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Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, xerosis, and eczematous lesions. In Japan, treatment options, such as topical corticosteroids and tacrolimus, are associated with efficacy and safety concerns. Crisaborole ointment, 2%, is a topical non-steroidal anti-inflammatory agent approved in several countries for the treatment of mild-to-moderate AD. This phase 2b, randomized, double-blind study (NCT03954158) assessed the efficacy and safety of two crisaborole regimens versus vehicle in the treatment of Japanese patients aged ≥2 years with mild-to-moderate AD. Each patient was assigned to one of two age cohorts (≥12 or 2-11 years) and randomized to crisaborole once daily (QD) or twice daily (BID). All patients had two target lesions that were each randomly assigned to crisaborole or vehicle at baseline and treated for 2 weeks. The primary endpoint was change from baseline in total sign score (TSS) in crisaborole- or vehicle-treated target lesions on day 15, and secondary endpoints included change from baseline in Investigator's Static Global Assessment (ISGA) and pruritic assessments (Cohort 1: peak pruritus numeric rating scale [NRS]; Cohort 2: Itch Severity Scale Self-Report and Caregiver-Reported Itch Severity NRS) and incidence of treatment-emergent adverse events (TEAEs). This study comprised 81 patients (Cohort 1: n = 41; Cohort 2: n = 40). Crisaborole-treated lesions showed statistically significant reductions in TSS versus vehicle-treated lesions at day 15 (p < 0.01), and numerically larger decreases in TSS were observed with crisaborole BID versus crisaborole QD in both cohorts. Furthermore, crisaborole-treated lesions generally demonstrated greater decreases in ISGA, peak pruritus NRS, Itch Severity Scale, and Caregiver-Reported Itch Severity NRS versus vehicle-treated lesions irrespective of regimen or cohort. Overall, TEAEs were mild; the most frequently reported TEAEs was application site irritation. In summary, both crisaborole regimens, particularly crisaborole BID, demonstrated efficacy and were well tolerated.

In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first‐line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28‐d cycles, in patients with EGFR‐activating mutation–positive (EGFR‐positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non‐small cell lung cancer (NSCLC). The primary endpoint was progression‐free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307‐0.961]; 2‐sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0‐31.3] mo, 9.3 [95% CI, 7.4‐14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first‐line dacomitinib in Japanese patients with EGFR‐positive advanced NSCLC., We evaluated the efficacy and safety of first‐line dacomitinib compared with gefitinib in a subgroup of Japanese patients with EGFR‐activating mutation–positive advanced non‐small cell lung cancer who were enrolled in the ARCHER 1050 randomized phase 3 trial. Results for the primary efficacy endpoint in the Japanese patients (n = 81) were consistent with the results in the overall ARCHER 1050 population; there was a clinically meaningful prolongation of median PFS by 8.9 mo favoring dacomitinib. The safety profile of dacomitinib was manageable by dose reduction or temporary dose interruption and no new safety signals were observed in the population of Japanese patients compared with the overall ARCHER 1050 study population.

OBJECTIVES: This study aims to evaluate the prevalence of hyperuricemia (HU) considering both serum uric acid (SUA) levels and medication status of urate-lowering drugs (ULDs), and the association between HU and its comorbidities using a Japanese healthcare database. MATERIALS AND METHODS: The study population consisted of 60,828 subjects who had at least one serum uric acid measurement between the fiscal years (FYs) 2010 and 2014 in a Japanese employment-based health insurance database (MinaCare Co., Ltd., Tokyo, Japan), which includes mutually linked medical/pharmaceutical claims data and health check-up data. Hyperuricemia was defined as a SUA level >7.0 mg/dL of the health check-up data and/or a prescription for a ULD. The association between HU and comorbidities were analyzed by comparing the prevalence of HU of each subgroup defined by presence or absence of comorbidity. RESULTS: The prevalence of HU in FY 2014 was 26.8% [95% confidence interval (CI): 26.2 to 27.3%] in male subjects and 0.9% (95% CI: 0.7 to 1.0%) in female subjects. According to the analyses by sex and age, a trend of increasing prevalence with age was observed in both males and females. The prevalence of HU remained stable both in males and females from FYs 2010 to 2014. The positive association between HU and well-known comorbidities were confirmed with the exception of diabetes mellitus and smoking status in male subjects. CONCLUSION: Our results provided a more accurate prevalence of HU in Japanese population. It is important to increase the awareness on HU in the society to reduce the burden of HU-related diseases.

Background The phase 3 JAVELIN Bladder 100 trial showed significantly prolonged overall survival (OS) with avelumab as first-line (1L) maintenance therapy + best supportive care (BSC) vs BSC alone in patients with advanced urothelial carcinoma (UC) that had not progressed with 1L platinum-containing chemotherapy. Efficacy and safety were assessed in patients enrolled in Japan. Methods Patients with locally advanced or metastatic UC that had not progressed with 4–6 cycles of 1L platinum-containing chemotherapy were randomized to avelumab (10 mg/kg intravenously every 2 weeks) + BSC or BSC alone. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS) and safety. Results In Japanese patients (n = 73) randomized to avelumab + BSC (n = 36) or BSC alone (n = 37), median OS was 24.7 months (95% CI, 18.2-not estimable) vs 18.7 months (95% CI, 12.8–33.0), respectively (HR, 0.81 [95% CI, 0.41–1.58]), and median PFS was 5.6 months (95% CI, 1.9–9.4) vs 1.9 months (95% CI, 1.9–3.8), respectively (HR, 0.63 [95% CI, 0.36–1.11]). In the avelumab + BSC and BSC-alone arms, grade ≥ 3 treatment-emergent adverse events (AEs) occurred in 50.0% vs 8.1%, including grade ≥ 3 treatment-related AEs in 13.9% vs 0%, respectively. Efficacy and safety results in Japanese patients were generally consistent with findings in the overall trial population. Conclusion Avelumab 1L maintenance treatment showed a favorable benefit-risk balance in Japanese patients, supporting avelumab 1L maintenance as a new standard of care in Japanese patients with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Trial registration Clinicaltrials.gov NCT02603432.

Background: Sevoflurane is generally the preferred anesthetic agent for general anesthesia in pediatric patients, due to its rapid induction and recovery characteristics. However, it has been recognized that a major complication is emergence agitation when awakening from general anesthesia. The aim of this study was to evaluate the occurrence rate of emergence agitation in the operating room and postoperative recovery area following intraoperative administration of midazolam to pediatric patients under general anesthesia. Patients and methods: One hundred and twenty pediatric patients undergoing dental treatment under sevoflurane anesthesia were enrolled in this study. The patients were divided into three groups (n=40 each in the 0.1 mg/kg midazolam, 0.05 mg/kg midazolam, and control with saline groups). Midazolam or saline was injected intravenously approximately 30 minutes before the end of the dental treatment. We used the Richmond Agitation and Sedation Scale (RASS) to assess the level of sedation and drowsiness at emergence phase in the operating room. We also used the Pediatric Anesthesia Emergence Delirium Scale (PAED) to assess the level of agitation and delirium at the full recovery phase from anesthesia in the recovery area. Results:At the emergence phase, the incidence of emergence agitation in the 0.1 mg/kg midazolam group was significantly lower than in the other groups (p=0.0010). At the recovery phase, there was no significant difference among the three groups. The odds ratio between PAED score and RASS score was 4.0 using logistic regression analysis. The odds ratio between PAED score and Disability was 2.5. Conclusion: Administration of a single dose of 0.1 mg/kg midazolam dose significantly decreases the incidence of severe emergence agitation at the emergence after sevoflurane anesthesia, but not at the recovery phase. Furthermore, the evaluation of sedative and agitation condition using RASS score at emergence from anesthesia is useful to predict occurrence of agitation in the recovery phase., Drug Design, Development and Therapy, 13, pp.1729-1737; 2019

Active oxygen and free radicals are involved in metabolism in cells and tissues. Immunohistological studies of related enzymes are few, and the morphological dynamics of these enzymes in dental pulp and odontoblasts remain to be elucidated. Nitric oxide synthase (NOS) has 3 isoforms: nNOS, iNOS, and eNOS. The aim of this study was to investigate the profiles of NOS isoforms in the absence of nNOS in dental pulp and odontoblasts. Five-week-old male C57BL/6 and nNOS knockout (KO) mice were sacrificed and expression of nNOS, iNOS, and eNOS determined immunohistochemically. Expression of nNOS was positive, whereas that of iNOS was negative and eNOS weakly positive in the dental pulp and odontoblasts of the control mice. In nNOS KO mice, expression of iNOS was positive in dental pulp and strongly positive in odontoblasts, whereas that of eNOS was stronger in fibroblasts, endothelial cells in the vicinity of blood vessels in the dental pulp, and odontoblasts. Expression of nNOS was negative in the nNOS KO mice. This suggests that iNOS and eNOS compensate for nNOS deficiency in vascular endothelial cells and fibroblasts in the dental pulp and odontoblasts.

BACKGROUND The relationship between oral and cognitive functions among older people is highly debated. OBJECTIVE To examine whether oral functions are related to changes in the levels of mild cognitive impairment (MCI) biomarkers in older Japanese outpatients. METHODS This observational study included 52 outpatients aged ≥65 years who underwent dental examinations at the Fukuoka Dental College Hospital. The Mini-Mental State Examination (MMSE) was performed, and MCI blood biomarker levels were assessed at baseline and after 2 years. The present dental and periodontal conditions and the oral functions (tongue pressure and masticatory performance) were evaluated. Changes in parameters from baseline to follow-up were compared using the Wilcoxon signed-rank test, McNemar test or chi-squared test. Associations among changes in the parameters were analysed using Spearman's rank correlation coefficient. RESULTS The follow-up rate in this study was 67%. The masticatory performance was improved (p

ナンキョクユスリカのアクアポリン遺伝子の発現に関して, Larvae of the Antarctic midge Belgica antarctica Jacobs (Diptera: Chironomidae) are highly tolerant of diverse environmental stresses, including freezing, severe desiccation, and osmotic extremes. Furthermore, dehydration confers subsequent desiccation and freeze tolerance. While a role for aquaporins-channels for water and other solutes-has been proposed in these dehydration processes, the types of aquaporins involved in dehydration-driven stress tolerance remain unknown. In the present study,...

Background and aim Recent shifts in the distribution of Japan's population towards older ages, have meant that the chance of encountering patients with dementia in dental clinics is increasing. Many studies have shown that the brain volume decreases along with the progression of dementia. Although previous studies have reported a relationship between tooth loss or periodontitis and the onset of dementia, the pathological mechanisms underlying this association have not been elucidated. In this study, we aimed to examine the relationship between the oral condition and brain atrophy and to discuss how to adequately deal with patients with dementia. Participants and methods This cross-sectional study included 15 participants who underwent brain magnetic resonance imaging (MRI). The participants were 60 years or older and presented with cognitive decline, including Alzheimer's disease (AD) and mild cognitive impairment (MCI), diagnosed by a neurologist. We obtained information on the oral condition, lifestyle, cognitive function, and brain atrophy. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). MR images of each patient were analyzed using the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) to provide a quantitative measure of the degree of brain atrophy. Results The study population included 4 male and 11 female patients. The mean age and mean number of present teeth were 75.9 years (SD 6.7) and 15.0 (SD 11.1), respectively. The median MMSE score was 25.6 (SD 3.7). The degree of atrophy of the whole brain was significantly correlated with the number of present teeth (ρ = −0.72, p Conclusion This study demonstrated that the number of present teeth could be an indicator of the progress of dementia. Preserving the teeth as well as the acquisition of a regular exercise habit might be important for preventing progression of dementia. Further research examining a larger study population and analyzing a greater number of factors is warranted.

Strong typhoons hit the Japanese Islands repeatedly in 2019. Here we study one of these typhoons (2019 #19 Hagibis 915 hPa, 86 casualties) that landed central Japan on Oct.12 (local time) during the Rugby World Cup tournament, using two different space geodetic approaches, i.e. water vapor and crustal deformation. The first approach is the recovery of Precipitable Water Vapor (PWV) using the zenith wet delays (ZWD) estimated by the dense GNSS array in Japan GEONET. Because atmospheric water vapor concentrates in relatively low altitudes, high humidity is often difficult to recognize in ZWDs when the surface altitude is high. To overcome the difficulty, we reconstructed ZWDs, converted to sea-level values, by spatially integrating the tropospheric delay gradient (azimuthal asymmetry of water vapor) vectors. We also calculated convergence of such delay gradients, equivalent to water vapor convergence index (WVCI) proposed by Shoji (2013 Jour. Met. Soc. Japan). We found that very strong rainfall occurs in the region where both reconstructed ZWD and the delay gradient convergence index are high. Next, we studied vertical crustal movements associated with the water load brought by the typhoon, using the two solutions of the GEONET station coordinates, one from the official F3 solution and the other from the UNR data base. We confirmed subsidence down to ~2 cm in multiple regions where severe flood occurred. Such subsidence was observed to recover with a time constant of 1-2 days reflecting rapid drain of rain water to ocean due to large topographic slope and proximity to the sea. We could not identify, however, crustal uplift due to the low atmospheric pressure at the center of the typhoon.

Aims Although it has been reported that general anesthesia affect the perioperative sleep cycle, no studies have yet evaluated how general anesthesia affects dentally disabled patients. In this study, we investigated the alteration of perioperative sleep cycles in dentally disabled patients receiving dental treatment under general anesthesia. Subjects and methods The study included 16 patients receiving dental procedures under general anesthesia. Using a sleep monitoring mat, the patients' sleep cycles were measured at home from 5 days before the scheduled surgery date until 5 days after discharge following general anesthesia. The change in all the variables of sleep cycles were analyzed in comparison to the value in preoperative period. Daily differences in these variables were assessed for statistical analysis. Results The percentage of deep sleep (Stages 3 and 4) decreased significantly on postoperative day 1, and the percentage of light sleep increased. Furthermore, sleep cycles were significantly extended on postoperative day 1. Conclusion The percentage of deep sleep decreased significantly on postoperative day 1 while the percentage of light sleep increased. Sleep cycles were also significantly extended on postoperative day 1. These results reveal that the sleep cycle is somehow affected on the first day following general anesthesia.

The Tenth Symposium on Polar Science/Ordinary sessions : [OB] Polar Biology, Wed. 4 Dec. / Entrance Hall (1st floor) , National Institute of Polar Research

We propose a method of eliciting requirements for several different systems together. We focus on systems used by one user at the same time become such systems inherently give influences on with other. We expect such influences help a requirements analyst to be aware of unknown requirements of the user. Any modeling notations are used to explore the combination among systems causing such influences because the differences among the notations give diverse viewpoints to the analyst. To specify such mutual influences, we introduce semantic tags represented by stereo types. We also introduce other semantic tags so that the analyst can judge whether the combination brings advantages to the user. We apply our method to an example and we confirm the method works.

Crisaborole ointment, 2%, is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD). This parallel-cohort, phase 1 study was conducted to investigate skin irritation potential and safety of crisaborole in healthy Japanese adults (cohort 1) and the safety and pharmacokinetic profile of crisaborole and metabolites AN7602 and AN8323 in Japanese adults with mild to moderate AD (cohort 2). In cohort 1, 20 healthy volunteers received single applications of crisaborole and vehicle simultaneously on separate locations under 48-h occlusion. In cohort 2, 12 patients with mild to moderate AD received crisaborole (n = 10) or vehicle (n = 2) twice daily for 8 days. Skin irritation and safety were assessed in cohort 1. Pharmacokinetics and safety were assessed in cohort 2. Skin irritation index (scale 0-400) was 40.0 for crisaborole and 5.0 for vehicle. No treatment-emergent adverse events (TEAE) were reported in cohort 1. The most common TEAE in the crisaborole group in cohort 2 were application site irritation (n = 7) and application site pain (n = 4). Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8 that was comparable with that seen in US-based participants in previous trials. Crisaborole had higher skin irritation than vehicle under occlusion in healthy Japanese adults and had an acceptable safety profile in Japanese adults with mild to moderate AD.

The purpose of this study was to survey parental satisfaction with ambulatory anesthesia during dental treatment in disabled patients. Factors associated with parental preference for general anesthesia during future dental treatment in such patients were also investigated. A questionnaire was mailed to the parents of 181 disabled individuals who underwent dental treatment under ambulatory anesthesia at Tokyo Dental College Suidobashi Hospital between 2012 and 2016. A total of 71 responses were received (39.2%). The mean patient age was 18 years, and disabilities included autism spectrum disorder, intellectual disability, cerebral palsy, and epilepsy. The items surveyed included dental treatment details, number of times patients received general anesthesia, type of anesthetic used, anesthesia induction method, durations of treatment and anesthesia, and the presence or absence of intraoperative or postoperative complications. Questionnaire items queried problems related to dental care, anesthesia history, preoperative anxiety, length of fasting period, induction of general anesthesia, nursing and hospital room environment, postoperative anxiety, overall evaluation, and whether the parent would prefer general anesthesia during future dental treatment. The patients were divided into 2 groups: those whose parents preferred general anesthesia during future dental treatment and those whose parents did not. The results revealed that, where disabled individuals had previously received general anesthesia during dental treatment, the parents were more likely to prefer general anesthesia during future dental treatment.

The super typhoon Hagibis traveled northeastward through eastern Honshu, Japan, causing disastrous heavy rainfalls along its path on October 11 and 12, 2019. We performed a comprehensive space geodetic study of water brought by this typhoon using a dense network of Global Navigation Satellite System (GNSS) receivers in Japan. First, we studied the time evolution of altitude-corrected precipitable water vapor field and compare the movement of water vapor centroid with the rain distribution from radar rain gauge analyzed precipitation. The total amount of water vapor derived by spatially integrating precipitable water vapor on land remained steady at similar to 20 Gt. The total precipitation by this typhoon was similar to 92, and similar to 33 Gt of it fell onto the land area of eastern Honshu. Next, we studied crustal subsidence caused by the typhoon rainwater as surface load. The GNSS stations located under the typhoon path temporarily subsided 1-2 cm on the landfall day and the subsidence mostly recovered on the next day. Using the vertical crustal movement data, we estimated the distribution of surface water in eastern Honshu assuming the layered spherical earth. The amount of the surface load on October 12 was similar to 71 Gt, which significantly exceeds the cumulative rainfall on land. We consider that the excess subsidence largely originates from the selective deployment of GNSS stations in the concave topography, for example, along valleys and within basins, in the mountainous Japanese Islands.

425 Background: A randomized phase III trial (JAVELIN Bladder 100; NCT02603432) to investigate avelumab (anti–PD-L1) as 1L maintenance therapy in patients with advanced UC met its primary objective, demonstrating significantly prolonged overall survival (OS) with Ave + BSC vs BSC alone in all randomized patients and in patients with PD-L1+ tumors. We report efficacy and safety in Japanese patients enrolled in this study. Methods: Eligible patients with unresectable locally advanced or metastatic UC that had not progressed with 4-6 cycles of gemcitabine with either cisplatin or carboplatin were randomized 1:1 to receive maintenance Ave (10 mg/kg IV every 2 weeks) + BSC or BSC alone, stratified by best response to 1L chemotherapy (complete/partial response vs stable disease) and by visceral vs nonvisceral disease when initiating 1L chemotherapy. The primary endpoint was OS, assessed from randomization in all randomized patients and in patients with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included progression-free survival (PFS) per blinded independent central review and safety. Results: Japanese patients (n=73) were randomized to receive Ave + BSC (n=36) or BSC alone (n=37); 52.8% vs 62.2% had PD-L1+ tumors, respectively. Median OS (95% CI) was 24.7 months (18.2-not estimable [NE]) with Ave + BSC vs 18.7 months (12.8-33.0) with BSC alone (HR, 0.81 [95% CI; 0.409-1.585]) in all randomized patients and 18.6 months (9.4-NE) with Ave + BSC vs 19.4 months (11.7-33.0) with BSC alone (HR, 1.00 [95% CI, 0.413-2.412]) in patients with PD-L1+ tumors. Median PFS (95% CI) was 5.6 months (1.9-9.4) with Ave + BSC vs 1.9 months (1.9-3.8) with BSC alone (HR, 0.63 [95% CI, 0.358-1.113]) in all randomized patients and 5.6 months (1.8-11.2) with Ave + BSC vs 1.9 months (1.9-3.8) with BSC alone (HR, 0.62 [95% CI, 0.298-1.301]) in patients with PD-L1+ tumors. The most common treatment-emergent adverse events (all grade; grade ≥3) in the Ave + BSC arm were pyrexia (10 [27.8%]; 0), nasopharyngitis (7 [19.4%]; 0), and anemia (7 [19.4%]; 4 [11.1%]). Conclusions: Ave 1L maintenance + BSC was efficacious and tolerable in Japanese patients with advanced UC, and results were generally consistent with those in the overall population. Clinical trial information: NCT02603432.

The SnO2 particles with different morphologies of nanorod, nanosheet, nanoparticle and nanodot were synthesized by liquid-phase methods. In addition, Pt was loaded on each prepared SnO2 by dispersing SnO2 particles into PtCl4 2− aqueous solutions containing 0.67 vol% methanol, followed by UV light irradiation for 6 h. The products were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and Brunauer–Emmett–Teller measurement. The gas sensing properties of the synthesized SnO2 were tested by detecting the change in electric resistivity in flowing aceton and methanol gases with nitrogen base. The gas sensing properties greatly changed depending on not only the specific surface area, but also the exposed crystal plane, i.e., the SnO2 nanorods exposing (111) planes showed the excellent sensitivity and quick response ability, indicating the excellent gas sensing ability of the (111) plane. Furthermore, the Pt loading exceedingly enhanced the gas sensing properties.

Fleming and Harrington's G(ρ,γ) class of weighted log-rank tests is appropriate for detecting delayed treatment effects such as those seen in cancer vaccines. A conditional power (CP) and an alpha spending function (ASF) approach are useful for interim analyses that are conducted with the aim of early termination due to futility and efficacy, respectively. However, calculation of the CP and the total Type I error probability are often not considered for delayed effects under the staggered patient entry. In this article, we first propose methods for calculating the CP analytically based on the weighted log-rank test. We compared the performances of the proposed methods with two other methods (i.e., usual log-rank test and optimal one) under the delayed alternatives. Our simulations demonstrated that the CP based on the weighted log-rank test was more powerful than that of the usual log-rank test and was comparable to the CP based on the optimal log-rank test. Second, we quantitatively evaluated the degree to which the Type I error probability was inflated when an ASF approach with forced independent increments assumption was applied to the weighted log-rank test. The proposed method will provide valuable tools in the decision-making stage of the interim analysis.

The Ninth Symposium on Polar Science/Ordinary sessions: [OB] Polar biology, Wed. 5 Dec. / Entrance Hall (1st floor), National Institute of Polar Research

The failure mode known as local failure could occur at structure discontinuities with multiaxial stress conditions. Experiments and analyses of notched bars, which generate multiaxial stress, were conducted. The experiments showed that the tensile strength of a notched bar was stronger than that of a smooth bar. The ratio of the maximum and minimum diameter has become the important factor of this notch strengthening. In addition, the initiation of failure was observed at the inner location from the notch root. According to the analysis results, the Mises-stress became the maximum at the notch root. On the other hand, hydrostatic stress became the maximum at the inner location from the notch root, and this location corresponded to the initiation of fracture. The maximum hydrostatic stress has good correlation with the notch strengthening ratio. These facts reveal that hydrostatic stress must be taken into account for strength evaluation as a dominant factor in addition to the Mises-stress. However, only Mises-stress is considered in the present structural design code of nuclear plants. From above results, the new criterion based on fracture surface, where the coordinate plane consists of hydrostatic stress and Mises-stress, was proposed for local failure. Furthermore, this fracture surface was extended to an isochronous fracture surface in a creep region based on isochronous stress-strain curves.

Various morphologies of SnO 2 were successfully synthesized using a solution process. The porous structure SnO 2 synthesized by sol–gel method using SiO 2 microparticles as a template showed excellent specific surface area and oxygen storage capacity (OSC) even after annealing at 1000 °C for 20 h. Alkali earth metal ion doped SnO 2 porous structure nanoparticles were also synthesized successfully by adding M(NO 3 ) 2 ·xH 2 O (M = Mg, Ca, Sr, Ba) to the reaction solution. The alkali earth metal ion doping greatly enhanced the thermal stability and OSC of SnO 2 . Especially, Sr 2+ doped SnO 2 with porous structure annealed at 1000 °C for 20 h possessed high BET surface area and exhibited a considerably high OSC and excellent thermal stability. Alkali earth metal ion doped SnO 2 particles showed a great potential for application to a novel oxygen storage material.

Alkaline earth metal doped tin oxide (SnO 2 ) hollow nanospheres with a diameter of 50 nm have been synthesized successfully via a facial solvothermal route in a very simple system composed of only ethanol, acetic acid, SnCl 4 ·5H 2 O and A(NO 3 ) 2 · x H 2 O (A = Mg, Ca, Sr, Ba). The synthesized undoped SnO 2 and A-doped SnO 2 hollow nanospheres were characterized by the oxygen storage capacity (OSC), X-ray diffraction, transmission electron microscopy and the Brunauer–Emmet–Teller (BET) technique. The OSC values of all samples were measured using thermogravimetric-differential thermal analysis. The incorporation of alkaline earth metal ion into tin oxide greatly enhanced the thermal stability and OSC. Especially, Ba-doped SnO 2 hollow nanospheres calcined at 1000 °C for 20 h with a BET surface area of 61 m 2 g −1 exhibited the considerably high OSC of 457 μmol-O g −1 and good thermal stability. Alkaline earth metal doped tin oxide has the potential to be a novel oxygen storage material.

Streptococcus pneumoniae is a major cause of severe disease worldwide, particularly in the elderly population. Due to increasing life expectancy in Japan and elsewhere, an effective vaccine which offers the possibility of prolonged protection is required. Protein conjugated pneumococcal vaccines, which have the ability to boost immunity (immunologic memory) on natural exposure or revaccination, may meet these requirements. An unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been available for decades; however data on protection against pneumonia are inconsistent. For the first time, a randomized, modified double-blind trial comparing the 13-valent pneumococcal conjugate vaccine (PCV13) with PPSV23 was conducted in PPSV23-naive adults ≥65 years of age in Japan. This study showed that statistically significantly greater functional antibody responses as measured by opsonophagocytic assays 1 month after vaccination were elicited in the PCV13 group (n = 366) compared with the PPSV23 group (n = 367) for 9 of the 12 serotypes in common with both vaccines and for serotype 6A, unique to PCV13. Local reactions collected within 14 days of vaccination were more frequent in the PCV13 (57.5%, 211/367) than PPSV23 (44.9%, 166/370) group, although severity was generally mild to moderate; systemic and adverse events were similar across groups. There were no treatment-related serious adverse events. Consistent with global studies comparing PCV13 with PPSV23, PCV13 use in Japanese subjects was safe and well-tolerated and elicited greater functional immune responses than PPSV23 for the majority of PCV13-serotypes. PCV13 has the potential to protect against pneumococcal disease in Japanese elderly adults.

Two kinds of mpyza-bridged copper(II) complexes, [Cu(mpyza)2](BF4)2·2H2O (1) and [Cu(mpyza)2](PF6)2·1.5H2O (2) were prepared (mpyza = N-methylpyrazine-2-carboxamide). Their crystal structures have been determined, and despite the different space groups (Pc and P21/c for 1 and 2, respectively) they exhibit a similar metal–organic framework. Four Cu ions construct rectangular arrangement providing an infinite molecular two-dimensional grid, which have an equatorial-axial-type coordinated pyrazine bridge. Compounds 1 and 2 contain two or one and a half uncoordinated water molecules in a void space. The former liberates the water at 45 °C, but the latter does not below 170 °C, being consistent with the channel of 1 loosely packed with the counter anion. The magnetic studies revealed that they involved very weak Cu- - -Cu superexchange antiferromagnetic interactions with J/kB = −0.277(5) and −0.166(5) K for 1 and 2, respectively, analyzed on the basis of a two-dimensional model.

Background Dacomitinib (d) is effective first-line (1L) therapy in patients (pts) with EGFR-mutation-positive (EGFR+) advanced NSCLC. In the ARCHER 1050 study (NCT01774721), 1L treatment with d was manageable and resulted in clinically meaningful, statistically significant improvement in PFS vs gefitinib (g). Here we present results for Japanese pts from ARCHER 1050. Methods Pts with newly diagnosed stage IIIB/IV or recurrent EGFR+ advanced NSCLC were randomized to once-daily (qd) oral d 45 mg or g 250 mg. Randomization was stratified by race and EGFR mutation subtype. The primary endpoint was PFS. All pts enrolled were part of the efficacy analysis. Pts who received ≥1 dose of study drug were part of the safety analysis. Results Of 452 total pts, 81 were Japanese; d (n = 40), g (n = 41). Median PFS was 18.2 mo for d (95% confidence interval [CI], 11.0-31.3) vs 9.3 mo for g (95% CI, 7.4-14.7). All 81 pts received study treatment. No grade (G) 4 or 5 adverse events (AEs) occurred in d-treated pts. Three G4 AEs (hepatic enzyme increases [n = 2], suicide attempt) and a G5 AE (disease progression) occurred in g-treated pts. The most common G3 AEs were dermatitis acneiform (27.5%) and paronychia (22.5%) with d and ALT increased (12.2%) and abnormal hepatic function (7.3%) with g. Dose reduction occurred in 85% of d-treated pts; 24.4% of g-treated pts changed from qd to every other day dosing. Frequency and severity of special interest AEs (diarrhea, stomatitis, dermatitis and paronychia) were generally decreased after d dose reduction. Although the frequency of d dose modifications in Japanese pts was higher than in the ARCHER 1050 overall population, median treatment duration for pts who had d dose reductions was longer vs those who did not. Conclusion D significantly improved PFS over g in 1L treatment of Japanese pts with EGFR+ advanced NSCLC and had a manageable safety profile. Tolerability was improved and treatment duration was prolonged in pts who had their d dose reduced.

A variety of [Cu(pyza)2](X)2 (X = BF4 (1), ClO3 (2), ClO4 (3), PF6 (4), AsF6 (5)) were synthesized (pyza = pyrazine-2-carboxamide). The crystal structures of 1–5 have been determined to be isomorphous to that of known 3 in a monoclinic P21/c space group. They form a quadratic copper(II) array with pyza bridges. The 1- and 4-nitrogen atoms in the pyrazine ring are coordinated to copper ions at equatorial and axial positions, respectively. Complexes 1–5 showed very weak antiferromagnetic interactions with J/kB = −0.439(6), −0.321(5), −0.304(1), −0.209(3), and −0.264(5) K, respectively, analyzed on the basis of an antiferromagnetic two-dimensional model. The magnitude of J almost correlates with the Cu⋯Cu distance and the cell volume.

Background The MEGA study is a randomized controlled trial conducted in Japan to evaluate the primary preventive effect of pravastatin against coronary heart disease (CHD), in which 8214 subjects are randomized to diet or diet plus pravastatin. Pravastatin reduces the incidence of CHD (hazard ratio = 0.67; 95%CI: 0.49—0.91). In the MEGA study, in addition to the usual loss to follow-up cases, there is another problem of drop-outs due to the refusal of further follow-up at 5 years. Purpose To estimate the treatment effect adjusting for some types of dependent censorings observed in the MEGA study and to assess the sensitivity of standard analysis results for these censoring cases. Methods The proposed method is a straightforward extension of the inverse probability of censoring weighted (IPCW) method for settings with more than one reason for censoring, where the propensities for drop-outs are modeled separately for each reason. Simulation studies are also conducted to compare the properties of the IPCW estimate with the standard analysis assuming independent censorings. Results Simulation studies show that the IPCW estimate can correct for selection bias due to dependent censoring that can be explained by measured factors, while the standard analysis is biased. Applying the proposed method to the MEGA study data, several prognostic factors are associated with the censoring processes, and after adjusting for these dependent censorings, slightly larger treatment effects for pravastatin are observed for both CHD (primary endpoint) and stroke (secondary endpoint) events. Limitations The method developed is based on the fundamental assumption of sequentially ignorable censoring. Conclusions Our proposed method provides a valuable approach for estimating treatment effect adjusting for several types of dependent censorings. Dependent censorings observed in the MEGA study did not cause a severe selection bias attributable to the covariates and the results from the standard analysis were robust in relation to the censorings. Clinical Trials 2007; 4: 318—328. http:// ctj.sagepub.com

To determine the etiology of obstructive sleep apnea (OSA) in children with cerebral palsy (CP), a survey using a questionnaire was conducted on parents of 233 CP children (1-5 years old, mean age: 2.7) and on those of 343 control children during a routine medical check-up at the age of three. The prevalence of habitual snoring and nasal obstruction was 63 and 20% in CP children, which were significantly higher than in control children. Sleep apnea episodes and stridor were noted in 19.7 and 15.4% of CP children. A screening sleep study was performed using Apnomonitor II and a pulseoximeter (Pulsox 5) in 48 CP children whose questionnaires revealed habitual snoring and sleep apnea, and it was found that 27 and 58% of the children had on apnea-hypopnea index (AHI) of greater than 5 and a low level of SaO2 (LSaO2) of less than 85%, respectively. When another 10 CP children visited our hospital for treatment of severe OSA, precise evaluations including pharyngeal pressure and fiberscopic examination during sleep as well as a sleep study using an inductive prezysmograph (Respigraph) were performed. Adenoid and/or tonsillar hypertrophy were noted in only 4 children, and the main cause of sleep apnea in the other 6 children was pharyngeal collapse at the lingual base. Their OSA was successfully treated by adenotonsillectomy in 2 children, adenotomy in 2 children, UPPP and lingualplasty in 1 child, tracheostomy in 2 children, and nasal CPAP in 1 child. Before treatment of OSA in CP children, precise evaluation is recommended in order to perform appropriate treatment.

Three hundred and ninety-three patients (292 male and 101 female) who visited our clinic complaining of snoring and/or apnea during sleep were evaluated for sleep apnea syndrome (SAS) by Apnomonitor screening. A total of 131 patients (114 male and 17 female) showed an apnea index (A. I.) higher than to apnea episodes/hour, and there was a significant correlation of the A. I. with age, sex, and body mass index (BMI) in these patients. All patients with severe SAS (more than 50 apnea episodes/hour) were men, who had a BMI greater than 25, with the exception of 1 patient. Significantly higher ages and BMI were found to exist in patients with SAS than in those without SAS.

DigitalEE II (Digitally Enhanced Experience) is an online digital platform for networked collaborative environmental learning through multiple discussions among diverse people. The platform interconnects real and virtual worlds via a photo-realistic 3D spatial metaphor, and supports video- and voice-based interaction between real participants (participants in real nature) and virtual participants (participants at distant locations). Both participants share time, space, vision, experiences, and emotion between the two different worlds. We conducted experiments on DigitalEE II to verify voluntary environmental learning through interactive communication. The experiments found that the desire to fill information gap between real and virtual worlds stimulated various interactive communication and voluntary environmental observation. DigitalEE II made contribution toward raising participants’ interests in the environment and their awareness to nature. The platform provided the participants with opportunities of considering environmental preservation. This research introduced diverse computational technologies in environmental learning, and enlarged the field of application of CSCL techniques.

The A1555G mutation in the mitochondrial 12S ribosomal RNA gene is often found in patients with hearing loss after aminoglycoside exposure. A second pathogenic mutation in this gene, deletion of thymidine at position 961 with varying numbers of cytosines inserted (delT961Cn), has recently been found to predispose patients to aminoglycoside-induced deafness. We report on a Japanese patient bearing the delT961Cn who had streptomycin-induced deafness. Our report suggests that the delT961Cn plays an important secondary role in the pathogenesis of deafness caused by aminoglycosides. The combination of taking family histories and molecular screening at the 1555 and 961 positions is thought to reduce the frequency of tragic irreversible deafness due to aminoglycosides.

The photoionization process of indole in alkaline aqueous solutions at 77°K and the recombination process of trapped electron with its mother molecule were investigated. The fluorescence spectrum of indole in these glassy media depended on the NaOH concentration; the disappearance of the 325 nm band at the NaOH concentrations higher than 5 M with the appearance of a fluorescence band at 375 nm. The latter emission is possibly ascribed to the fluorescence of indole anion formed by proton dissociation in the excited singlet state of indole. The intensities of the 375 nm band and the ESR signal due to trapped electrons were dependent on the NaOH concentration and increased steeply with increasing the NaOH concentration. There was a parallel relation between the indole anion concentration and the trapped electron density to some extent. The dependence of the ESR signal intensity on irradiation intensity suggested that the photoionization of indole in alkaline aqueous solution occurred through a two photon process. The presence of a photoactive intermediate for absorbing the second photon was further investigated with simultaneous irradiation of two different wavelength lights. The trapped electron was detrapped with the irradiation of visible light (e.g. 580 nm), and its recombination with mother molecule caused an emission with the same spectrum as indole phosphorescence. The molecular species of the photoactive intermediate in alkaline aqueous solutions seems to be the indole anion. The photoionization in NaOH aqueous solution at 77°K was also compared with that in methanolic glassy solution.