficacy is superior to A1 toxins. We conducted an open study exploring its safety and tolerability profile in comparison with A1LL (LL type A1 toxin, or onabotulinumtoxinA) and a low-molecular-weight (150 kD) A1 neurotoxin (A1NTX). Those who had been using A1LL (n = 90; 50–360 mouse LD50 units) or A1NTX (n = 30; 50–580 units) were switched to A2NTX (n = 120; 25–600 units) from 2010 to 2018 (number of sessions ~27, cumulative doses ~11,640 units per patient). The adverse events for A2NTX included weakness (n = 1, ascribed to alcoholic polyneuropathy), dysphagia (1), local weakness (4), and spread to other muscles (1), whereas those for A1LL or A1NTX comprised weakness (n = 2, A1NTX), dysphagia (8), ptosis (6), local weakness (7), and spread to other muscles (15). After injections, 89 out of 120 patients preferred A2NTX to A1 for the successive sessions. The present study demonstrated that A2NTX had clinical safety up to the dose of 500 units and was well tolerated compared to A1 toxins.

All the available botulinum type A neurotoxins for clinical uses are of A1 subtype. We developed a subtype A2 low molecular weight (150kD) neurotoxin (A2NTX), with less spread and faster entry into the motor nerve terminal than A1 in vitro and in vivo. Preliminary clinical studies showed its efficacy superior to A1 toxins. We conducted an open study exploring its safety and tolerability profile in comparison with A1LL (onabotulinumtoxinA) and low molecular weight (150kD) A1 neurotoxin (A1NTX). Those who had been using A1LL (n=90; 50-360 mouse LD50 units) or A1NTX (n=30; 50-580 units) were switched to A2NTX (n=120; 25-600 units) from 2010 till 2018 (number of sessions ~ 27, cumulative doses ~11,640 units per patient). Adverse events for A2NTX included weakness (n=1, ascribed to alcoholic polyneuropathy), dysphagia (1), local weakness (4), spread to other muscles (1), whereas those for A1LL or A1NTX comprised weakness (n=2, A1NTX), dysphagia (8), ptosis (6), local weakness (7) and spread to other muscles (15). After injections, 89 out of 120 patients preferred A2NTX to A1 for the successive sessions. The present study demonstrated that A2NTX had the clinical safety up to the dose of 500 units, and was well tolerated compared to A1 toxins.

In this article, we propose a new concept of information and communication technology on eduinformatics in higher education. Eduinformatics is a novel field of education that combines both education and informatics. Eduinformatics not only deals with students’ data but also provides new analysis methods and concepts to handle data in education, similar to bioinformatics. In September 2020, a subcommittee for universities from the Ministry of Education, Culture, Sports, Science, and Technology in Japan shared a perspective of the connection between education and research in universities in the future. In this paper, we assess our research question on how to connect education and research in universities to enhance the quality of higher education. To investigate this question, we introduce two practical examples from Kobe Tokiwa University in Japan, and we present results of recent eduinformatics. From these examples, we find that Information and Communication Technology (ICT) is the connection between education and research.

Background The premamillary artery (PMA) usually arises from the posterior communicating artery. Thus, an internal carotid artery (ICA) origin for PMA is rare. We report a rare case of a patient who presented with subarachnoid hemorrhage resulting from kissing aneurysms arising from the origin of the anterior choroidal artery and the aberrant origin of PMA and was successfully treated with coil embolization. Case Description A conscious and alert 36-year-old woman arrived at our hospital with a severe headache. Computed tomography (CT) of the head showed a thin subarachnoid hemorrhage. CT angiography revealed kissing aneurysms arising from the ICA. Digital subtraction angiography showed that these kissing aneurysms had arisen from the anterior choroidal artery and the aberrant origin of the PMA. Endovascular coil embolization was performed for both aneurysms. Her clinical course was good, and she was discharged from our hospital 20 days after admission. Conclusions To the best of our knowledge, the present study is the first report of a ruptured saccular PMA aneurysm arising from ICA that was successfully treated with coil embolization. Three-dimensional digital subtraction angiography and cone-beam CT were useful for confirming the precise vasculature of the PMA.

Aim To investigate the characteristics of adverse drug reactions (ADR) and their risk factors among very old patients in five geriatric wards in Japan. Methods A retrospective observational multicenter study was carried out to investigate factors related to ADR in older inpatients from geriatric wards of five university hospitals in Japan. Data including drugs profile and short-form comprehensive geriatric assessment were obtained from medical charts. ADR were identified from geriatrician's reports. For each ADR, symptoms and causal drugs were clarified, and factors associated with ADR were analyzed statistically. Results In 1155 patients (52.5% women, mean age 82.8 ± 7.0 years), the proportion with ADR was 15.4%. There was a great variety of signs and symptoms of ADR, and a great variety of drugs suspected to be the cause of ADR. On multiple logistic regression analysis, ADR was significantly associated with an increase in drugs (odds ratio 1.11, 95% CI 1.07-1.16) and emergency admission (odds ratio 2.76, 95% CI 1.82-4.15). Receiver operating characteristic curve analysis showed that the optimal cut-off number of drugs for predicting ADR was ≥7. Conclusions In geriatric inpatients, polypharmacy (especially ≥7 drugs) and emergency admission were associated with ADR. Because there was a great variety of ADR in the study, clinicians must consider reviewing all drugs to prevent adverse drugs reactions during admission in this vulnerable population. Geriatr Gerontol Int 2019; ••: ••-••. Geriatr Gerontol Int 2020; 20: 144-149.

Patients often take several different medications for multiple conditions concurrently. Therefore, when adverse drug events (ADEs) occur, it is necessary to consider the mechanisms responsible. Few approaches consider the mechanisms of ADEs, such as changes in physiological states. We proposed that the ontological framework for pharmacology and mechanism of action (pharmacodynamics) we developed could be used for this approach. However, the existing knowledge base contains little data on physiological chains (PCs). We aimed to investigate a method for automatically generating missing PC from the viewpoint of anatomical structures. This study was conducted to determine dysuria-related adverse events more likely to occur during multidrug administration. We adopted a systematic approach to determine drugs suspected to cause adverse events and incorporated existing data and data generated in our newly developed method into our ontological framework. The performance of automated data generation was evaluated using this newly developed system. Suspected drugs determined by the system were compared with those derived from adverse events databases. Of the 242 drugs involving suspected drug-induced urinary retention or dysuria, 26 suspected drugs were determined. Of these, five were drugs with side effects not listed in drug package inserts. The system derived potential mechanisms of action, PCs, and suspected drugs. Our method is novel in that it generates PC data from anatomical structural properties and could serve as a knowledge base for determining suspected drugs by potential mechanisms of action.

3-[3-Amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)-phenyl]-propionic acid (AK106-001616) is a novel, potent, and selective inhibitor of the cytosolic phospholipase A2 (cPLA2) enzyme. Unlike traditional nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors, AK106-001616 reduced prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production by stimulated cells. The suppression of PGE2 and LTB4 production was also confirmed using an air pouch model in rats administered a single oral dose of AK106-001616. AK106-001616 alleviated paw swelling in a rat adjuvant-induced arthritis (AIA) model. The maximum effect of the inhibitory effect of AK106-001616 was comparable with that of naproxen on paw swelling in a rat AIA model. Meanwhile, the inhibitory effect of AK106-001616 was more effective than that of naproxen in the mouse collagen antibody-induced arthritis model with leukotrienes contributing to the pathogenesis. AK106-001616 dose dependently reversed the decrease in paw withdrawal threshold not only in rat carrageenan-induced hyperalgesia, but also in a rat neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI). However, naproxen and celecoxib did not reverse the decrease in the paw withdrawal threshold in the CCI model. Furthermore, AK106-001616 reduced the disease score of bleomycin-induced lung fibrosis in rats. In addition, AK106-001616 did not enhance aspirin-induced gastric damage in fasted rats, increase blood pressure, or increase the thromboxane A2/ prostaglandin I2 ratio that is thought to be an underlying mechanism of thrombotic cardiovascular events increased by selective cyclooxygenase-2 inhibitors. Taken together, these data demonstrate that oral AK106-001616 may provide valuable effects for wide indications without attendant gastrointestinal and cardiovascular risks.

Nerve root injury can occur in complex spine surgeries. Recording transcranial motor-evoked potentials (TcMEPs) has been the most popular method to monitor motor function during surgery. However, TcMEPs cannot detect single nerve root injury satisfactorily. Recently, multi-train stimulation (MTS) was demonstrated to effectively enhance TcMEPs. The aim of this study was to investigate the utility of TcMEPs elicited by MTS for intraoperative nerve root monitoring. TcMEPs were recorded from the quadriceps femoris (QF) and gastrocnemius (GC) muscles in the hindlimbs of 20 rats before and after transection of the nerve root at L6 (dominant root innervating the GC). For MTS, a multipulse (train) stimulus was delivered repeatedly at 5 Hz. The change ratio of the amplitude after transection of the nerve root was compared between MTS and conventional single-train stimulation (STS). The change in TcMEP amplitudes for QF after transection of the nerve root at L6 was 97.8 ± 12.2% with MTS and 100.1 ± 7.2% with STS (p = 0.496), whereas that for GC was 40.6 ± 11.5% with MTS and 64.8 ± 8.8% with STS (p

Municipalities in Japan have various urban problems such as traffic accidents, illegally parked bicycles, and noise pollution. However, using these data to solve urban problems is difficult, as these data are not structurally constructed. Hence, we aim to construct the Linked Data set that will facilitate the solving of urban problems. In this paper, we propose a method for semi-automatic construction of Linked Data with the causality of urban problems, based on Web pages and open government data. Specifically, we extracted causal relations using natural language processing and crowdsourcing to include problem causality in the Linked Data. Then, we provided an example query to confirm the relationships between several problems. Finally, we discussed our crowdsourcing task design for extracting urban problem causality.

In recent years, Bulk heterojunction organic solar cells (BHJ OSCs) based small molecules take leading position of industrialization for their considerable opto-electronic properties and uncomplicated fabrication process. Materials based on cyclopentadithiophene (CPDT) have been widely used thanks to their interesting structural and electronic characteristics. Here we report a combined experimental and theoretical investigation of a CPDT-based material namely 6,6′-(2,5-bis (hexyloxy)-1,4-phenylene) bis(2-methyl −4H- cyclopenta [2,1-b:3,4-b'] dithiophen-4-one) (CPDT-alt-BHP) as donor small molecule in a BHJ OSC. The synthesized molecule shows a rigid and planar structure with small band gap energy. The electronic properties have been investigated by means of Density Functional Theory (DFT) at B3LYP/6-31g(d) level of theory. The studied molecule displayed an optical absorption in the visible region with $\lambda\_\text{max}=404$ nm. Transition density matrix (TDM) plot was carried out to get insight into the hole-electron coherences at the first excited state. The photovoltaic parameters of CPDTBHP:[70]PCBM system were simulated using wxAMPS software. The designed BHJ OSC exhibited respectable fill factor (FF) of 81.13%, short-circuit current density (Jsc) of 6.089 mA cm-2 and power conversion efficiency (PCE) of 4.922%. The studied compound offers significant structural and optoelectronic properties that could be enhanced via judicious molecular tuning.

Geriatric syndromes are symptoms and signs, such as falls, incontinence, delirium, pressure ulcers, dysphagia and so on, that often threaten the independence of older adults, rather than the disease itself. Although the syndromes are very common in older people, it is difficult to treat those by modern medicine due to their complexity. To mitigate the intractable geriatric symptoms, we review the efficacy of aromatherapy, especially for dysphagia, dyspnea, cognitive dysfunction and falls in geriatric syndrome. Olfactory stimulation using a volatile black pepper oil on institutional residents improved the swallowing reflex, which is a crucial risk factor of aspiration pneumonia. Brain imaging study showed that olfactory stimulation using volatile black pepper oil activated cerebral regions of the anterior cingulate and the insular cortex, which play a role in controlling appetite and swallowing. Also, aromatherapy with volatile l-menthol decreased the sense of dyspnea and improved the efficacy of exercise therapy. The fragrance of the combination of rosemary and lemon oils in the morning, and the combination of lavender and orange oils in the night-time were reported to improve cognition and behavioural and psychological symptoms of dementia, respectively. Also, the combination of lavender and lemon balm oils was reported to be effective for irritability-related agitation in older adults. Furthermore, aromatherapy with lavender fragrance could improve both static and dynamic balance, resulting in a reduction in the number of fallers and the incidence rate in older people. Thus, aromatherapy is a promising remedy for geriatric syndrome. Geriatr Gerontol Int 2021; 21: 377-385.

Since the end of 2019, a life-threatening infectious disease (coronavirus disease 2019: COVID-19) has spread globally, and numerous victims have been reported. In particular, older persons tend to suffer more severely when infected with a novel coronavirus (SARS-CoV-2) and have higher case mortality rates; additionally, outbreaks frequently occur in hospitals and long-term care facilities where most of the residents are older persons. Unfortunately, it has been stated that the COVID-19 pandemic has caused a medical collapse in some countries, resulting in the depletion of medical resources, such as ventilators, and triage based on chronological age. Furthermore, as some COVID-19 cases show a rapid deterioration of clinical symptoms and accordingly, the medical and long-term care staff cannot always confirm the patient's values and wishes in time, we are very concerned as to whether older patients are receiving the medical and long-term care services that they wish for. It was once again recognized that it is vital to implement advance care planning as early as possible before suffering from COVID-19. To this end, in August 2020, the Japan Geriatrics Society announced ethical recommendations for medical and long-term care for older persons and emphasized the importance of conducting advance care planning at earlier stages. Geriatr Gerontol Int 2020; 20: 1112-1119.

Despite the growing evidences that immune dysfunction contributes to tumor progression, the prognostic value in patients with neuroblastoma regarding circulating immune blood cell counts has not been well characterized. To answer this, we conducted a retrospective study to evaluate the prognostic value of the circulating immune cell counts at diagnosis in a cohort of 55 patients with neuroblastoma. Based on a novel index by multiplying the absolute monocyte count (AMC)/μl and absolute lymphocyte count (ALC)/μl, we sub-grouped patients with AMC × ALC ≥ 1 × 106 (/μl)2 as high group and patients with AMC × ALC < 1 × 106 (/μl)2 as low group. In the entire cohort, the 4-year progression-free survival (PFS), and overall survival (OS) for high group (n = 38) vs low group (n = 17) was 81.7% (95%CI; 63.6–91.3%) and 90.7% (95%CI; 73.8–96.9%) vs 31.7% (11.6–54.1%) and 56.5% (29.7–76.4%; p < 0.001 for PFS and p = 0.015 for OS), respectively, suggesting that a low AMC × ALC is associated with poor prognosis. In the subgroup analysis for high-risk patients, the 4-year PFS and OS for high group (n = 17) vs low group (n = 13) was 59.8% (31.2–79.7%) and 79.8% (49.4–93.0%) vs 8.5% (0.5–31.7%) and 42.0% (15.4–66.8%; p < 0.001 for PFS and p = 0.089 for OS), respectively. Our data demonstrate that AMC × ALC at diagnosis is a cost-effective and easily measurable biomarker for predicting prognosis in neuroblastoma.

STUDY DESIGN This was a retrospective cohort study. OBJECTIVE The objective of this study was to characterize the long-term clinical and radiographic results of articular segmental decompression surgery using endoscopy [cervical microendoscopic laminotomy (CMEL)] for cervical spondylotic myelopathy (CSM) and to compare outcomes to conventional expansive laminoplasty (ELAP). SUMMARY OF BACKGROUND DATA The spinal cord compression in CSM consists of a pincer mechanism due to bulging disk and a hypertrophied ligamentum flavum. The long-term clinical benefits of segmental decompression surgery, which removes the dorsal compressive elements of articular segment in CSM patients, have not yet been elucidated. MATERIALS AND METHODS Consecutive patients with CSM who required surgical treatment were enrolled. All enrolled patients (n=81) underwent CMEL or ELAP. All patients were followed postoperatively for >5 years. The preoperative and 5-year follow-up evaluation included neurological assessment [Japanese Orthopaedic Association (JOA) score], JOA recovery rates, axial neck pain (visual analog scale), and cervical sagittal alignment (C2-C7 subaxial cervical angle). RESULTS Sixty-four patients (CMEL group: 33, ELAP group: 31) were included for analysis. The preoperative JOA score was 10.1 points in the CMEL group and 11.1 points in the ELAP group (P=0.15). The JOA recovery rates were similar, 58.6% in the CMEL group and 55.2% in the ELAP group (P=0.55). The axial neck pain in the CMEL group was significantly lower than that in the ELAP group (P

Background Neurogenic origin intermittent claudication is typically caused by lumbar spinal canal stenosis. However, there are few reports of intermittent claudication caused by cervical spinal cord compression. Case presentation We present the case of a 75-year-old woman who presented with intermittent claudication. She had a history of lumbar spinal fusion surgery, but there was no sign of lumbar spinal stenosis. She also reported bilateral thigh pain on cervical extension. Electromyogram (EMG), posture-induced test, myelogram, and post-myelogram dynamic computed tomography (CT) were performed. Myelography and post-myelogram dynamic CT in the cervical extension position showed narrowing of the subarachnoid space; the patient reported pain in the front of the both thigh during the procedure. We performed an electromyogram (EMG), which implied neurogenic changes below the C5 level. Based on these results, we diagnosed cervical spinal cord compression and underwent laminoplasty at C4–6 including dome-like laminectomy, which significantly relieved the thigh pain and enabled her to walk for 40 minutes. Conclusions In this case, funicular pain presented as leg pain, but was resolved by the decompression of the cervical spinal cord. Funicular pain has various characteristics without any upper extreme symptom. This often leads to errors in diagnosis and treatment. We avoid the misdiagnosis by evaluating post-myelogram dynamic CT compared between flexion and extension. In cases of intermittent claudication, clinicians should keep in mind that cervical cord compression could be a potential cause.

This prospective observational study analyzed the pharmacokinetics of busulfan in Japanese children and evaluated the predicting accuracy of previous pediatric PPK models of busulfan. This study enrolled five patients (aged 2-12 years, BW 14-48 kg) receiving a busulfan-based conditioning regimen for hematopoietic stem cell transplantation at our hospital between January 2017 and December 2018. All patients received a 2-hour intravenous busulfan infusion four times daily for a total of 16 doses. After the infusions, 51 plasma samples were collected with the plasma busulfan concentration measured by liquid chromatography-tandem mass spectrometry. PPK model fitting was analyzed using the (%MPE) and the (%MAPE). Limited sampling strategies for estimating busulfan AUC were also evaluated. High interpatient variability was observed in the PK parameters. The most suitable PPK model that reflected our data was McCune's two-compartment model (%MPE -8.7, %MAPE 19.3). A combination sampling method using the busulfan concentration at 2 and 6 hours after the start of the first busulfan dose was found to be able to estimate AUC4 day . These results provide useful information on busulfan therapeutic drug monitoring in the Japanese pediatric population.

Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. Properties of three-dimensional tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a tumoroid-based screening system. We screened 6 pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The effects of one of the hit compounds were examined on tumor formation and progression in vitro and in vivo. Antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and properties of cancer stem cells / cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.

In this study, a three-dimensional (3D) micromanipulator mounted on a glass capillary is developed for handling biological samples, such as multicellular spheroids and embryos. To fabricate the micromanipulator, we developed an additive manufacturing system based on high-resolution microstereolithography using a 405-nm blue laser. The fabrication system makes it possible to fabricate 3D microstructures on a glass capillary with 2.5 &micro, m lateral resolution and 25 &micro, m layer thickness. We also demonstrated the capture and release of a spheroid with the micromanipulator fabricated using our additive manufacturing system. We showed that spheroids can be easily handled by a simple operation with minimal damage using a cage-like multiple finger structure. Additive manufacturing of tailor-made micromanipulators mounted on a glass capillary will be useful in biological and tissue engineering research.

A new challenge for knowledge graph reasoning started in 2018. Deep learning has promoted the application of artificial intelligence (AI) techniques to a wide variety of social problems. Accordingly, being able to explain the reason for an AI decision is becoming important to ensure the secure and safe use of AI techniques. Thus, we, the Special Interest Group on Semantic Web and Ontology of the Japanese Society for AI, organized a challenge calling for techniques that reason and/or estimate which characters are criminals while providing a reasonable explanation based on an open knowledge graph of a well-known Sherlock Holmes mystery story. This paper presents a summary report of the first challenge held in 2018, including the knowledge graph construction, the techniques proposed for reasoning and/or estimation, the evaluation metrics, and the results. The first prize went to an approach that formalized the problem as a constraint satisfaction problem and solved it using a lightweight formal method; the second prize went to an approach that used SPARQL and rules; the best resource prize went to a submission that constructed word embedding of characters from all sentences of Sherlock Holmes novels; and the best idea prize went to a discussion multi-agents model. We conclude this paper with the plans and issues for the next challenge in 2019.

Background X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immune deficiency, which is caused by SH2D1A gene mutations. XLP1 is commonly associated with Epstein–Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphoma. The only curative treatment for XLP1 is allogeneic hematopoietic cell transplantation. However, published data detailing the clinical course of, and indications for, allogeneic hematopoietic cell transplantation in asymptomatic patients with XLP1 is lacking. Although relevant family history could be useful in identifying patients with XLP1 before disease onset, no guidelines have been established on the management of asymptomatic patients with XLP1. Therefore, clinicians and families face dilemmas in balancing between the risk of waiting for the disease onset, and the risk of transplant-related mortality associated with allogeneic hematopoietic cell transplantation, which is often performed at a very young age. We first describe the detailed clinical course of an asymptomatic patient with XLP1 who successfully underwent allogeneic hematopoietic cell transplantation. Case presentation A boy was born at 39 weeks of gestation, weighing 3016 g at birth. He appeared fine, but he underwent genetic testing because his maternal cousin had XLP1. He was found to have a novel c.207_208insC (p.Pro70ProfsX4) mutation in exon 3 of SH2D1A, which was also found in his cousin. There was no HLA-identical donor in his family. Immunoglobulin was administered monthly to prevent EBV infection while searching for an alternative donor. He underwent allogeneic bone marrow transplantation (BMT) from an allele HLA 8/8 fully matched, unrelated donor with a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, melphalan, and low-dose total body irradiation (TBI) at 20 months of age. The patient has been doing well for 2 years post transplantation and maintaining complete donor chimerism without any evidence of chronic graft versus host disease. Conclusions We describe a case of an asymptomatic patient with XLP1, who successfully underwent unrelated BMT with RIC regimen consisting of fludarabine, melphalan, and 3 Gy TBI. That was well tolerated and successfully generated complete chimerism in every subpopulation. This case delineates the option of allogeneic hematopoietic cell transplantation even in asymptomatic patients with XLP1.