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Aim: This retrospective cohort study aimed to compare the risk of serious infections in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor-α inhibitors (TNFαi) and interleukin-6 inhibitors (IL-6i), with no prior use of biological disease-modifying antirheumatic drugs (bDMARDs)., Methods: We employed the nationwide insurance claims database encompassing the years 2005 to 2018 in Japan. The inclusion criteria specified patients who were prescribed any type of bDMARDs, including TNFαi and IL-6i. The following exclusion criteria were applied: missing prescription dates, RA not diagnosed, below 16 years of age, bDMARDs prescribed within 6 months of registration, RA diagnosed post-bDMARDs prescription, and incidence of serious infections within 2 weeks before bDMARDs therapy. We applied stabilized inverse probability weights and utilized a Cox regression model to estimate the risk of serious infections associated with TNFαi and IL-6i., Results: The cohort of 2493 patients with RA was categorized into a TNFαi group and an IL-6i group of 2018 and 475 participants, respectively. The median follow-up duration (interquartile range) was 347 (147-820) days in the TNFαi group and 369 (149-838) days in the IL-6i group. In the inverse probability-weighted cohort, the incidence rates (95% confidence interval) of serious infections were 2.13 (1.65-2.71) and 3.25 (2.15-4.69) per 100 person-years for the TNFαi and IL-6i groups, respectively. The hazard ratio (95% confidence interval) comparing the TNFαi group to the IL-6i group was 0.66 (0.36-1.20, p = 0.168)., Discussion: The results underscore the lack of evidence to preferentially favor either TNFαi or IL-6i as later-line therapy in the management of bDMARDs-naive RA to mitigate the risk of serious infections., (© 2024 Pharmacotherapy Publications, Inc.)

We conducted a cross-sectional study of patient safety culture aimed at examining the factors that influence patient safety culture in university hospitals under a universal health insurance system. The Hospital Survey on Patient Safety Culture developed by the Agency for Healthcare Research and Quality was used. The survey was distributed to 1066 hospital employees, and 864 responded. The confirmatory factor analysis showed a good fit of the results to the 12-composites model. The highest positive response rates were for "(1) Teamwork within units" (81%) and "(2) Supervisor/manager expectations and actions promoting patient safety" (80%), and the lowest was for "(10) Staffing" (36%). Hayashi's quantification theory type 2 revealed that working hours per week had the greatest negative impact on patient safety culture. Under a universal health insurance system, workload and human resources might have a significant impact on the patient safety culture., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Japanese cultivated gentians are perennial plants that flower in early summer to late autumn in Japan, depending on the cultivar. Several flowering-related genes, including Gt FT1 and Gt TFL1 , are known to be involved in regulating flowering time, but many such genes remain unidentified. In this study, we obtained transcriptome profiling data using the Gentiana triflora cultivar 'Maciry', which typically flowers in late July. We conducted deep RNA sequencing analysis using gentian plants grown under natural field conditions for three months before flowering. To investigate diurnal changes, the plants were sampled at 4 h intervals over 24 h. Using these transcriptome data, we determined the expression profiles of leaves based on homology searches against the Flowering-Interactive Database of Arabidopsis . In particular, we focused on transcription factor genes, belonging to the BBX and MADS-box families, and analyzed their developmental and diurnal variation. The expression levels of representative BBX genes were also analyzed under long- and short-day conditions using in-vitro-grown seedlings, and the expression patterns of some BBX genes differed. Clustering analysis revealed that the transcription factor genes were coexpressed with Gt FT1 . Overall, these expression profiles will facilitate further analysis of the molecular mechanisms underlying the control of flowering time in gentians.

Migrants face several challenges in their daily lives in the host country due to limited knowledge about the language, culture, and social system of the host country. Their vulnerability increases in a time of crisis. During the COVID-19 pandemic, migrant communities were severely affected. Evidence on migrants' access to COVID-19-related information and services is limited. We conducted a qualitative, descriptive study among migrants from Vietnam, Myanmar, and Nepal living in Japan to explore the barriers and promoting factors for their access to health-related information, health services, and welfare services during the first wave of COVID-19. We used a thematic analysis to identify key themes according to the study's objectives. Further, these themes were assessed using an adapted version of the ecological model. The migrants mainly relied on the information available on social networking sites and were not aware of formal sources of information. Language was a major barrier, followed by cognitive bottlenecks and time constraints for migrants accessing health-related information and services. Social media, short-form information provided using their native language or plain Japanese and illustrations, and supportive people around could help them to access health-related information and services. The findings from this study demonstrate how migrants can represent a vulnerable group in a host country, even more so in a time of crisis.

Background: Previous studies have shown an association between hyperoxemia and mortality in patients with out-of-hospital cardiac arrest (OHCA) after cardiopulmonary resuscitation (CPR); however, evidence is lacking in the extracorporeal CPR (ECPR) setting., Objective: The aim of this study was to test the hypothesis that hyperoxemia is associated with poor neurological outcomes in patients treated by ECPR., Methods: The Japanese Association for Acute Medicine OHCA Registry is a multicenter, prospective, observational registry of patients from 2014 to 2017. Adult (18 years or older) patients who had undergone ECPR after OHCA were included. Eligible patients were divided into two groups based on the partial pressure of oxygen in arterial blood (PaO 2 ) levels at 24 h after ECPR: the high-PaO 2 group (n = 242) defined as PaO 2 ≥ 157 mm Hg (median) and the low-PaO 2 group (n = 211) defined as PaO 2 60 to < 157 mm Hg. The primary outcome was the favorable neurological outcome, defined as a Cerebral Performance Categories Scale score of 1 to 2 at 30 days after OHCA., Results: Of 34,754 patients with OHCA, 453 patients were included. The neurological outcome was significantly lower in the high-PaO 2 group than in the low-PaO 2 group (15.9 vs. 33.5%; p < 0.001). After adjusting for potential confounders, high PaO 2 was negatively associated with favorable neurological outcomes (adjusted odds ratio [aOR] 0.48; 95% confidence interval [CI] 0.24-0.97; p = 0.040). In a multivariate analysis with multiple imputation, high PaO 2 was also negatively associated with favorable neurological outcomes (aOR 0.63; 95% CI 0.49-0.81; p < 0.001)., Conclusions: Hyperoxemia was associated with worse neurological outcomes in OHCA patients with ECPR., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The profile of ceftriaxone-induced encephalopathy is not well understood., Aim: To identify risk factors associated with ceftriaxone-induced encephalopathy., Method: In this observational study, anonymised patient data were retrieved from the open-access Japanese Adverse Drug Event Report database for ceftriaxone users aged 20 years or higher., Results: Data of 256,788 individuals and 12,160 cases of encephalopathy were extracted, and 2,939 ceftriaxone users, of whom 193 had encephalopathy, were identified. A disproportionate prevalence of encephalopathy was observed among the ceftriaxone users (reported odds ratio = 1.42; 95% confidence interval [CI] = 1.23-1.65; p < 0.001). Multivariate logistic regression analysis of 2,057 ceftriaxone users showed encephalopathy was associated with female sex (odds ratio [OR] = 1.52; 95% CI, 1.05-2.19; p = 0.027), chronic kidney disease (OR = 2.32; 95% CI, 1.47-3.67; p < 0.001), a ceftriaxone dosage of > 2 g/day (OR = 2.66; 95% CI, 1.66-4.26; p < 0.001), and a treatment duration of > 14 days (OR = 1.94; 95% CI, 1.21-3.11; p = 0.006)., Conclusion: Patients with chronic kidney disease, receiving ceftriaxone at a dosage of > 2 g/day, being treated for over 14 days, and/or females may be at an increased risk of ceftriaxone-induced encephalopathy., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims: The delayed administration of epinephrine has been proven to worsen the neurological outcomes of patients with out-of-hospital cardiac arrest (OHCA) and shockable rhythm or asystole. We aimed to investigate whether the delayed administration of epinephrine might also worsen the neurological outcomes of patients with witnessed OHCA and initial pulseless electrical activity (PEA)., Methods and Results: The JAAM-OHCA Registry is a multicentre registry including OHCA patients between 2014 and 2017. Patients with emergency medical services (EMS)-treated OHCA and initial PEA rhythm were included. The primary exposure was the time from the EMS call to the administration of epinephrine. The secondary exposure was the time to epinephrine dichotomized as early (≤15 min) or delayed (>15 min). The primary outcome was the achievement of a favourable neurological outcome, defined as Cerebral Performance Categories Scale 1-2 at 30 days after OHCA. Out of 34 754 patients with OHCA, 3050 patients were included in the present study. After adjusting for potential confounders, the delayed administration of the epinephrine was associated with a lower likelihood of achieving a favourable neurological outcome [adjusted odds ratio (OR) 0.96; 95% confidence interval (CI) 0.93-0.99; P = 0.016]. The percentage of patients who achieved a favourable neurological outcome in the delayed epinephrine group was lower than that in the early epinephrine group (1.3% vs. 4.7%; adjusted OR 0.33; 95% CI 0.15-0.72; P = 0.005). A restricted cubic spline analysis demonstrated that delayed epinephrine administration could decrease the likelihood of achieving a favourable neurological outcome; this was significant within the first 10 min., Conclusions: The delayed administration of epinephrine was associated with worse neurological outcomes in patients with witnessed OHCA patients with initial PEA., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Pregabalin is a first-line treatment option for neuropathic pain. Recently, some cases of pregabalin-induced hypoglycemia have been reported, which can complicate the treatment of neuropathic pain and worsen patient outcomes. Therefore, a better understanding of the clinical condition of patients with pregabalin-induced hypoglycemia is desirable. In this study, we evaluated the risk of hypoglycemia in patients administered pregabalin, using the Japanese Adverse Drug Event Report database. All patients on pregabalin not taking any antidiabetic agents were screened from April 2004 to July 2020, and data on adverse events related to hypoglycemia, sex, age, weight, and the presence of chronic kidney disease were collected. Gabapentin and duloxetine, which are usually indicated for neuropathic pain, were used for comparison. Among 242 275 patients, 4287 were administered pregabalin, which included 37 patients who reported hypoglycemic incidents. Disproportionality of hypoglycemia was observed in patients administered pregabalin (reporting odds ratio, 2.25; 95%CI, 1.16-3.13; P < .01), whereas this was not the case in patients taking gabapentin and duloxetine. Multivariate logistic regression showed that hypoglycemia in patients on pregabalin was associated with age ≥70 years (odds ratio, 2.76; 95%CI, 1.29-5.91; P < 0.01) and weight <40 kg (odds ratio, 2.97; 95%CI, 1.32-6.71; P < 0.01). These findings suggest that pregabalin may be associated with a higher risk of hypoglycemia, especially in elderly individuals with low body weight. Health care providers may need to be aware of pregabalin-induced hypoglycemia in patients with these risk factors during therapy., (© 2021, The American College of Clinical Pharmacology.)

Introduction: Inadequate vaccine response is a common concern among healthcare workers at the frontlines of the COVID-19 pandemic. We aimed to investigate if healthcare workers with history of weak immune response to HBV vaccination are more likely to have weak responses against the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine., Methods: We prospectively tested 954 healthcare workers for the Anti-SARS-CoV-2 spike (S) protein antibody titers prior to the first and second BNT162b2 vaccination doses and after four weeks after the second dose using Roche's Elecsys® assay. We calculated the percentage of patients who seroconverted after the first and second doses. We estimated the relative risk of non-seroconversion after the first BNT162b2 vaccine (defined as anti-SARS-CoV-2-S titer <15 U/mL) among HBV vaccine non-responders (HBs-Ab titer <10 mIU/mL) and weak responders (≥10 and <100 mIU/mL) compared to normal responders (≥100 mIU/mL)., Results: Among 954 healthcare workers recruited between March 9 and March 24, 2021 at Osaka Medical and Pharmaceutical University, weak and normal HBV vaccine responders had comparable S-protein titers after the first BNT162b2 dose (51.4 [95% confidence interval 25.2-137.0] versus 59.7 [29.8-138.0] U/mL, respectively). HBV vaccine non-responders were more likely than normal responders to not seroconvert after a single dose (age and sex-adjusted relative risk 1.85 95% confidence interval [1.10-3.13]) although nearly all participants seroconverted after the second dose. After limiting the analysis to 382 patients with baseline comorbidity data, the comorbidity-adjusted relative risk of non-seroconversion among HBV vaccine non-responders to normal responders was 1.32 (95% confidence interval [0.59-2.98])., Discussion: Long term follow-up studies are needed to understand if protective immunity against SARS-CoV-2 wanes faster among those with history of HBV vaccine non-response and when booster doses are warranted for these healthcare workers., Competing Interests: The authors have declared that no competing interests exist.

Main Conclusion: Post-transcriptional gene silencing of the chalcone synthase gene CHS specifically suppresses anthocyanin biosynthesis in corolla lobes and is responsible for the formation of a stripe type bicolor in Japanese gentian. The flower of Japanese gentian is a bell-shaped corolla composed of lobes and plicae, which is painted uniformly blue. However, the gentian cultivar 'Hakuju' shows bicolor phenotype (blue-white stripe corolla), in which anthocyanin accumulation is suppressed only in corolla lobes. Expression analysis indicated that steady-state levels of chalcone synthase (CHS) transcripts were remarkably reduced in corolla lobes compared with plicae during petal pigmentation initiation. However, no significant difference in expression levels of other flavonoid biosynthetic structural and regulatory genes was detected in its lobes and plicae. On feeding naringenin in white lobes, anthocyanin accumulation was recovered. Northern blotting probed with CHS confirmed the abundant accumulation of small RNAs in corolla lobes. Likewise, small RNA-seq analysis indicated that short reads from its lobes were predominantly mapped onto the 2nd exon region of the CHS gene, whereas those from the plicae were scarcely mapped. Subsequent infection with the gentian ovary ringspot virus (GORV), which had an RNA-silencing activity, showed the recovery of partial pigmentation in lobes. Hence, these results strongly suggested that suppressing anthocyanin accumulation in the lobes of bicolored 'Hakuju' was attributed to the specific degradation of CHS mRNA in corolla lobes, which was through post-transcriptional gene silencing (PTGS). Herein, we revealed the molecular mechanism of strip bicolor formation in Japanese gentian, and showed that PTGS of CHS was also responsible for flower color pattern in a floricultural plant other than petunia and dahlia., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

BACKGROUND AND OBJECTIVE: Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are used either when conventional synthetic DMARDs are ineffective or when disease activity is high and with poor prognostic factors, based on various clinical guidelines. The purpose of this study was to investigate the prescribing trends of bDMARDs for patients with rheumatoid arthritis in Japan, and to clarify whether the pharmacological therapy of bDMARDs is administered based on guidelines., Methods: We conducted a descriptive epidemiological study from 2012 to 2018 using the JMDC Claims Database, a nationwide claims database, and described the annual changes based on the number of patients prescribed bDMARDs. Anti-rheumatic drugs were identified based on the Anatomical Therapeutic Chemical codes, including methotrexate, glucocorticoids, non-steroidal anti-inflammatory drugs and bDMARDs., Results: From the database including 6,862,244 people, the data of 6407 patients with rheumatoid arthritis were extracted. The present study demonstrated that the proportion of patients prescribed bDMARDs was 1.0 per 1000 people, with those aged ≥ 65 years being the most common age group. The proportion of patients with rheumatoid arthritis who were prescribed bDMARDs increased significantly over time (p < 0.0001). Additionally, the concomitant proportions of methotrexate (p < 0.0001), non-steroidal anti-inflammatory drugs (p < 0.0001) and glucocorticoids (p = 0.0001) prescribed with bDMARDs decreased significantly over time., Conclusions: The increase in bDMARD monotherapy may be attributed to the new bDMARDs that have been launched sequentially; furthermore, physicians have come to recognise monotherapy as the mainstay of treatment. Future studies must accumulate evidence on the long-term efficacy and safety of bDMARDs., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Clozapine is the only effective antipsychotic drug used for the treatment of treatment-resistant schizophrenia. Although it has been shown that the frequency of clozapine use is very low in Japan, our previous study revealed that the number of clozapine prescriptions has been increasing in recent years, and that risk factors leading to discontinuation of clozapine were also identified as age ≥40 years, poor tolerability to olanzapine, previous treatment with clozapine, and white blood cell count <6000/mm 3 . The main cause for discontinuation of clozapine is the occurrence of a wide range of adverse events, including neutropenia/leukopenia and fatal cardiac disorders. In this study, we analyzed the physical details and backgrounds of patients with adverse events that led to clozapine discontinuation using a national registry database of more than 8000 Japanese patients. The physical adverse events that led to discontinuation of clozapine were neutropenia/leukopenia, glucose intolerance, cardiac disorders, gastrointestinal disorders, neuroleptic malignant syndrome, pleurisy, pulmonary embolism, sedation/somnolence, and seizures. Neutropenia/leukopenia had the highest incidence (5.0%). Neutropenia/leukopenia and cardiac disorders tended to occur early in the treatment period, indicating the need for careful monitoring for these adverse events in the early stages of clozapine treatment. Gastrointestinal disorders occurred over a long period of time, suggesting the need for careful observation during the maintenance period. The data obtained in our study will lead to the optimal and safe use of clozapine treatment., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This survey was conducted to identify the actual usage of clozapine and changes required to increase the number of patients with schizophrenia who would benefit from clozapine. We obtained Clozaril® Patient Monitoring Service (CPMS) data for 8,263 patients that received clozapine between July 2009 and January 2020. Patients were divided into the early (n=3,696 cases, which have been analyzed previously) and late groups (n=4,567 cases) according to the date of the treatment initiation. In total, 417 facilities offered the drug, with a surge in cases in the late group (40.0 hospitals/year, 568.6 cases/year vs. 39.3 hospitals/year, 1,141.8 cases/year). We found a significant between-group difference in the mean dosage during treatment (early group: 309.1 mg/day; late group: 247.9 mg/day). The treatment continuation rates at 1 and 4 years in all study participants were 77.2% and 65.1%, respectively. The incidences of granulocytopenia and agranulocytosis were 5.5% and 1.0%, respectively. The discontinuation rate because of granulocytopenia was significantly lower in the late group. There were no differences in the discontinuation rate because of glucose intolerance between the groups. An assessment of the current CPMS regulations may be required to further examine the clozapine use effectiveness., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: We investigated whether the proportion of intracerebral haemorrhage (ICH) due to cerebral amyloid angiopathy (CAA) differs between patients admitted to hospitals in the East and the West., Methods: This international cross-sectional study included consecutive spontaneous ICH patients admitted to one stroke centre in the United Kingdom (Western centre origin) and one in Japan (Eastern centre origin) during the same period. We classified spontaneous ICH into "CAA-related" or "other" using the Edinburgh CT-based diagnostic criteria. We used multivariable logistic regression analyses to assess the relationship between CAA-related ICH and geographical location or ethnicity (White vs. East Asian or other ethnicities). Sensitivity analyses were performed using the modified Boston MRI-based diagnostic criteria for CAA-related ICH., Results: Of 433 patients (median age, 72 years; Western centre origin, 55%), 15% were classified as CAA-related ICH. In the multivariable logistic regression model, Eastern centre and ethnicity had a lower proportion of CAA-related ICH (odds ratio [OR] vs Western centre origin 0.55, 95%CI 0.31-0.98; OR [vs. White] 0.47, 95%CI 0.25-0.87); these findings remained robust in sensitivity analyses. The estimated incidence of "other" (non-CAA) ICH (attributed to hypertensive arteriopathy) was 2.5-fold higher in East Asian populations., Conclusions: The proportion CAA-related ICH is lower in an Eastern compared to a Western hospital ICH population; this might be explained by a higher incidence of ICH related to hypertensive arteriopathy in East Asian populations, suggesting that optimal ICH prevention strategies might differ between the East and West., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Gentian is an important ornamental flower in Japan. The corolla of the majority of cultivated Japanese gentians have green spots, which are rarely encountered in flowers of other angiosperms. Little information is available on the functional traits of the green spots. In this study, we characterized the green spots in the Japanese gentian corolla using a number of microscopic techniques. Opto-digital microscopy revealed that a single visible green spot is composed of approximately 100 epidermal cells. The epidermal cells of a green spot formed a dome-like structure and the cell lumen contained many green structures that were granular and approximately 5 μm in diameter. The green structures emitted red autofluorescence when irradiated with 488 nm excitation light. Transmission electron microscopy revealed that the green structures contained typical thylakoids and grana, thus indicating they are chloroplasts. No grana were observed and the thylakoids had collapsed in the plastids of epidermal cells surrounding green spots. To estimate the rate of photosynthetic electron transfer of the green spots, we measured chlorophyll fluorescence using the MICROSCOPY version of an Imaging-PAM (pulse-amplitude-modulated) fluorometer. Under actinic light of 449 μmol m-2 s-1, substantial electron flow through photosystem II was observed. Observation of green spot formation during corolla development revealed that immature green spots formed at an early bud stage and developed to maturity associated with chloroplast degradation in the surrounding epidermal cells. These results confirmed that the Japanese gentian corolla contains functional chloroplasts in restricted areas of epidermal cells and indicated that a sophisticated program for differential regulation of chloroplast formation and degradation is operative in the epidermis., Competing Interests: The authors have declared that no competing interests exist.

The current study aimed to describe the use of antipsychotics to clarify the gap between clinical guidelines and health care practice in Japan. We used data from the JMDC Claims Database (JMDC Inc., Tokyo, Japan), a nationwide claims database, from 2005 to 2016. Antipsychotics were defined as drugs coded as N05A with the Anatomical Therapeutic and Chemical (ATC) codes. We described the annual changes in proportions based on the number of patients prescribed any antipsychotics. From the database of 4,081,102 people, the data of 12,382 patients was extracted by applying the following exclusion criteria: no use of antipsychotics, missing the prescription date or dose, inpatients, prescribed antipsychotics only for use as needed, prescribed only injectable antipsychotics except for long-acting injections (LAIs), without schizophrenia as the primary disease, not exceeding 75 mg/day chlorpromazine equivalent, and less than 18 years old. The use of second-generation antipsychotics (SGA) has been expanding, while the use of first-generation antipsychotics has been decreasing. Aripiprazole accounted for the highest proportion of prescribed antipsychotics (31.9%) in 2016. Even though clozapine is categorized as a SGA, it accounted for a paltry 0.2%. The proportion of prescribed antipsychotics accounted for by LAIs was less than 5%. Although the use of antipsychotics for schizophrenia in Japan mostly corresponds to various clinical guidelines, limited use of clozapine and LAIs was identified. Further research focusing on the factors affecting the prescription of these underused antipsychotics may help advance the pharmacological therapy of schizophrenia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Dr. Kanazawa has received speaker's honoraria from Janssen, Meiji Seika Pharma, Otsuka, Shionogi, Sumitomo Dainippon Pharma, and Takeda Pharmaceutical Company and research grants from Ministry of Health, Labor and Welfare. Dr. Yoneda has received speaker's honoraria from Meiji Seika Pharma, Otsuka, Sumitomo Dainippon Pharma, Yoshitomiyakuhin, Eli Lilly Japan and Takeda Pharmaceutical Company and research grants from Ministry of Health, Labor and Welfare. The other authors report no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

High doses of daptomycin (DAP) (>6 mg/kg/day) have been preliminarily recommended in recent practical guidelines for methicillin-resistant Staphylococcus aureus infection, to achieve better clinical effects. While such doses can elevate the plasma trough concentration (Cmin) of DAP, there is an associated risk of creatine phosphokinase (CPK) elevation warranting further investigation. In the current study relationships between DAP Cmin and CPK elevation were investigated, and optimal DAP doses were determined. Plasma DAP concentrations were measured in 20 patients. Logistic regression analysis was performed to assess relationships between DAP Cmin and CPK elevation, then a population pharmacokinetic model of DAP was developed. To determine an optimal DAP dose a Monte Carlo simulation (MCS) was performed to minimize the risk of CPK elevation and maximize the probability of successful treatment. In logistic regression analysis DAP Cmin was significantly associated with CPK elevation (odds ratio 1.21, p = 0.048). With respect to dose-dependent increases in the probability of CPK elevation and exposure to DAP, MCS estimated an optimal DAP dose of 4-6 mg/kg/day, corresponding to a minimum inhibitory concentration (MIC) of ≤0.5 μg/mL. For an MIC of 1 μg/mL, MCS estimated an optimal DAP dose of 10 mg/kg/day. However, the probability of CPK elevation associated with high doses of DAP was higher than that associated with the approved doses. In cases where high doses of DAP are administered, close CPK monitoring is required and therapeutic drug monitoring of DAP may be desirable., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Phellodendron bark ("Obaku") is an important crude drug used in Kampo-medicine. Recently, powder formulation of phellodendron bark was approved as an "efficacious treatment for bruise, sprain, and periodontal diseases", and it has been marketed as an OTC agent. To obtain this approval, the examination of quality control-related characteristics is necessary. Therefore, we established a quantitative method for jatrorrhizine, palmatine, and berberine determination. In this study, we compared the contents of the three constituents obtained from the extracts of Japanese and Chinese phellodendron bark and found remarkable difference.

Background: Natural disasters have long-term negative impacts on the health and socioenvironmental conditions of a population, affecting the physical environment as well as the relationships within the community, including social networks. Mothers in post-disaster communities may have difficulty receiving social support not only from family members and relatives but also from members of their community, such as people in their neighborhoods. This study focused on mothers with infants and preschool-aged children in post-disaster communities. The associations of social support with sociodemographic characteristics and socioenvironmental conditions related to child-rearing among mothers in post-disaster communities were assessed., Methods: An anonymous self-administered questionnaire survey was conducted in October 2015 in 988 households in areas affected by the Great East Japan Earthquake and Tsunami. The data collected on sociodemographic and socioenvironmental characteristics included the presence of pre-disaster acquaintances in the neighborhood and social support for child-rearing. The associations of sociodemographic and socioenvironmental characteristics with social support were examined., Results: We analyzed 215 completed questionnaires from mothers living in different houses from those they lived in before the disaster to reflect continuous relationships with people from the pre-disaster communities. Social support was significantly associated with infant sex, extended family, support obtained from relatives not living together, pre-disaster acquaintances, use of child support resources, and no perceived difficulties in child-rearing. In addition, the presence of pre-disaster acquaintances was associated with categories of mental/physical place of comfort and child-rearing support, with adjusted odds ratios of 1.88 (95% CI 1.03-3.44) and 2.84 (95% CI 1.46-5.52) compared with mothers who did not have any pre-disaster acquaintances., Conclusions: Factors associated with the obtainment of social support in child-rearing among mothers in post-disaster communities were attributed not only to mothers themselves and family members but also to socioenvironmental factors such as the presence of pre-disaster acquaintances. The presence of pre-disaster acquaintances promoted rich social support in child-rearing in post-disaster communities. When reconstructing a community following changes in residence location after a disaster, the pre-disaster relationships among the community dwellers should be considered from the viewpoint of child-rearing support.

Objective: To assess lung function at 8 years old in extremely low birthweight (ELBW) survivors and to identify perinatal determinants associated with impaired lung function., Design: Retrospective cohort study., Setting: Level III neonatal intensive care unit., Patients: ELBW survivors born in 1990-2004 with available spirometry at 8 years old were studied. Children were excluded if they had a Wechsler Intelligence Scale for Children Third Edition full IQ <70., Main Outcome Measures: Multivariate logistic regression analysis was used to identify perinatal determinants associated with airway obstruction (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <80%) at school age and the predictive power of potential determinants. Potential risk factors and predictors assessed in this study were gestational age, birth weight, small for gestational age, sex, chorioamnionitis, premature rupture of membranes, antenatal steroids, surfactant administration, respiratory distress syndrome, postnatal steroids, severe bronchopulmonary dysplasia and bubbly/cystic appearances of the lungs by X-ray during the neonatal period., Results: Of 656 ELBW survivors, 301 (45.9%) had attended a school-age follow-up at 8 years old. A total of 201 eligible children completed the lung function test. Bubbly/cystic appearance of the lungs (OR 4.84, 95% CI 1.26 to 18.70) was associated with a low FEV1/FVC ratio. Children with bubbly/cystic appearance had characteristics of immaturity and intrauterine inflammation., Conclusions: Within a cohort of ELBW infants, a bubbly/cystic appearance of the lungs in the neonatal period was the strongest determinant of a low FEV1/FVC ratio at school age., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Chronic pain is recognized as a public health problem that affects the general population physically, psychologically, and socially. However, there is little knowledge about the associated factors of chronic pain, such as the influence of weather, family structure, daily exercise, and work status., Objectives: This survey had three aims: 1) to estimate the prevalence of chronic pain in Japan, 2) to analyze these associated factors, and 3) to evaluate the social burden due to chronic pain., Methods: We conducted a cross-sectional postal survey in a sample of 6000 adults aged ≥20 years. The response rate was 43.8%., Results: The mean age of the respondents was 57.7 years (range 20-99 years); 39.3% met the criteria for chronic pain (lasting ≥3 months). Approximately a quarter of the respondents reported that their chronic pain was adversely influenced by bad weather and also oncoming bad weather. Risk factors for chronic pain, as determined by a logistic regression model, included being an older female, being unemployed, living alone, and no daily exercise. Individuals with chronic pain showed significantly lower quality of life and significantly higher psychological distress scores than those without chronic pain. The mean annual duration of absence from work of working-age respondents was 9.6 days (range 1-365 days)., Conclusions: Our findings revealed that high prevalence and severity of chronic pain, associated factors, and significant impact on quality of life in the adult Japanese population. A detailed understanding of factors associated with chronic pain is essential for establishing a management strategy for primary care.

Objective: The distribution of the Mini-Mental State Examination (MMSE) scores by age and educational level was investigated in subjects that underwent comprehensive brain examinations., Methods: This cross-sectional study included 1,414 adults without neurological disorders who underwent health-screening tests of the brain, referred to as the "Brain Dock," in our center. The MMSE scores were compared between age groups (40-44, 45-49, 50-54, 55-59, 60-64, 65-69, or ≥70 years) and educational levels [the low education level group (6-12 years) and the high education level group (≥13 years)]., Results: The median age was 59 years, and 763 (54%) were women. There was no significant difference in the MMSE total score between women and men. The stepwise method of the multiple linear regression analysis confirmed that a higher age [β value, -0.129; standard error (S.E.), 0.020; p<0.001], low education level (6-12 years) (β value, -0.226; S.E., 0.075; p=0.003), and women (β values, 0.148; S.E., 0.066; p=0.024) was significantly associated with decreased MMSE score. In general, both the percentile scores and mean scores decreased with aging and were lower in the low education level group than in the high education level group. The degree of decrement in scores with age was stronger in the low education level group than in the high education level group., Conclusion: The provided data for age- and education-specific reference norms will be useful for both clinicians and investigators who perform comprehensive brain examinations to assess the cognitive function of subjects.

Purpose: Our purpose was to identify the causal factors for the perfusion distribution obtained with ASL-MRI by comparing ASL-MRI with clinical information and other MRI findings in moyamoya disease., Methods: Seventy-one patients with moyamoya disease underwent ASL-MRI and other MRI, including fluid-attenuated inversion recovery imaging (FLAIR) and three-dimensional time-of-flight magnetic resonance angiography (MRA) on 3.0-Tesla MRI system. Cerebral blood flow (CBF) values (ASL values) for the cerebral hemispheres (142 sides) were measured on CBF maps generated by ASL-MRI. Relationships between the ASL values and the following 9 factors were assessed: sex, family history, revascularization surgery, age at MR exam, age at onset, the steno-occlusive severity on MRA (MRA score), degree of basal collaterals, degree of leptomeningeal high signal intensity seen on FLAIR, and size of ischemic or hemorrhagic cerebrovascular accident lesion (CVA score)., Results: Patients with a family history had significantly higher ASL values than those without such a history. There were significant negative correlations between ASL values and age at MR exam, MRA score, and CVA score., Conclusions: ASL-MRI may have cause-and-effect or mutual associations with family history, current patient age, size of CVA lesion, and intracranial arterial steno-occlusive severity in Moyamoya disease., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Rice cake is a traditional but very popular food in Asia including Japan and has never been known as a cause of ileus. Rice cake is now becoming widespread in the United States and European countries along with other Japanese foods. We may encounter rice cake ileus all over the world. This study was aimed at characterizing the rice cake ileus., Methods: We consecutively encountered 14 patients with rice cake ileus from April 2003 to October 2010 in our hospital. All of the characteristics of the cases were reviewed and analyzed., Results: All patients had ingested rice cake by swallowing without chewing. It has most frequently occurred in January (57.1%). The main symptoms were abdominal colicky pain (100%) and nausea (85.7%) and physical findings included abdominal tenderness (100%) and muscular defense (28.6%). All patients improved by conservative therapy including fluid supply (100%), naso-gastric tube (28.6%) and long tube (28.6%) insertion. No patient needed emergency open surgery., Conclusion: Rice cake ileus which is caused by swallowing the rice cake without chewing, frequently occurs in January, has previous history of abdominal surgery and shows high density intestinal contents on CT and only needs conservative therapy. Globalism in food culture may provide a new disease entity. Therefore, we should be aware of this type of ileus and be prepared to manage it appropriately.

An epidemiological study of 422 stone-formers who visited our hospital from 1997 to 2001 was conducted. The mean annual prevalence and incidence of both upper and lower urinary tract stones were higher than what was found in a nationwide urolithiasis survey carried out in Japan in 1995. The incidence of upper and lower urinary tract stones was 90.8% and 9.2%, respectively. The frequency of lower urinary tract stones was higher than that found in the previously mentioned nationwide study. The male-to-female ratio of upper and lower urinary tract stones was 1.68:1 and 2.25:1, respectively. The frequency in females was higher in this study than that found in the nationwide survey. The peak age for incidence of upper urinary tract stones is 50s in males and females. In the treatment of upper urinary tract stones, ureteroscopic lithotripsy was carried out more often than shock wave lithotripsy (SWL), because our hospital had no SWL device. Many endoscopic lithotripsy procedures were performed to treat stones located in the lower urinary tract. Of the upper urinary tract stones 83.7% were composed of calcium, the incidence of uric acid stones was high (6.6%), whereas the incidence of infectious stones was low (1.9%). For lower urinary tract stones, the frequency of infectious stones was high (52.6%). In the present study, the epidemiological features were as follows: high annual prevalence and incidence, high frequency of lower urinary tract stones, high frequency in females, many endoscopic treatment procedures and high frequency of uric acid stones in the upper urinary tract.

Growth hormone (GH) is secreted in a pulsatile manner, but the underlying mechanisms of GH pulse generation remain to be resolved. In the present study, we investigated the relationship between GH pulses in the peripheral circulation and GH-releasing hormone (GHRH) and somatostatin (SRIF) profiles in the cerebrospinal fluid (CSF) of male goats. The effects of an intracerebroventricular (icv) injection of neuropeptide Y (NPY), galanin and ghrelin were also analyzed. Blood and CSF samples were collected every 15 min for 8 hr from the jugular vein and third ventricle, respectively. GH pulsatility in the goat was found to consist of distinct large pulses of 5 hr periodicity and small pulses of 1 hr periodicity. GHRH and SRIF in the CSF fluctuated in a pulsatile manner with 1 hr periodicity, and most of the descending phase of SRIF pulses were associated with the initiation of GH pulses. Icv injections of NPY, galanin and ghrelin stimulated GHRH release without affecting SRIF release. In addition, NPY suppressed, and galanin and ghrelin induced large GH pulses, although ghrelin was much more effective than galanin. These results suggest that an hourly fall in SRIF is involved in generating intrinsic circhoral rhythm of GH pulsatility. The mechanisms underlying the generation of large GH pulses of 5 hr periodicity remain unknown, while direct action of NPY and/or ghrelin on the pituitary might be involved.

Childhood-onset asthma is frequently found in association with atopy. Although asthmatic children may develop IgE antibodies against variety of allergens, asthma is associated primarily with allergy to house-dust mites, molds, or other allergens. In this study, we conducted a genome-wide linkage search in 47 Japanese families (197 members) with more than two mite-sensitive atopic asthmatics (65 affected sib-pairs) using 398 markers. Multipoint linkage analysis was carried out for atopic asthma as a qualitative trait using the MAPMAKER/SIB program. We observed significant evidence for linkage with maximum lod scores (MLS) of 4.8 near the interleukin 12 B gene locus on chromosome 5q31-q33. In addition, suggestive evidence on 4q35 with MLS = 2.7 and on 13q11 with MLS = 2.4 was obtained. The other possible linkage regions included 6p22-p21.3 (MLS = 2.1), 12q21-q23 (MLS = 1.9), and 13q14.1-q14.3 (MLS = 2.0). Many of the linkage loci suggested in this study were at or close to those suggested by genome-wide studies for asthma in Caucasian populations. The present study suggests the contribution of the interleukin 12 B gene or nearby gene(s) to mite-sensitive atopic asthma and a considerable number of genetic variants common across Caucasians and Japanese populations contributing to asthma, although the relative importance of various variants may differ between the groups., (Copyright 2000 Academic Press.)