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The aim of this study was to determine the proportion of near-miss dispensing errors in hospital pharmacies in Japan. A prospective multi-center observational study was conducted between December 2018 and March 2019. The primary objective was to determine the proportion of near-miss dispensing errors in hospital pharmacy departments. The secondary objective was to determine the predictive factors for near-miss dispensing errors using multiple logistic regression analysis. The study was approved by the ethical committee at The Institute of Medical Sciences, University of Tokyo, Japan. A multi-center prospective observational study was conducted in 20 hospitals comprising 8862 beds. Across the 20 hospitals, we assessed data from 553 pharmacists and 53039 prescriptions. A near-miss dispensing error proportion of 0.87% (n = 461) was observed in the study. We found predictive factors for dispensing errors in day-time shifts: a higher number of drugs in a prescription, higher number of quantified drugs, such as liquid or powder formula, in a prescription, and higher number of topical agents in a prescription; but we did not observe for career experience level for clinical pharmacists. For night-time and weekend shifts, we observed a negative correlation of near-miss dispensing errors with clinical pharmacist experience level. We found an overall incidence of near-miss dispensing errors of 0.87%. Predictive factors for errors in night-time and weekend shifts was inexperienced pharmacists. We recommended that pharmacy managers should consider education or improved work flow to avoid near-miss dispensing errors by younger pharmacists, especially those working night or weekend shifts.

S1. The expression of CD137 on splenic CD8+ T cells and the expression of PD1 and CD137 on CD8+ TILs of tumor bearing mice. S2. Analysis of TILs. (A) CD137 expression of TILs and RLN cells. S3. Transfection of TCR cDNA into splenic T cells. S4. IFN-γ-induced expression of MHC class I molecules on the surface of B16F10 cells. S5. The IFN-γ-secretion of TIL-derived TCR-transduced spleen T cells. S6. The cytotoxicity of TIL-derived TCR-expressing T cells against unstimulated B16F10 cells. S7. A correlation between the INF-γ production and the cytotoxicity. S8. Transfection efficiency of TCR gene into splenic T cellsforin vivoexperiment. S9. MHC-restriction of TIL-derived TCR. (A) Expression of H-2Kband H-2Dbmolecules on H-2Kbor H-2DbcDNA-transfected B16F10 cells. S10. IFN-γ-induced expression of MHC class I molecules on the surface of cells. Supplementary Table 1. Clonally expanded populations in human cancer TILs

T-cell receptor (TCR) gene therapy is a promising next-generation antitumor treatment. We previously developed a single–T-cell analysis protocol that allows the rapid capture of paired TCRα and β cDNAs. Here, we applied the protocol to analyze the TCR repertoire of tumor-infiltrating lymphocytes (TIL) of various cancer patients. We found clonally expanded populations of T cells that expressed the same clonotypic TCR in 50% to 70% of CD137+CD8+ TILs, indicating that they responded to certain antigens in the tumor environment. To assess the tumor reactivity of the TCRs derived from those clonally expanded TILs in detail, we then analyzed the CD137+CD8+ TILs from the tumor of B16F10 melanoma cells in six C57BL/6 mice and analyzed their TCR repertoire. We also found clonally expanded T cells in 60% to 90% of CD137+CD8+ TILs. When the tumor reactivity of dominant clonotypic TCRs in each mouse was analyzed, 9 of 13 TCRs induced the secretion of IFNγ in response to, and showed killing of, B16F10 cells in vitro, and 2 of them showed strong antitumor activity in vivo. Concerning their antigen specificity, 7 of them reacted to p15E peptide of endogenous murine leukemia virus-derived envelope glycoprotein 70, and the rest reacted to tumor-associated antigens expressed on EL4 lymphoma as well as B16 melanoma cells. These results show that our strategy enables us to simply and rapidly obtain the tumor-specific TCR repertoire with high fidelity in an antigen- and MHC haplotype–independent manner from primary TILs. Cancer Immunol Res; 6(4); 378–88. ©2018 AACR.

Supplementary Figure 6 from Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA

Supplementary Tables 1-5 from Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA

Supplementary Methods from Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA

Supplementary Figure 5 from Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA

Supplementary Figure and Table Legends from Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA

Supplementary Figures 1-4 from Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA

Crop field trials were conducted to investigate the residues of sprayed pesticides on the different sizes of tomatoes. Pesticide residue data in tomatoes varied due to different locations of the three crop fields selected and/or physicochemical properties of the three pesticides tested. The pesticide residue levels in the medium- and small-sized tomatoes were 1.5 and 2.4 times higher than the level in large-sized tomatoes under similar spray conditions, whereas amount of pesticides adhered per unit surface area were approximately equal among all three sizes of tomatoes. The results of this study suggested that the differences in pesticide residue levels were due to differences in the degree of specific surface area of each tomato size. Resultant residue data of medium-sized tomatoes demonstrated a proportional relationship between pesticide residue levels and the specific surface area of tomatoes.

natriuretic peptide is associated with myocardial fibrosis in animal models and among patients with heart disease. However, it remains unclear whether serum N-terminal pro-B-type peptide (NT-proBNP) levels are associated with histopathologically proven myocardial fibrosis among individuals without apparent heart disease. This study aimed to evaluate the association between serum NT-proBNP levels and the histopathologically estimated myocardial fibrotic area in autopsied samples from a community.we selected 63 cases without apparent heart disease with available data of serum NT-proBNP concentrations within six years before death (average age: 82 years; male: 52%) from autopsied cases in a community, and evaluated the percentage areas of myocardial fibrosis in four cardiac segments from each case (i.e. 252 cardiac segments in total). The association between serum NT-proBNP levels and the percentage area of myocardial fibrosis was estimated using a linear mixed model for repeated measures.serum NT-proBNP levels were positively correlated with myocardial fibrotic area [Pearson's correlation coefficient: r = 0.49 (95% confidence interval: 0.28-0.66), p 0.001]. Serum NT-proBNP levels were significantly associated with the percentage areas of myocardial fibrosis after adjusting for potential confounding factors. There was no evidence of heterogeneity in the association between the subgroups with and without reduced estimated glomerular filtration rate (60 mL/min/1.73 mthe present study demonstrated that elevated serum NT-proBNP levels were associated with the histopathologically measured myocardial fibrotic area in autopsied cases from a community. These findings may help clarify the association between elevated serum NT-proBNP levels and myocardial fibrosis and their influence on prognosis.

Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition with no established treatment. Intravenous immunoglobulin (IVIG) is a unique therapy with both anti-inflammatory and anti-infective effects. Therefore, we hypothesized that IVIG may have a positive effect on AE of interstitial pneumonia. This study aimed to determine the effect of IVIG in patients with AE of fibrotic idiopathic interstitial pneumonias (IIPs), including IPF.We retrospectively analyzed consecutive patients who were diagnosed with AE of fibrotic IIPs and treated with pulse corticosteroid therapy (methylprednisolone 500-1000 mg/day for 3 days) between April 2018 and May 2021 at Kagawa Rosai Hospital and KKR Takamatsu Hospital.This study included 52 patients with AE of fibrotic IIPs (IPF,41; fibrotic IIPs other than IPF,11). Thirteen patients received IVIG (5 g/day for 3-5 days) concurrently with pulse corticosteroid therapy. The remaining 39 patients were assigned to the control group. The survival rate on day 90 was significantly higher in the IVIG group than that in the control group (76.9% vs. 38.5%, p = 0.02). IVIG administration (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.02-0.69; p = 0.02) and C- reactive protein (OR, 1.19; 95% CI, 1.06-1.33, p0.01) were independently associated with 90-day mortality.The results indicate that administration of IVIG may improve the survival of patients with AE of fibrotic IIPs. We are now conducting a prospective study to confirm the effect of IVIG on AE of IPF since May 2022 (jRCT1061220010).

Objective Many cancer patients need for new treatment options with lower side effects. Herein, we report on the antitumor effect of thujopsene derived from the volatile components of Thujopsis dolabrata (asunaro). Methods The antitumor effect of the asunaro essential oil was analyzed using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay and in vivo cancer metastasis model. Thujopsene was isolated from asunaro essential oil by liquid chromatography, and the tumor growth inhibitory mechanism of thujopsene was assessed using Western blotting and DARTS (Drug affinity responsive target stability) analysis. Results The volatile components of asunaro essential oil exhibited an antitumor effect on MCF7 and SKBR3 breast cancer cells as well as on MKN45 gastric and DLD1 colon cancer cells. Thujopsene was identified as an antitumor factor that tended to have a stronger tumor growth inhibitory effect. Pyruvate kinase M2 (PKM2) was found to be associated with thujopsene in cancer cells. The reaction of thujopsene with MKN45 cells reduced intracellular lactate production. These results indicate that thujopsene binds to PKM2 in cancer cells and inhibits the nutritional metabolic pathway, and causing apoptosis. In conclusion, thujopsene may suppress tumor growth and metastasis by inhibiting the trophic metabolism pathway of cancer cells.

BACKGROUND Atrial fibrillation (AF) is a common arrhythmia in the elderly, and causes complications such as cardioembolic stroke. Serum high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation, has been reported to be a risk factor for developing AF in Western countries. However, few community-based studies have examined this issue in general Asian populations.Methods and Results:A total of 2,510 community-dwelling Japanese participants aged ≥40 years without a history of AF were divided into 4 groups according to the sex-specific quartiles of serum hs-CRP concentrations (Q1, lowest and Q4, highest) and followed up for 24 years. The hazard ratios and their 95% confidence intervals for the development of AF were estimated using a Cox proportional hazards model. During the follow up, 234 subjects developed AF. The risk of AF increased significantly with elevating serum hs-CRP levels after adjustment for potential confounding factors (hazard ratio [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.26 [0.83-1.92]; Q3, 1.77 [1.18-2.66]; and Q4, 1.89 [1.24-2.86]; P for trend

Introduction Serum N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels have been associated with the progression of kidney impairment among patients with chronic kidney disease (CKD), but only a few studies have investigated the association between serum NT-proBNP levels and incident CKD in general populations. Methods A total of 2486 Japanese community-dwelling residents ≥40 years of age without CKD at baseline were followed up by repeated annual health examinations for 10 years. Participants were divided into 4 groups according to serum NT-proBNP levels. CKD was defined as an estimated glomerular filtration rate (eGFR), Graphical abstract

Objectives To investigate the association of loneliness and its component subscales with the risk of dementia in a general Japanese older population. Method A total of 1,141 community-dwelling Japanese residents aged ≥65 years without dementia were prospectively followed up for a median 5.0 years. We evaluated any loneliness and its component subscales—namely, social and emotional loneliness—by using the 6-item de Jong Gierveld Loneliness Scale. Cox proportional hazards models were used to estimate hazard ratios (HRs) of each loneliness type on the risk of dementia controlling for demographic factors, lifestyle factors, physical factors, social isolation factors, and depression. Results During the follow-up, 114 participants developed dementia. The age- and sex-adjusted incidence rate of dementia was significantly greater in participants with any loneliness and emotional loneliness than those without. The multivariable-adjusted HRs (95% confidence intervals) of participants with any loneliness and emotional loneliness on incident dementia were 1.61 (1.08–2.40) and 1.65 (1.07–2.54), respectively, as compared to those without. However, there was no significant association between social loneliness and dementia risk. In subgroup analyses of social isolation factors, excess risks of dementia associated with emotional loneliness were observed in participants who had a partner, lived with someone, or rarely communicated with relatives or friends, but such association was not significant in participants who had no partner, lived alone, or frequently communicated with friends or relatives. Discussion The present study suggested that loneliness, especially emotional loneliness, was a significant risk factor for the development of dementia in the general older population in Japan.

Background: Bevacizumab (BEV) + Paclitaxel (PTX) and Eribulin represent the most frequently agents for the treatment of HER2-negative metastatic breast cancer (MBC). Eribulin has improved overall survival (OS) in EMBRACE trials. On the other hand, BEV has improved progression free survival (PFS) in several clinical studies, but not revealed prolongation of OS in them. There are difficult situations in making a clinical decision of when to choose which treatment option.Purpose: The purpose of this study is to compare two treatment strategies, Eribulin followed by BEV + PTX versus BEV + PTX followed by Eribulin. We evaluated whether sequential order of treatment affects survival benefit in patients who have been treated with both BEV + PTX and Eribulin in the real world. Methods: All patients who started BEV + PTX and Eribulin treatment for MBC from Aug-2011 to Jun-2018 were selected. Among 264 patients recorded in the TBCRG (14 institutions of Research Group) database, 180 patients had HER2-negative MBC. Of these, 84 patients were treated with both BEV + PTX and Eribulin sequentially regardless of treatment line. To evaluate the influence of sequential order, we compared the efficacy of Eribulin followed by BEV + PTX (arm E-B) to treatment with the reverse sequence (arm B-E). We used the two different analytical approaches to rubstify the findings from this study. Results: 38 patients were treated with E-B and 46 patients with the B-E sequence. We analyzed 60 cases within 3rd-line. In the entire cohort, the median time to failure of strategy (TFS) was 9.9 and 16.8 months in arm E-B and arm B-E, respectively (HR = 0.503, 95%CI 0.298-0.889, p=0.017). The respective median OS was 17.2 and 28.0 months (HR = 0.663, 95%CI 0.349-1.261. p=0.21). Similar HRs were derived from the PSMA and IPTWA cohort in TFS. Using PSMA, TFS was 9.0 and 14.1 months in arm E-B and arm B-E, respectively (HR = 0.406, 95%CI 0.172-0.955, p=0.039). The respective median OS was 12.8 and 24.0 months (HR = 0.61, 95%CI 0.232-1.6, p=0.315). Using IPTWA, TFS was 10.2 and 14.8 months in arm E-B and arm B-E, respectively (HR = 0.621, 95%CI 0.423-0.913, p=0.015). The respective median OS was 17.5 and 24.0 months (HR = 0.86, 95%CI 0.547-1.352, p=0.513).Conclusion: These results suggest that when patients with HER2-negative MBC are treated with both BEV + PTX and Eribulin, patients with prior BEV + PTX treatment is more likely to show more significant difference in results benefit than patients who are treated with prior Eribulin treatment. Citation Format: Koshi Matsui, Mitsuharu Earashi, Takuya Nagata, Akemi Yoshikawa, Wataru Fukushima, Zensei Nozaki, Yasuko Tanada, Kaeko Oyama, Katsuo Shimada, Kaoru Kiyohara, Tetsuro Shimizu, Keiko Iwata, Toru Yoshida, Kiichi Maeda, Akiyoshi Nakakura, Satoshi Morita, Tsutomu Fujii. Effect of Bevacizumab and Eribulin for metastatic breast cancer in the real world evaluated using the propensity score matching analysis (PSMA) and inverse probability of treatment weighting analysis (IPTWA) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-12.

The importance of genetic counseling has been noted for hereditary breast cancer. We report the cases of two 32-year-old woman, unmarried, BRCA mutation-positive patients.In Case 1, the chief complaint was awareness of a right breast mass. There was a family history of breast cancer(3 previous cases in the family). The BRCA2 mutation was positive during the BRACAnalysis test. Right breast mastectomy and axillary dissection were performed. Genetic counseling was performed postoperatively, and her eggs were cryopreserved. In Case 2, the chief complaint was calcification of the right breast. She also had a family history of breast cancer(3 previous cases in the family). The BRCA1 mutation was positive during the BRACAnalysis test. Nipple-sparing mastectomy and sentinel lymph node biopsy were performed, and the pathological diagnosis was DCIS. After genetic counseling, she did not desire the cryopreservation of her eggs.In these cases, the histological type, stage, subtype, BRCA mutation site, etc., were different from each other, and detailed support by genetic counseling was taken according to each medical condition such as surgery and postoperative adjuvant therapy.

INTRODUCTION Glioblastoma is a brain tumor with a very poor prognosis that is highly resistant to treatment. Hiba (Thujopsis dolabrata) has been used as a building material because of its insect repellent effect and refreshing fragrance. In this study, we analyzed the antitumor effects of thujopsen, which is contained in the essential oil of hiba, and investigated its antitumor aroma therapy.Methods and RESULTS We investigated the anti-tumor aroma effect of hiba essential oil on glioblastoma cells (U251, T98G), gastric cancer cells (MKN45), and breast cancer cells (MCF7). The anti-tumor effect of hiba essential oil varied depending on the carcinoma, with strong inhibition of cell proliferation observed in MKN45, U251, and T98G cells. Hinokitiol in hiba essential oil has been reported to have antitumor effects, and we isolated and identified a new antitumor factor, thujopsene, by liquid chromatography analysis. In tumor cell proliferation assays, thujopsen inhibited tumor cell proliferation more rapidly and potently than hinokitiol. Comparing the reach of the two compounds, hinokitiol showed a broader anti-tumor effect than thujopsen. The expression of caspase-3 and caspase-9 was increased by thujopsen, and DARTS analysis identified PKM2 as an intracellular binding protein of thujopsen. DISCUSSION The present study revealed that thujopsen induces apoptosis via caspase-3 and caspase-9. Furthermore, unlike hinokitiol, thujopsen was suggested to exhibit antitumor effects mediated by PKM2. CONCLUSION Thujopsen is a low molecular weight compound and easily evaporates into the air, it is expected to be applied to a new glioblastoma therapy using "aroma".

Introduction The optimal indication for the nucleic acid amplification test (NAAT) in areas with low endemicity for coronavirus disease 2019 (COVID-19) is unclear. This study aimed to identify patients who should undergo the NAAT for COVID-19 diagnosis. Methods We retrospectively analyzed the clinical data of patients with suspected COVID-19 who underwent NAAT between October 5, 2020, and May 31, 2021 in our institution. Results A total of 1238 patients were enrolled and NAAT positive results were observed in 40 patients (3.2%). The NAAT positivity rate was 34.3% (23/67) in patients with a history of close contact and 1.5% (17/1171) in patients without a history of close contact. Olfactory/gustatory dysfunction and a history of stay in other prefectures were independent risk factors of COVID-19 in patients without a history of close contact. On the other hand, the NAAT positivity rate was only 0.7% (8/1073) in patients without olfactory/gustatory dysfunction and a history of stay in other prefectures. Among them, the group without respiratory symptoms/sign had only one NAAT-positive case (0.1%: 1/1073). Conclusions This study revealed that a history of close contact, olfactory/gustatory dysfunction, and a history of stay in other prefectures are key eligibility criteria for NAAT in areas with relatively few patients with COVID-19. On the other hand, NAAT may not be necessary in cases without all of these factors and respiratory symptoms/sign.