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The existence of molecular orientational order in nanometer-thick films of molecules has long been implied by surface potential measurements. However, direct quantitative determination of the molecular orientation is challenging, especially for metastable amorphous thin films at low temperatures. This study quantifies molecular orientation in amorphous N 2 O at 6 K using infrared multiple-angle incidence resolution spectrometry (IR-MAIRS). The intensity ratio of the weak antisymmetric stretching vibration band of the 14 N 15 NO isotopomer between the in-plane and out-of-plane IR-MAIRS spectra provides an average molecular orientation angle of 65° from the surface normal. No discernible change is observed in the orientation angle when a different substrate material is used (Si and Ar) at 6 K or the Si substrate temperature is changed in the range of 6-14 K. This suggests that the transient mobility of N 2 O during physisorption is key in governing the molecular orientation in amorphous N 2 O.

Background: Although the American Joint Committee on Cancer TNM classification has been amended to include human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) as an independent entity, to the authors' knowledge the optimized de-escalating treatment modality has not been established to date., Methods: The authors conducted a retrospective, nationwide, observational study in patients with HPV-related OPSCC who were treated from 2011 to 2014 in Japan to determine the best treatment modality., Results: A total of 688 patients who were newly diagnosed with HPV-related OPSCC who were treated with curative intent at 35 institutions and had coherent clinical information and follow-up data available were included in the current study. In patients with T1-T2N0 disease (79 patients), both the 3-year recurrence-free survival and overall survival (OS) rates were 100% in the group treated with radiotherapy (RT) as well as the group receiving concurrent chemoradiotherapy (CCRT). The 3-year OS rates were 94.4% (for patients with T1N0 disease) and 92.9% (for patients with T2N0 disease) among the patients treated with upfront surgery. In patients with stage I to stage II HPV-related OPSCC, the 5-year recurrence-free survival and OS rates were 91.4% and 92%, respectively, in the patients treated with CCRT with relatively high-dose cisplatin (≥160 mg/m 2 ; 114 patients) and 74.3% and 69.5%, respectively, in the patients treated with low-dose cisplatin (<160 mg/m 2 ; 17 patients)., Conclusions: Despite it being a retrospective observational trial with a lack of information regarding toxicity and morbidity, the results of the current study demonstrated that patients with T1-T2N0 HPV-related OPSCC could be treated with RT alone because of the equivalent outcomes of RT and CCRT, and patients with stage I to stage II HPV-related OPSCC other than those with T1-T2N0 disease could be treated with CCRT with cisplatin at a dose of ≥160 mg/m 2 ., (© 2020 American Cancer Society.)

Background/aim: Immune-related adverse events (irAEs) are associated with the efficacy of immune-checkpoint inhibitors in patients with melanoma and non-small cell lung cancer. We therefore evaluated the relationship between irAEs and nivolumab efficacy against metastatic renal cell carcinoma., Patients and Methods: The medical records of 53 consecutive patients were reviewed and analyzed., Results: Median overall survival was significantly better in patients who showed irAEs at any time compared to patients without irAEs (p=0.013). We identified irAEs in 24 of 53 patients (45.3%), including four patients (7.5%) with grade 3 events. Multivariate analysis also revealed that risk factors for the onset of irAEs were positively associated with a platelet-to-lymphocyte ratio <156 before nivolumab treatment (p=0.006)., Conclusion: Development of irAEs was associated with survival outcomes of nivolumab treated patients with metastatic renal cell carcinoma., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This paper describes a seven-step synthesis of the proposed structure for chaunopyran A produced by cocultivation of a Chaunopycnis sp. and Trichoderma hamatum . This synthesis included a coupling of a diene sulfone and a tetrahydropyranyl aldehyde as a key step. The sign of the specific rotation value of the synthetic sample was opposite that of the natural product, suggesting that the absolute configuration of the natural product should be revised.

Because ice surfaces catalyze various key chemical reactions impacting nature and human life, the structure and dynamics of interfacial layers between water vapor and ice have been extensively debated with attention to the quasi-liquid layer. Other interfaces between liquid water and ice remain relatively underexplored, despite their importance and abundance on the Earth and icy extraterrestrial bodies. By in situ optical microscopy, we found that a high-density liquid layer, distinguishable from bulk water, formed at the interface between water and high-pressure ice III or VI, when they were grown or melted in a sapphire anvil cell. The liquid layer showed a bicontinuous pattern, indicating that immiscible waters with distinct structures were separated on the interfaces in a similar manner to liquid-liquid phase separation through spinodal decomposition. Our observations not only provide a novel opportunity to explore ice surfaces but also give insight into the two kinds of structured water.

Objectives: Crescentic IgA nephropathy (C-IgAN) is defined as IgAN with more than 50% of glomeruli showing crescents. C-IgAN in children is rare; we investigate in detail for the first time., Methods: We retrospectively analyzed the 515 consecutive children who were newly diagnosed with biopsy-proven IgAN between June 1976 and May 2010. We compared clinical and pathological findings between C-IgAN and non-C-IgAN., Results: Among 515 cases of childhood IgAN, 25 children (4.9%) had C-IgAN. Of these 25, 16 children (64%) were referred to hospitals by annual school screening. Clinical findings showed significant differences in gross hematuria (76 vs. 50%, p = .03), excretion of proteinuria (1.9 vs. 0.5 g/day/m 2 , p < .0001), eGFR (102 vs. 108 ml/min/1.73 m 2 , p = .03), and duration from onset to renal biopsy (4.0 vs. 8.0 months, p = .04) between groups. Pathological findings showed significant differences in M1 (88 vs. 55%, p = .02), E1 (83 vs. 53%, p = .008), and presence of tubular atrophy/interstitial fibrosis (88 vs. 53%, p < .0001) between groups. The 16 children with C-IgAN were treated with prednisolone and immunosuppressant. Four cases (16%) reached chronic renal failure (eGFR < 60) at the latest observation (mean observation period: 6.0 ± 3.6 years). Patients with C-IgAN had significantly lower renal survival curve than non-C-IgAN patients according to Kaplan-Meier analysis (77.1% vs. 92.6% at 13 years, p < .0001). Compared with previous reports, however, they had better renal outcome., Conclusions: We confirmed the importance of school screening to find C-IgAN. Although most crescents (mean: 98.1%) of C-IgAN were cellular/fibrocellular, and acute lesions were well modified with combination therapy, the presence of tubular atrophy in C-IgAN may be the reason for poorer prognosis.

The origin and evolution of solar system bodies, including water on the Earth, have been discussed based on the assumption that the relevant ingredients were simply silicates and ices. However, large amounts of organic matter have been found in cometary and interplanetary dust, which are recognized as remnants of interstellar/precometary grains. Precometary organic matter may therefore be a potential source of water; however, to date, there have been no experimental investigations into this possibility. Here, we experimentally demonstrate that abundant water and oil are formed via the heating of a precometary-organic-matter analog under conditions appropriate for the parent bodies of meteorites inside the snow line. This implies that H 2 O ice is not required as the sole source of water on planetary bodies inside the snow line. Further, we can explain the change in the oxidation state of the Earth from an initially reduced state to a final oxidized state. Our study also suggests that petroleum was present in the asteroids and is present in icy satellites and dwarf planets.

The relationship between fouling development in a continuous laboratory-scale membrane reactor (MBR/Lab) and the membrane material was investigated using flat-sheet membranes prepared from four materials (polyvinylidene difluoride (PVDF), polyethersulfone, chlorinated polyvinyl chloride, and polytetrafluoroethylene). Further, the characteristics of the suspension liquid in MBR/Lab were compared with those of samples from actual wastewater treatment plants. It was found that, in addition to the membrane material's own characteristics, the structural vulnerability of the membranes had a determining effect on fouling development. The PVDF membrane showed the highest transmembrane pressure during MBR operation and its surface experienced significant damage because of the shearing stress caused by aeration, resulting in the penetration of the membrane by the fouling compounds. The characteristics of suspension liquid in MBR/Lab were almost similar to those in the MBR at a night-soil treatment plant and the aeration tank of a sewage treatment plant., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Although a short hydration protocol for cisplatin has been recently developed for use in lung cancer, this has yet to be established for gastric cancer. This study reviewed medical records of patients with gastric cancer who received XPT(capecitabine/cisplatin/trastuzumab) therapy containing cisplatin. Patients received either the conventional or short hydration regimen. Nephrotoxicity was compared between these two regimens by monitoring the serum creatinine. Out of the 26 total patients, 19 received the conventional regimen while 7 received the short hydration regimen. There was a higher nephrotoxicity was observed in the group receiving the conventional regimen (42.1%, 8/19) as compared to the short hydration regimen (0%, 0/7). There was a statistically significant difference in nephrotoxicity between the regimens ( P  = 0.039). Study results suggest that short hydration may be a feasible regimen for XPT therapy in gastric cancer patients.

Background: Epigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair enzyme via promoter hypermethylation (hmMGMT) may increase mutations in the TP53 oncosuppressor gene and contribute to carcinogenesis. The effects of smoking, which is a risk factor for head and neck squamous cell carcinoma (HNSCC), were investigated to determine whether they up- or down-regulate hmMGMT. Additionally, the impact of hmMGMT and disruptive TP53-mutations on relapse was investigated in patients with HNSCC., Methods: This study included 164 patients with HNSCC who were negative for both p16 protein expression and human papilloma virus infection. The association of smoking and hmMGMT was investigated using multiple logistic regression analysis. Competing risk regression was used to evaluate the effects of hmMGMT and TP53-mutations in exon 2 to 11 on relapse of HNSCC., Results: hmMGMT was observed in 84% of the 164 patients. TP53-mutations, specifically, G:C>A:T transition, were more frequent in patients with hmMGMT (32%) than in those without hmMGMT (8%). The frequency of disruptive TP53-mutations was not significantly different between groups. Compared with nonsmoking, heavy smoking of 20 pack-years or more was significantly associated with decreased hmMGMT (adjusted odds ratio, 0.08; 95% CI, 0.01 to 0.56; P = 0.01). Patients who had both hmMGMT and disruptive TP53-mutations showed a significantly higher relapse rate than all other patients (subdistribution hazard ratio, 1.77; 95% CI, 1.07 to 2.92; P = 0.026)., Conclusions: It was found that hmMGMT was suppressed by heavy smoking, and hmMGMT combined with disruptive TP53-mutations may indicate a poor prognosis in patients with HNSCC., Competing Interests: The author SM is an employee of Chugai Pharmaceutical Co. Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors AM, NK, TH and MU have declared that there are no competing interests.

Background/aim: This study aimed was to clarify the impact of pegfilgrastim (PEG) 3.6 mg primary prophylaxis of febrile neutropenia (FN) on the average relative dose intensity (ARDI) of neoadjuvant/adjuvant FEC-100 for breast cancer., Materials and Methods: This retrospective, single-centre cohort study including 296 patients who received FEC-100 compared PEG and non-PEG groups. The PEG group received PEG 3.6 mg as a single subcutaneous injection in each study cycle. The primary endpoint was the ARDI of FEC-100. The secondary endpoints were patient percentage of ARDI≥85%, factors associated with ARDI≥85%, and reasons for reduced ARDI., Results: The PEG group showed significantly higher mean ARDI (95.6% versus 90.7%, p<0.001) and patient percentage of ARDI≥85% (93.0% versus 79.9%, p=0.001). PEG was significantly associated with ARDI≥85% (p=0.009). Neutropenia and FN, the main reasons for reduced ARDI, were significantly lower in the PEG group (p<0.05)., Conclusion: Primary PEG 3.6 mg prophylaxis increased the ARDI of FEC-100., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The air-water interface plays central roles in "on-droplet" synthesis, living systems, and the atmosphere; however, what makes reactions at the interface specific is largely unknown. Here, we examined carbocationic reactions of monoterpene (C 10 H 16 isomer) on an acidic water microjet by using spray ionization mass spectrometry. Gaseous monoterpenes are trapped in the uppermost layers of a water surface via proton transfer and then undergo a chain-propagation reaction. The oligomerization pathway of β-pinene ( β-P ), which showed prompt chain-propagation, is examined by simultaneous exposure to camphene ( CMP ). ( CMP )H + is the most stable isomer formed via rearrangement of ( β-P )H + in the gas phase; however, no co-oligomerization was observed. This indicates that the oligomerization of ( β-P )H + proceeded via ring-opening isomerization. Quantum chemical calculations for [carbocation-(H 2 O) n =1,2 ] complexes revealed that the ring-opened isomer is stabilized by hydrogen-π bonds. We propose that partial hydration is a key factor that makes the interfacial reaction unique.

Background: The reported incidence of venous thromboembolism (VTE) in cancer patients is 4-20%. The Khorana VTE risk score (KRS) and the Vienna VTE risk score (VRS) have been proposed as scoring models for evaluation of cancer-associated VTE. However, the risk factors of VTE in Japanese lung cancer patients have not been clarified., Methods: This retrospective study included 682 hospitalized Japanese patients with newly diagnosed lung cancer who were examined for VTE on admission between January 2014 and December 2016., Results: Seventy-one (10.4%) of the 682 patients were diagnosed with VTE. Multivariate logistic regression analysis showed that body mass index (BMI) ≥25 kg/m 2 (OR, 2.02; 95% CI, 1.06-3.72), white blood cell (WBC) count >11 × 10 9 /L (OR, 2.31; 95% CI, 1.11-4.61), pre-chemotherapy serum D-dimer concentration ≥1.44 μg/mL (OR, 2.73; 95% CI, 1.49-4.99), and non-small cell lung cancer (OR, 3.13; 95% CI, 1.32-9.23) were significantly associated with VTE in these patients. The cut-off values for BMI, WBC count, and D-dimer concentration determined using receiver operating characteristic curves were 25.4 kg/m 2 , 11.2 × 10 9 /L, and 1.95 µg/mL, respectively., Conclusions: In this study, we were able to identify four independent risk factors for cancer-associated VTE in Japanese lung cancer patients for the first time. Moreover, we showed that a cut-off level of ≥25 kg/m 2 for BMI was a risk factor for VTE in this cohort., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The long-term orthostatic and/or exercise hemodynamic effects in children years after Kawasaki disease (KD) were studied using clinical data from the treadmill exercise test (TMET). Heart rate (HR) and blood pressures (BPs) recorded in TMET were compared between two age, gender, and body scale-matched groups of patients with and without a history of KD. The KD group included 60 patients (9.8 ± 2.7 years old) 6.6 ± 2.6 years after KD without coronary arterial aneurysm. The non-KD group included 60 children (10.2 ± 2.7 years old) with other diagnoses. The exercise tolerance in TMET was not statistically different between the two groups. The KD group had a faster HR on standing than the non-KD group by 8.6% (101.5 ± 12.2 vs. 93.5 ± 15.9 bpm, respectively; P < 0.01), suggesting weaker and/or retarded orthostatic vasoconstriction. The pulse pressure was largely augmented above the 4th stage beyond 160 mmHg in 10.6 versus 0% (5 vs. 0) of the KD and non-KD groups (P < 0.05), respectively, while HR and BPs were not significantly different through exercise stages between the two groups. The KD group also showed a faster HR recovery five minutes after exercise than the non-KD group, by 5.7% (108.0 ± 11.6 vs. 102.2 ± 14.2 bpm, respectively; P < 0.05). Our results might indicate long-term subclinical impacts on the vascular tonus of children years after the disease that have not been recognized in previous studies.

Purpose: Immune-related adverse events (irAEs) have been associated with the efficacy of programmed cell death protein 1 (PD-1) inhibitors in patients with urothelial cancer. We therefore evaluated the relationship between irAEs and pembrolizumab efficacy in urothelial cancer patients., Methods: Patients with urothelial cancer who were treated with pembrolizumab in a second-line setting or later between January 2018 and December 2018 were identified by reviewing their medical records from the Cancer Institute Hospital, Japanese Foundation for Cancer Research. Data were updated as of December 31, 2018. Kaplan-Meier curves for overall survival (OS) and time to treatment failure (TTF) according to irAE grade were evaluated using the log-rank test. Risk factors for exacerbation of irAEs were also evaluated with multivariate analysis., Results: In this retrospective study, 43 patients received pembrolizumab. We identified irAEs in 22 of the 43 patients (51.2%), including 11 patients (25.6%) with grade 2 or 3 events. In patients with irAE grade 0 or 1, median TTF was 127 days, and median OS was 160 days according to the Kaplan-Meier method. On the other hand, in patients with irAE grade ≥2, median TTF and OS were not reached. Multivariate analysis also revealed that risk factors for exacerbation of irAEs (to grade ≥2) were positively associated with lymphocyte count at baseline (>2,000/µL) before pembrolizumab treatment (p = 0.021)., Conclusions: Development of irAEs was associated with survival outcome of pembrolizumab treatment in patients with advanced urothelial cancer., (© 2020 S. Karger AG, Basel.)

Several studies have reported increased anticoagulation effect of warfarin(WF)when combined with tyrosine kinase inhibitors(TKIs), such as gefitinib and erlotinib. However, effects of TKIs other than gefitinib and erlotinib on the anticoagulation effect of WF have not been clarified. To assess the degree and onset of prothrombin time-international normalized ratio (PT-INR)elevation and changes in WF daily doses in patients additionally receiving TKIs, this retrospective, single-center observational study compared PT-INR values and WF daily doses during WF treatment in the absence and presence of TKIs. Seven different TKIs(afatinib, alectinib, axitinib, crizotinib, pazopanib, regorafenib, and vandetanib)were prescribed during treatment with WF of venous thromboembolism in 10 cancer patients. Compared to baseline PT-INR, significant PT-INR elevations were observed in all patients during the combination therapy. The median PT-INR increased 1.6-fold from the baseline in the presence of TKIs(p<0.01), and the onset of PT-INR elevation was observed at a median of 18 days. As all patients receiving WF with the 7 TKIs showed PT-INR elevation, enhancement of the anticoagulation effect of WF in the presence of TKIs appears to be highly frequent. PT-INR should be carefully monitored, and adjusting the WF dosage may become necessary during the WF and TKI combination therapy.

Introduction: Regorafenib is an oral multikinase inhibitor for the treatment of metastatic colorectal cancer (mCRC). The clinical factors that may affect adherence to regorafenib remain unclear. The aim of this study was to evaluate adherence to regorafenib with mCRC and to identify factors that might affect adherence to regorafenib., Methods: A total of 108 consecutively enrolled Japanese patients with mCRC received regorafenib. Adherence was measured by pharmacists using pill counts and a self-reported treatment diary for patients at a pharmaceutical outpatient clinic. The median relative dose intensities of regorafenib and the factors adversely affecting adherence were retrospectively surveyed. Logistic regression analysis was then performed using patient socio-demographic factors and clinical factors., Results: A total of 96 patients were included in the analysis. The median adherence rate was 61.7% in the first cycle. The median relative dose intensity was 57.1%. The most common reason for non-adherence was a hand-foot-skin reaction (35.6%). On multivariate analysis, increased non-adherence to regorafenib was significantly associated with sex (female) [odds ratio (OR) = 4.36; 95% confidence interval (CI): 1.43-13.22, p = 0.01]., Discussion: Hand-foot-skin reactions and female sex were associated with lower adherence to regorafenib. Since these factors could be associated with lower adherence to regorafenib, it would be useful to consider these factors when assessing adherence., Competing Interests: The abstract of this paper was presented at the 2017 Gastrointestinal Cancer Symposiumu (ASCO-GI) as poster presentation. The poster’s abstract was published in “Poster Abstracts” in J Clin Oncol, 35 (suppl 4S) (2017). K. Yamaguchi has received speaking honorariums from Taiho Pharmaceutical, Chugai Pharmaceutical, Merck Serono, Takeda Pharmaceutical, Yakult, Bayer, Ono Pharmaceutical, Eli Lilly, Sanofi and Bristol-Myers Squibb, and has received research grants from MSD, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Daiichi Sankyo, Eli Lilly, Gilead Sciences and Yakult, and has served on consulting or advisory role for Bristol-Myers Squibb. The other authors declare that they have no competing interests., (© 2019 Kawakami et al.)

Background: Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib., Objective: To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity., Methods: This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study., Results: Compared with international normalized ratio at the baseline significant ( P  < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing., Conclusion: In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.

Few studies have evaluated the influence of anticancer drugs on the anticoagulation response to warfarin(WF). This retrospective, single-center, observationalstudy evaluated the changes in prothrombin time-internationalnormal ized ratio (PT-INR)in patients receiving a combination of WF and anticancer drugs. We compared(a)PT-INR changes between groups receiving WF and concomitantly started on either tyrosine kinase inhibitors(TKI)(WF+TKI group: n=14)or anticancer drugs other than TKI(WF+non-TKI group: n=20)and(b)PT-INR changes between groups that were started on WF concomitantly while receiving either TKI(TKI+WF group: n=16)or anticancer drugs other than TKI(non-TKI+WF group: n=13). (a)PT-INR changes were significantly larger in the WF+TKI group than in the WF+non-TKI group(2.23 vs 0.42, p<0.001). In the WF+TKI group, the WF dose was reduced after all 14 patients(100.0%)showed increased PT-INR.(b)PT-INR changes during the WF induction period were significantly larger in the TKI+WF group than in the non-TKI+WF group(2.18 vs 0.68, p<0.001). In the TKI+WF group, the WF dose was reduced after 12 patients(75.0%)showed increased PT-INR. It might be necessary to consider a reduction in WF dose when WF is administered in combination with TKIs.

Aims and Objectives: To explore the differences in clinical practice activities and work-related burden between nurses with past work experience other than nursing (second career nurses: SCNs) and nurses without any past work experience (nonsecond career nurses: NSCNs)., Background: The number of SCNs is increasing. Some studies note that SCNs must perform additional clinical practice activities and experience more work-related burden than NSCNs. However, there are no quantitative studies exploring SCNs' clinical practice and work-related burden., Design: A cross-sectional survey., Methods: Research was conducted according to the STROBE statement. Participants were 2,013 nurses working at 56 hospitals in Japan. A 30-item questionnaire was developed to capture clinical practice activities using clinical ladders, asking about the types of clinical practice activities participants had practiced. Every practiced activity received a score of 1. The total count of each clinical practice activity was then summed. The quantitative workload (QW) scale score was used to investigate levels of QW. Higher QW scores indicated higher levels of work-related burden. These variables were then compared between SCNs and NSCNs, and the factors that were associated with high QW among SCNs were examined., Results: Altogether, 961 participants (328 SCNs and 633 NSCNs) were included in the analyses. No significant differences were shown in clinical practice activities between the groups; however, SCNs' QW was significantly higher than was NSCNs' after controlling for demographic variables. SCNs' high QW was associated with the following variables: unmarried marital status, not having role model nurses and previous employment as a care worker., Conclusions: Quantitative workload was significantly higher among SCNs than among NSCNs. Tailored support for SCNs' high QW based on their specific needs should be considered., Relevance to Clinical Practice: These results can help nurse managers reduce SCNs' work-related burden and illustrate future research directions for this minority group., (© 2019 John Wiley & Sons Ltd.)

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a potentially lethal hyperinflammatory disorder. For further understanding of the pathogenesis of HLH, we examined serum levels of high mobility group box protein 1 (HMGB1) in children with HLH., Patients and Methods: Serum HMGB1 levels were measured in 28 patients with HLH and 6 normal controls using a quantitative enzyme-linked immunosorbent assay. The patients were 21 boys and 7 girls, aged from 10 days to 21 years, with a median age of 8.5 years. The underlying conditions of HLH were infection-associated HLH in 18 patients, malignancy-associated HLH in 7 patients, and genetic HLH in 3 patients. The relations between serum HMGB1 levels and clinical symptoms and laboratory parameters were analyzed., Results: Serum HMGB1 levels were significantly higher in patients with HLH than in normal controls (median, 6.5 ng/mL, interquartile range, 4.25-13.1). The serial serum HMGB1 levels in one patient fell to reflect the disease activity. Serum HMGB1 levels were significantly higher in patients with disseminated intravascular coagulation (DIC) than in patients without DIC ( p <0.001) and were also significantly higher in patients with central nervous system (CNS) complications than in patients without CNS complications ( p< 0.01). Serum HMGB1 levels were positively correlated with aspartate aminotransferase ( r s   =0.48, p <0.01, Spearman's rank correlation coefficient) and negatively correlated with fibrinogen ( r s   = -0.475, p =0.011) and hemoglobin ( r s   = -0.465, p =0.013)., Conclusion: Serum HMGB1 levels reflect clinical features of childhood HLH. HMGB1 is a potential mediator involved in the pathogenesis and determining the clinical findings of HLH., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Tsujimoto et al.)

The surface of most aerial plant organs is covered with the cuticle, a membrane consisting of a variety of organic compounds, including waxes, cutin (a polyester) and polysaccharides. The cuticle serves as the multifunctional interface between the plant and the environment, and plays a major role in protecting plants against various environmental stress factors. Characterization of the molecular arrangements in the intact cuticle is critical for the fundamental understanding of its physicochemical properties; however, this analysis remains technically challenging. Here, we describe the nondestructive characterization of the intact cuticle of Brassica oleracea L. leaves using polarization modulation-infrared (IR) reflection-absorption spectroscopy (PM-IRRAS). PM-IRRAS has a probing depth of less than several hundreds of nanometers, and reveals the crystalline structure of the wax covering the cuticle surface (epicuticular wax) and the nonhydrogen-bonding character of cutin. Combined analysis using attenuated total reflection-IR spectra suggested that hemicelluloses xylan and xyloglucan are present in the outer cuticle region close to the epicuticular wax, whereas pectins are dominant in the inner cuticle region (depth of ≤2 μm). PM-IRRAS can also determine the average orientation of the cuticular molecules, as indicated by the positive and negative spectral peaks. This unique advantage reveals the orientational order in the intact cuticle; the hydrocarbon chains of the epicuticular wax and cutin and the backbones of hemicelluloses are oriented perpendicular to the leaf surface. PM-IRRAS is a versatile, informative and easy-to-use technique for studying plant cuticles because it is nondestructive and does not require sample pretreatment and background measurements., (� The Author(s) 2019. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Chrysotile asbestos has been used in Thailand for over 30 years mainly in asbestos-cement wall and roof tiles. In non-exposed subject, asbestos fiber can contaminate in ambient indoor and outdoor environments., Objective: The aim of the present study is to evaluate the current prevalence and volume of AB load in general Thai population., Methods: Lung tissues were obtained from 200 autopsy cases. Asbestos Bodies (AB) were identified with light microscopy using the tissue digestion and membrane filtration method. Results are reported as AB/g wet lung tissue., Results: AB was identified in 97(48.5%) out of 200 cases. The AB level ranged from 0.19-14.4 AB/g wet lung. Most of the positive cases (99%) have less than 10 AB/g wet lung. Only one case exhibited a high value at 14.4 AB/g wet lung. Age, gender, occupation and hometown were found to have no effect on AB burden in autopsy lung tissue from this study., Conclusion: The prevalence of AB in autopsy lung tissue from general Thai population is 48.5% and the AB level ranges from 0-14.4 AB/g wet lung in consistent with non-occupational asbestos exposure level regarding several reference reports., (© 2019 Bentham Science Publishers.)

Regorafenib is a multikinase inhibitor for the treatment of metastatic colorectal cancer. Regorafenib-induced hand-foot skin reaction (HFSR) is a common side effect during treatment. The reported frequency of HFSR was 80% (grade 3: 28%) in the Japanese subpopulation in the CORRECT trial; however, more detailed data regarding HFSR in terms of onset and sites of susceptibility are unclear. Additionally, the risk factors for regorafenib-induced severe HFSR are unknown. The aim of this study was to compare HFSR between the hands and feet and identify preexisting risk factors for severe HFSR in Japanese patients receiving regorafenib. We retrospectively examined the onset and severity of HFSR on the hands and feet of patients with metastatic colorectal cancer treated with regorafenib from May 2013 to October 2015 in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. In addition, we examined the possible association between preexisting clinical factors and severe HFSR. Our results showed that no significant difference in the incidence of HFSR of any grade was observed between the hands (71%) and feet (74%) ( p  = 0.63). The incidence of grade 3 HFSR was more frequent on the feet (33%) than on the hands (8%) ( p  < 0.01). The onset of grade 3 HFSR was earlier on the feet than on the hands ( p  < 0.001). No preexisting risk factor was identified. Our findings indicate that severe HFSR was more prevalent on the feet than on the hands, suggesting the need for appropriate screening for early detection and treatment of regorafenib-induced HSFR.

The ice premelt, often called the quasi-liquid layer (QLL), is key for the lubrication of ice, gas uptake by ice, and growth of aerosols. Despite its apparent importance, in-depth understanding of the ice premelt from the microscopic to the macroscopic scale has not been gained. By reviewing data obtained using molecular dynamics (MD) simulations, sum-frequency generation (SFG) spectroscopy, and laser confocal differential interference contrast microscopy (LCM-DIM), we provide a unified view of the experimentally observed variation in quasi-liquid (QL) states. In particular, we disentangle three distinct types of QL states of disordered layers, QL-droplet, and QL-film and discuss their nature. The topmost ice layer is energetically unstable, as the topmost interfacial H 2 O molecules lose a hydrogen bonding partner, generating a disordered layer at the ice-air interface. This disordered layer is homogeneously distributed over the ice surface. The nature of the disordered layer changes over a wide temperature range from -90 °C to the bulk melting point. Combined MD simulations and SFG measurements reveal that the topmost ice surface starts to be disordered around -90 °C through a process that the topmost water molecules with three hydrogen bonds convert to a doubly hydrogen-bonded species. When the temperature is further increased, the second layer starts to become disordered at around -16 °C. This disordering occurs not in a gradual manner, but in a bilayer-by-bilayer manner. When the temperature reaches -2 °C, more complicated structures, QL-droplet and QL-film, emerge on the top of the ice surface. These QL-droplets and QL-films are inhomogeneously distributed, in contrast to the disordered layer. We show that these QL-droplet and QL-film emerge only under supersaturated/undersaturated vapor pressure conditions, as partial and pseudopartial wetting states, respectively. Experiments with precisely controlled pressure show that, near the water vapor pressure at the vapor-ice equilibrium condition, no QL-droplet and QL-film can be observed, implying that the QL-droplet and QL-film emerge exclusively under nonequilibrium conditions, as opposed to the disordered layers formed under equilibrium conditions. These findings are connected with many phenomena related to the ice surface. For example, we explain how the disordering of the topmost ice surface governs the slipperiness of the ice surface, allowing for ice skating. Further focus is on the gas uptake mechanism on the ice surface. Finally, we note the unresolved questions and future challenges regarding the ice premelt.

There are growing concerns about nitrate contamination in Kumamoto City, where >700,000 people completely depend on groundwater as a source of drinking water. We found that some groundwater samples showed considerably different nitrate concentrations although their sampling locations were close to one another, and we speculated that this phenomenon was due to the differences in subsurface geological properties. In order to verify this hypothesis, we carried out temporally intensive long-term monitoring of the groundwater levels and water qualities at three of the closely related sampling wells, and the results revealed that the changes in water level and water quality were different at each well. The water level at well T1, where nitrate concentrations ranged from 12 to 26 mg N/L, showed a significantly sensitive and unique response to heavy rain, which indicated that the subsurface at this site might be highly permeable; this would have allowed for the influent water to easily reach the groundwater aquifer over a short period. However, wells T2 and T3, which were located within 0.6 and 1.9 km from well T1, respectively, had nitrate concentrations that were lower than that in well T1 (4.5-8.0 mg N/L) and showed only gradual responses to heavy rain. These observations suggest that the highly permeable subsurface properties in the vicinity of well T1 contributed to the more serious nitrate contamination in well T1 than those at wells T2 and T3. This study demonstrates the importance of temporally intensive, long-term monitoring for capturing changes in groundwater level and water quality with precipitation fluctuations, and we showed how this approach can lead to a better understanding of the nitrate contamination situation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: The triplet antiemetic regimen is recommended for cisplatin-based highly emetogenic chemotherapy, in the current guidelines for antiemetic prophylaxis. Although risk factors related to chemotherapy-induced nausea and vomiting (CINV) have been identified by several prior studies, there are only few studies evaluating risk factors associated with the prophylactic triplet antiemetic therapy, particularly in palonosetron use. The present study aimed to reveal the risk factors related to CINV development in patients receiving cisplatin and to compare CINV risk factors between palonosetron and granisetron use., Methods: In total, 825 patients in a phase III trial receiving palonosetron with graniestron were evaluated. Multivariate logistic regression models were used to predict risk factors associated with CINV development. Additionally, risk factors associated with CINV development were separately evaluated in each treatment group., Results: Multivariate analysis of the entire study group revealed that sex, age, cisplatin dose, and granisetron use were significant and independent factors affecting CINV development in the overall phase. Similarly, sex and age were risk factors for CINV in both treatment groups. Kaplan-Meier curves classified by each treatment group showed no significant difference between the groups among patients without any risk factors for CINV (P = 0.353). Conversely, complete response rates for patients with at least one risk factor were higher in patients receiving palonosetron (P = 0.049)., Conclusions: This analysis revealed the importance of previously reported CINV risk factors when using triplet antiemetics. Palonosetron might be preferred for patients with at least one risk factor.

Nutrients are heterogeneously distributed in the soil environment. Plants have evolved a variety of mechanisms to maximise their ability to compete for limited resources, with differential root growth considered among the more important mechanisms. Despite the significant costs of root growth, little data is available regarding carbon (C) allocation to roots growing in heterogeneous conditions. Here, we investigate the allocation of recently assimilated C in Poa annua plants growing in uniform or heterogeneous nutrient conditions. In the first experiment we grew plants in split-root boxes, providing N either equally between the two chambers (0.5 mg/0.5 mg, 8 mg/8 mg) or with one side receiving more N (0.5 mg/8 mg, 8 mg/0.5 mg), and quantified C allocation and N uptake using 13 CO 2 and K 15 NO 3 . Where N was supplied equally to the two chambers, C was allocated equally to the roots irrespective of the total N supply. However, the 13 C label was preferentially allocated (60:40) to high-N roots in the unequal treatments. N uptake was a function of local supply and was not affected by N supply to the roots in the other chamber. C allocation had no discernible effect on N uptake. In the second experiment, we tested whether differential N supply would lead to increased root growth in the high-N side. In this experiment, equal amounts of N were supplied to all plants as ammonium, with half receiving an equal distribution to the two root chambers (50/50), while the other half received an unequal supply (94/6). While no difference in root growth was noted in 50/50 plants, a 60:40 mass allocation was noted from day six onwards in plants receiving the 94/6 N supply. Despite increased root growth in the high-N side, the plants receiving the 94/6 treatment could not achieve the same shoot mass or N concentration as the 50/50 plants. No difference in total C allocation to the roots between treatments was noted in the first experiment, and no difference in total root mass between treatments was found in the second experiment, suggesting that root C supply was source-limited, while allocation to specific roots was strongly influenced by sink strength. Differential C allocation appears to be an important pre-requisite for increased root growth in N-rich patches., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Nitrogen-removal processes using anammox bacteria are expected to achieve high-rate removal while remaining economical, and their practical applications have been investigated. However, anammox bacteria still have unfavorable characteristics for practical use, including susceptibility to a change in environmental conditions. In this study, with an aim of exploring the adaptability of mixed anammox bacteria to environmental conditions, the shift of nitrogen-removal performance and bacterial community in a mixed culture comprising freshwater anammox bacteria (FAB) and marine anammox bacteria (MAB) were investigated by a continuously stirred tank reactor (CSTR). The CSTR inoculated with the mixed anammox bacteria was operated for 180 days under an averaged condition between freshwater and marine conditions with a temperature of 27.5 °C and a synthetic medium with 15 g/L NaCl was used. Nitrogen-removal performance became stable after 114 days and more than 90% of nitrogen that was loaded into the reactor was removed in the range of nitrogen loading rate 0.07-0.42 kg N/m 3 /d. After operating at 0.42 kg N/m 3 /d for one month, a biomass sample was taken and its bacterial community was analyzed by clone-library analysis using a partial sequence of 16S rRNA. Among the clones of anammox bacteria that were made by an anammox-bacteria-specific primer, 97% of them were MAB and only 3% were FAB. These results indicate that the bacterial community including anammox bacteria was evidently changed due to environmental conditions and that the averaged condition in this study was suitable for marine bacteria rather than freshwater bacteria., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4. Diagnosis is conventionally made pathologically, but recent advances in comprehensive genetic analysis have enabled genetic testing to be performed for the diagnosis of AS as first-line diagnosis. Because of these advances, substantial information about the genetics of AS has been obtained and the genetic background of this disease has been revealed, including genotype-phenotype correlations and mechanisms of onset in some male XLAS cases that lead to milder phenotypes of late-onset end-stage renal disease (ESRD). There is currently no radical therapy for AS and treatment is only performed to delay progression to ESRD using nephron-protective drugs. Angiotensin-converting enzyme inhibitors can remarkably delay the development of ESRD. Recently, some new drugs for this disease have entered clinical trials or been developed in laboratories. In this article, we review the diagnostic strategy, genotype-phenotype correlation, mechanisms of onset of milder phenotypes, and treatment of AS, among others.

Primary Objective : The aim of this study was to demonstrate the clinical outcomes of long-term multidisciplinary attentive treatment (MAT) in patients with chronic disorders of consciousness (DOC) due to severe traumatic brain injury (TBI) following automotive accidents. Research Design : Five hundred and ten patients (mean age: 40.4 years) were enrolled in this retrospective study. Methods and Procedures : Patients were provided MAT for one to several years in the eight medical facilities of the National Agency for Automotive Safety and Victims' Aid (NASVA) in Japan. Clinical status for consciousness, communication, and activities of daily living were evaluated using the NASVA grading system. Outcomes and results : Following MAT, NASVA scores at discharge were significantly improved compared to those at admission in every patient subgroup including sex, age, NASVA score, and association with/without hypoxic encephalopathy at admission. Younger age, shorter interval between injury and admission, and better neurocognitive function at admission were found to be significant and independent factors for a good prognosis. Conclusions : MAT can partially improve the cognitive and physical abilities of patients with chronic DOC. From the perspective of not only restoring a patient's daily life, but also reducing the caregiver's burden, this type of treatment program warrants more public attention.

Purpose: Hand-foot skin reaction (HFSR) can deteriorate quality of life in patients receiving regorafenib. Cutaneous toxicity is a main adverse effect of multikinase inhibitors and has also been associated with clinical outcome. This study assessed the association between the antitumor efficacy of regorafenib and HFSR in patients with metastatic colorectal cancer (mCRC)., Methods: Patients who received regorafenib at 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they developed HFSR between May 2013 and October 2015. Estimates of overall survival and progression-free survival were calculated using the Kaplan-Meier method., Results: Ninety-seven patients received at least one dose of regorafenib in this retrospective study. Of these patients, 81.4% (n = 79) experienced HFSR of any grade, and 34.0% (n = 33) had grade 3 HFSR. Among those patients with HFSR at any time during the study, 68.0% (n = 66) underwent the first HFSR event (any grade) during cycle 1. Both overall survival and progression-free survival were improved in patients who had HFSR grade ≥2 at any time compared with those who had HFSR grade ≤1. Multivariate logistic regression analysis revealed a history of HFSR grade ≥2 induced by capecitabine as a significant risk factor for severe HFSR (grade ≥2)., Conclusions: Patients with mCRC treated using regorafenib who experienced severe HFSR showed better overall survival than patients without severe HFSR. Severe HFSR may offer an early surrogate marker for the efficacy of regorafenib in patients with mCRC., (© 2019 S. Karger AG, Basel.)

Background: We conducted an economic assessment using test data from the phase III TRIPLE study, which examined the efficacy of a 5-hydroxytryptamine 3 receptor antagonist as part of a standard triplet antiemetic regimen including aprepitant and dexamethasone in preventing chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy (HEC)., Methods: We retrospectively investigated all medicines prescribed for antiemetic purposes within 120 h after the initiation of cisplatin administration during hospitalization. In the TRIPLE study, patients were assigned to treatment with granisetron (GRA) 1 mg ( n  = 413) or palonosetron (PALO) 0.75 mg ( n  = 414). The evaluation measure was the cost-effectiveness ratio (CER) assessed as the cost per complete response (CR; no vomiting/retching and no rescue medication). The analysis was conducted from the public healthcare payer's perspective., Results: The CR rates were 59.1% in the GRA group and 65.7% in the PALO group ( P  = 0.0539), and the total frequencies of rescue medication use for these groups were 717 (153/413 patients) and 573 (123/414 patients), respectively. In both groups, drugs with antidopaminergic effects were chosen as rescue medication in 86% of patients. The costs of including GRA and PALO in the standard triplet antiemetic regimen were 15,342.8 and 27,863.8 Japanese yen (JPY), respectively. In addition, the total costs of rescue medication use were 73,883.8 (range, 71,106.4-79,017.1) JPY for the GRA group and 59,292.7 (range, 57,707.5-60,972.8) JPY for the PALO group. The CERs (JPY/CR) were 26,263.4 and 42,628.6 for the GRA and PALO groups, respectively, and the incremental cost-effectiveness ratio (ICER) between the groups was 189,171.6 (189,044.8-189,215.5) JPY/CR., Conclusions: We found that PALO was more expensive than GRA in patients who received a cisplatin-based HEC regimen., Competing Interests: HS, RPh.: Pharmacist at Showa University Hospital; KS, RPh. Ph.D.: Pharmacist at Cancer Institute Hospital, Japanese Foundation for Cancer Research; TU, RPh. Ph.D.: Pharmacist at Showa University Hospital; DT, Ph.D.: Pharmacist at School of Pharmaceutical Sciences, University of Shizuoka; TY, M.D. Ph.D.: Statistician at Yokohama City University; HH, RPh.: Pharmacist at National Cancer Center Hospital; KG, M.D. Ph.D.: Doctor at National Cancer Center Hospital East; RM, RPh.: Pharmacist at National Cancer Center Hospital East; NS, M.D. Ph.D.: Doctor at Teikyo University School of Medicine; T Shimada, RPh.: Pharmacist at Teikyo University Hospital; SI, M.D. Ph.D.: Doctor at International University of Health and Welfare; NI, M.D. Ph.D.: Doctor at St Luke’s International University; TH, RPh. Ph.D.: Pharmacist at Cancer Institute Hospital, Japanese Foundation for Cancer Research; NY, M.D. Ph.D.: Doctor at Wakayama Medical University; T Sasaki, RPh. Ph.D.: Pharmacist at Showa University Hospital.Not applicable.Not applicable.The authors have no conflicts of interest directly relevant to the content of this article.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cabazitaxel, which is a novel semi-synthetic anti-cancerous agent, is newly approved for the treatment of metastatic castration resistant prostate cancer(CRPC). The main dose-limiting toxicity is considered to be febrile neutropenia(FN). In this study, we retrospectively investigated the safety profiles of Japanese patients during cabazitaxel therapy. From September 2014 to August 2016, 17 patients initiated receiving cabazitaxel therapy in our institution. Prophylactically, pegfilgrastim was administered to all patients. Among 17 patients, 5 patients(29.4%)developed FN. Four of these patients(80%)developed FN in the first cycle and could continue the cabazitaxel therapy with dose modification, whereas 1 patient(20%)developed FN leading to septic shock in the 8th cycle. Although he recovered after appropriate medical treatment, he discontinued the cabazitaxel therapy. Regarding non-hematological adverse events, no unknown adverse events were observed. The most frequently observed adverse event was back pain(n=4, 23.5%). There was no influence on the continuation of treatment. Treatment discontinuation due to adverse events was observed in 1 patient(5.9%). Due to the prophylactic pegfilgrastim in combination, the occurrence rate of FN seemed to decrease. However, we must remember that FN is still frequently expressed even under the prophylactic pegfilgrastim.

The estimated domestic usage of DD (a typical nematocide) has been the greatest among all the agricultural chemicals in Japan. DD is involved in a document which is used to establish tap water quality standard in Japan. The document indicates that DD is potentially detectable in raw water for tap waters. DD in raw water will be treated with chlorine at waterworks, which raises concerns about formation of mutagenic chlorination by-products through the treatment. The objective of this work was to identify a mutagenic chlorination by-product by using high resolution mass spectrometers and multivariate analyses. Mutagenicity of the chlorination by-product was evaluated with the Ames Salmonella mutagenicity assay. (E)-1,3-Dichloropropene (DCP) was used as a model compound of DD. The mutagenicity of chlorine treated model aqueous solutions of DD increased with increasing chlorine dosages up to 3.00 mol-Cl 2 /mol-DCP. From the chlorine treated aqueous solutions of DD, 1,3-dichloroacetone (DCA) was identified as a major mutagen by a cochromatography with an authentic standard, precursor ion analyses and first-generation product ion analyses with the high resolution mass spectrometers. The mutagenicity of DCA against TA100 strain without microsomal activation was 160,000 net revertant colony/μmol (the toxicity equivalent factor was 0.14). Based on the mutagenicity of the chlorine treated DCP sample, the specific mutagenicity of DCA, and the DCA concentration in the sample, the mutagenic contribution of DCA to the chlorine treated DCP sample was calculated. High contribution (98%) clearly shows that DCA is a major mutagen in the chlorine treated DCP sample. Because the exploration of DCA was performed by using the unrealistic high concentration samples of DCP and chlorine, formation of DCA in the practical concentration samples (0-200 μg-DCP/L, 0.10 or 1.27 mg-Cl 2 /L) was examined. It was proven that DCA formation reaction takes place in the practical concentrations of DCA and chlorine., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Atmospheric particles contain a wide range of oligomers, but the formation mechanism and the origin of complexity are still unclear. Here, we report the direct detection of carbocationic oligomers generated from the exposure of a series of cyclic unsaturated hydrocarbon gases to acidic water microjets through interface-sensitive mass spectrometry. By changing gas concentrations, H2O (D2O) solvent, bulk pH and comparing results from experiments on acyclic, cyclic, and aromatic compounds, we elucidated three competing reaction mechanisms: chain propagation (CP), chain transfer (CT), and hydride abstraction (HA). We found that conjugative π-electron delocalization in the carbocation is the most important factor for the interfacial oligomerization processes. Our results showed that electrophilic attack on C[double bond, length as m-dash]C double bonds (CP and CT) is limited, and that on C-H single bonds (HA) is enhanced for carbocations lacking conjugation, which is not the case in bulk organic solutions. Carbocationic oligomers generated by the encounter of gaseous unsaturated hydrocarbons and acidic water surfaces potentially contribute to the molecular complexity in atmospheric particles.

Background: Eighty percent of children with steroid-sensitive nephrotic syndrome (SSNS) relapse within 2 years and 40-50% patients show frequently-relapsing nephrotic syndrome (FRNS). Patients showing a relapse within 6 months after initial remission are at high risk of FRNS. Since frequent prednisolone treatment for FRNS induces severe prednisolone side effects, development of a treatment to prevent patients from shifting to FRNS is desirable. Mizoribine is an immunosuppressive drug with fewer side effects than prednisolone. Recent studies reported the efficacy of high-dose mizoribine in children with FRNS., Methods/design: We conduct a multicenter, open, randomized controlled trial to investigate the efficacy and safety of standard prednisolone plus high-dose mizoribine therapy in children with SSNS showing a relapse within 6 months after an initial remission. Patients are allocated to either standard prednisolone alone treatment group, or standard prednisolone plus high-dose mizoribine group. For the former group, mizoribine is administered at a dose of 10 mg/kg/day once daily and continued for 2 years. The primary endpoint is the duration to frequent relapse., Discussion: The results provide important data on use of high-dose mizoribine to prevent SSNS patients from shifting to FRNS. Since blood concentrations of mizoribine have not been investigated in detail until now, there is a possibility that mizoribine is underestimated in favor of other immunosuppressive drugs. In future, high-dose mizoribine therapy may lead to prevention of relapse in children at high risk of FRNS, and to decreased total dose of prednisolone., Trial Registration: UMIN000005103 , (Prospectively registered 1st March 2011).

Recent studies have shown that atmospheric particles are sufficiently acidic to enhance the uptake of unsaturated volatile organic compounds (VOCs) by triggering acid-catalyzed oligomerization. Controlling factors of oligomerization at the aqueous surfaces, however, remain to be elucidated. Herein, isoprene (2-methyl-1,3-butadiene, ISO), 1,3-butadiene (1,3-b), 1,4-pentadiene (1,4-p), 1-pentene (1-p), and 2-pentene (2-p) vapors are exposed to an acidic water microjet (1 ≤ pH ≤ 5), where cationic products are generated on its surface within ∼10 μs and directly detected using surface-sensitive mass spectrometry. We found that carbocations form at the air-water interface in all the cases, whereas the extent of oligomerization largely depends on the structure in the following order: ISO ≫ 1,3-b > 1,4-p ≫ 1-p ≈ 2-p. Importantly, the cationic oligomerization of ISO yields a protonated decamer ((ISO)10H+, a C50 species of m/z 681.6), while the pentenes 1-p/2-p remain as protonated monomers. We suggest that ISO oligomerization is uniquely facilitated by (1) the resonance stabilization of (ISO)H+ through the formation of a tertiary carbocation with a conjugated C[double bond, length as m-dash]C bond pair, and (2) π-electron enrichment induced by the neighboring methyl group. Experiments in D2O and D2O : H2O mixtures revealed that ISO oligomerization on the acidic water surface proceeds via two competitive mechanisms: chain-propagation and proton-exchange reactions. Furthermore, we found that ISO carbocations undergo addition to relatively inert 1-p, generating hitherto uncharacterized co-oligomers.

Purpose: Younger age and female sex have already been well-known risk factors for chemotherapy-induced nausea and vomiting (CINV), and 30-50% of cancer patients still suffer from CINV. Genetic polymorphisms are suggested to influence antiemetic treatment response., Methods: This study included a subset of patients previously enrolled in a randomised controlled trial; 156 patients were evaluated. This study aimed to evaluate the role of pharmacogenomic polymorphisms relevant to antiemetic response in patients with cancer receiving cisplatin-based chemotherapy. The study's efficacy endpoint was the proportion of patients with complete response (CR). The study endpoint was evaluated separately in the acute (CR 0-24 ) and delayed (CR 24-120 ) phases. Thirteen polymorphisms were genotyped, and the association of these genotypes with the efficacy of prophylactic antiemetics was then investigated. Confounding variables for the CR were identified using stepwise multivariate logistic regression analysis. Age and sex were included as independent variables by the forced-entry method, and the stepwise method was used to select the pharmacogenomic factors for inclusion as independent variables., Results: Multivariate logistic regression analysis revealed that the ERCC1 8092AA (odds ratio [OR] = 11.25; 95% confidence interval [CI] 1.74-72.71; p = 0.011) and female sex (OR = 3.63; 95% CI 1.14-11.58; p = 0.029) were significant predictors of CR 0-24 . No significant association of CR 24-120 with pharmacogenomic polymorphisms was found via multivariate logistic regression analysis., Conclusions: ERCC1 polymorphism influenced the extent of CINV control in patients receiving cisplatin-based chemotherapy., Trial Registration: Clinical trial information: UMIN 000009335.

Background: Whether an individually determined appropriate level of cardiac rehabilitation (CR) has a favorable effect on the renal function still remains unclarified. The aim of this study was to confirm the effect of CR on the estimated glomerular filtration rate (eGFR) using cystatin C, which is known to be unaffected by physical exercise., Methods: The study population was comprised of 86 patients (61 males; average age 74 y/o) with a lower-moderate level of chronic kidney disease (CKD) who was admitted to our hospital for treatment of cardiovascular disease (CVD) and who participated in our 3-month CR program. The exercise capacity was assessed by cardiopulmonary exercise testing (CPX) and the eGFR was measured by a formula based on the serum cystatin C concentration (eGFRcys) in each patient both at the beginning and end of the CR., Results: In the CVD patients with CKD, both the peak oxygen uptake (VO 2 ) and peak work rate (WR) improved significantly after CR (15.0 ± 3 to 15.8 ± 3 ml/min/kg, p  = 0.002. 65.5 ± 21 to 70.2 ± 25 W, p  = 0.001). Regarding the renal function, the eGFRcys improved (45.2 ± 11 to 47.3 ± 13 ml/min/1.73 m 2 , p  = 0.023), however, the eGFR assessed by the serum creatinine (eGFRcr) did not improve after CR (45.1 ± 12 to 44.9 ± 13 ml/min/1.73 m 2 , p  = 0.834)., Conclusions: In CVD patients, a novel CR program significantly improved the exercise capacity. Further, CR was shown to have a favorable effect on the renal function when it was estimated by the eGFRcys.

Anaerobic ammonium oxidation (anammox) bacteria were enriched in continuous packed-bed columns with marine sediment. One column (SB-C) was packed with only marine sediment collected from a shrimp-aquaculture pond, and another column (SB-AMX) was inoculated with marine anammox bacteria (MAB) as a control. These columns were continuously fed with natural or artificial seawater including ammonium (NH 4 + ) and nitrite (NO 2 - ). The SB-AMX showed anammox activities from the beginning and continued for over 200 days. However, the SB-C had no nitrogen removal performance for over 170 days. After adding a bicarbonate solution (KHCO 3 ) to the sediment-only packed column, anammox activity was observed within 13 days. The column exhibited a nitrogen removal efficiency (NRE) of 88% at a nitrogen loading rate (NLR) of 1.0 kg-N·m -3 ·day -1 , which was comparable to the control one. A next-generation sequencing analysis revealed the predominance of MAB related to "Candidatus Scalindua spp.". In addition, the co-occurrence of sulfur-oxidizing denitrifiers was observed, which suggests their symbiotic relationship. This study suggests the applicability of MAB for in-situ bioremediation of nitrogen-contaminated marine sediments and reveals a potential microbial interaction between anammox and sulfur-oxidizing communities responsible for nitrogen and sulfur cycling in marine aquaculture systems., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The outermost surface of the leaves of land plants is covered with a lipid membrane called the cuticle that protects against various stress factors. Probing the molecular-level structure of the intact cuticle is highly desirable for understanding its multifunctional properties. We report the in situ characterization of the surface structure of Kalanchoe pinnata leaves using polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS). Without sample pretreatment, PM-IRRAS measures the IR spectra of the leaf cuticle of a potted K. pinnata plant. The peak position of the CH 2 -related modes shows that the cuticular waxes on the leaf surface are mainly crystalline, and the alkyl chains are highly packed in an all-trans zigzag conformation. The surface selection rule of PM-IRRAS revealed the average orientation of the cuticular molecules, as indicated by the positive and negative signals of the IR peaks. This unique property of PM-IRRAS revealed that the alkyl chains of the waxes and the main chains of polysaccharides are oriented almost perpendicular to the leaf surface. The nondestructive, background-free, and environmental gas-free nature of PM-IRRAS allows the structure and chemistry of the leaf cuticle to be studied directly in its native environment.

Cystic epithelia acquire mesenchymal-like features in polycystic kidney disease (PKD). In this phenotypic alteration, it is well known that transforming growth factor (TGF)-β/Smad3 signaling is involved; however, there is emerging new data on Smad3 phosphoisoforms: Smad3 phosphorylated at linker regions (pSmad3L), COOH-terminal regions (pSmad3C), and both (pSmad3L/C). pSmad3L/C has a pathological role in colorectal cancer. Mesenchymal phenotype-specific cell responses in the TGF-β/Smad3 pathway are implicated in carcinomas. In this study, we confirmed mesenchymal features and examined Smad3 phosphoisoforms in the cpk mouse, a model of autosomal recessive PKD. Kidney sections were stained with antibodies against mesenchymal markers and domain-specific phospho-Smad3. TGF-β, pSmad3L, pSmad3C, JNK, cyclin-dependent kinase (CDK) 4, and c-Myc were evaluated by Western blotting. Cophosphorylation of pSmad3L/C was assessed by immunoprecipitation. α-Smooth muscle actin, which indicates mesenchymal features, was expressed higher in cpk mice. pSmad3L expression was increased in cpk mice and was predominantly localized in the nuclei of tubular epithelial cells in cysts; however, pSmad3C was equally expressed in both cpk and control mice. Levels of pSmad3L, JNK, CDK4, and c-Myc protein in nuclei were significantly higher in cpk mice than in controls. Immunoprecipitation showed that Smad3 was cophosphorylated (pSmad3L/C) in cpk mice. Smad3 knockout/ cpk double-mutant mice revealed amelioration of cpk abnormalities. These findings suggest that upregulating c-Myc through the JNK/CDK4-dependent pSmad3L pathway may be key to the pathophysiology in cpk mice. In conclusion, a qualitative rather than a quantitative abnormality of the TGF-β/Smad3 pathway is involved in PKD and may be a target for disease-specific intervention., (Copyright © 2017 the American Physiological Society.)

Adherence has become an important issue in modern oncology treatment. Most studies have included heterogeneous target tumor types, regimens, and therapy settings. Our study focused on capecitabine during capecitabine plus oxaliplatin (XELOX) treatment as an adjuvant therapy for colorectal cancer. The main aims of this study were to evaluate real-life adherence to capecitabine and to investigate candidate factors that might decrease adherence. We studied 338 consecutive patients who received XELOX treatment between December 1, 2011, and April 30, 2015, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Our study assessed adherence to capecitabine through patient-reported treatment diaries and interviewed nonadherents to determine the reasons for not taking capecitabine at a pharmaceutical outpatient clinic. We calculated the adherence rate in a cycle as: number of times the patient took capecitabine/28. Relative dose intensities and factors associated with deteriorating adherence to capecitabine were retrospectively surveyed from electronic patient records. Uni- and multivariate logistic regression analyses were used to investigate factors associated with optimal adherence. The study covered 282 patients who received 2,055 cycles of XELOX. Median adherence rate was 94.0% in the first cycle, and median relative dose intensity of capecitabine was 77.8%. The most common reasons for nonadherence were nausea/vomiting and diarrhea. The presence of the following factors was not significantly associated with adherence: ECOG performance status ≥1 (p = 0.715), clinical stage (p = 0.408), primary tumor site (p = 0.576), age ≥70 years at study entry (p = 0.757), female gender (p = 0.504), and not living alone (p = 0.579). The adherence rate from this study was significantly higher than the adherence from metastatic settings. Adherence-enhancing interventions for capecitabine in XELOX treatment as adjuvant therapy comprised management of nausea/vomiting and diarrhea.

Abstract-For the past decades Japan has remained number one in a range of population health metrics including the world's longest healthy life expectancy. While this was achieved through various socioeconomic factors besides public health interventions, health promotion policies to prevent and control non-communicable diseases (NCDs) played a major role. Japan introduced its first comprehensive national plan to prevent and control NCDs in 1978 and has revised the plan every decade since. These 10-year policy packages were instrumental in galvanizing stakeholders, while adapting to changing social, behavioral, and epidemiological trends. In this article, we provide an overview of trends in policy on the prevention and control of NCDs in Japan with a focus on successes and challenges especially due to a rapidly aging population. Through this review we aim to share the lessons learned in Japan for other countries tackling or expecting to be challenged by NCDs. These lessons include the role of multisectoral approaches, clear goals and targets with effective monitoring and evaluation mechanisms, addressing social aspects, adjustment to the local context, and foreseeing future demographic transition. Japan is committed to contributing to the world as a forerunner of the health challenges posed by unprecedented demographic change, by sharing its lessons in the global quest to create a world where all people can live longer and healthier lives.

Resistance to antiemetic treatment with 5-hydroxytryptamine-3 receptor antagonist is an issue. This study evaluated the potential roles of ABCB1 and ABCG2 polymorphisms in antiemetic treatment resistance in patients with cancer previously enrolled in a randomized controlled trial. A total of 156 patients were evaluated for their responses to antiemetic therapy and then subdivided into granisetron or palonosetron groups. The genotypes were evaluated for their association with antiemetic efficacy in each treatment groups. Additional risk factors associated with complete response (CR) were examined using a multivariate regression analysis. No significant associations were identified for genetic polymorphisms in the palonosetron group. In the granisetron group, patients with ABCB1 2677TT and 3435TT genotypes had higher proportion of CR. In addition to ABCB1 polymorphisms, gender and cisplatin dose were associated with granisetron response by univariate analysis. Multivariate logistic regression analysis revealed that the ABCB1 3435C>T polymorphism and cisplatin dose were significant predictors of CR.

Interstellar ice is believed to be a cradle of complex organic compounds, commonly found within icy comets and interstellar clouds, in association with ultraviolet (UV) irradiation and subsequent warming. We found that UV-irradiated amorphous ices composed of H 2 O, CH 3 OH, and NH 3 and of pure H 2 O behave like liquids over the temperature ranges of 65 to 150 kelvin and 50 to 140 kelvin, respectively. This low-viscosity liquid-like ice may enhance the formation of organic compounds including prebiotic molecules and the accretion of icy dust to form icy planetesimals under certain interstellar conditions.

Crystalline ice formation requires water molecules to be sufficiently mobile to find and settle on the thermodynamically most stable site. Upon cooling, however, diffusion and rearrangement become increasingly kinetically difficult. Water ice grown by the condensation of water vapor in laboratory is thus generally assumed to be in a metastable amorphous form below 100 K. Here, we demonstrate the possibility of crystalline ice formation at extremely low temperature using a water/neon matrix (1/1000, 30 000 monolayers) prepared at 6 K, which is subsequently warmed to 11-12 K. In situ infrared spectroscopy revealed the assembly of the dispersed water molecules, forming crystalline ice I during the sublimation of the neon matrix for 40-250 seconds. This finding indicates that the high mobility of the water molecules during matrix sublimation can overcome the kinetic barrier to form crystals even at extremely low temperature.

Nucleation and subsequent rapid growth are enigmatic due to the unrevealed pathways. Despite the relatively simpler mechanism compared to nucleation and growth in solution, that in vapor has received little attention. The largest hindrance to unveiling this process may be observing the rapid and mesoscopic-scale phenomena. To overcome this hindrance, we combine an experimental approach with in situ spatial scanning Fourier-transform infrared spectroscopy, which reveals the nucleating and growing nanoparticles in vapor. The nanoparticles are then collected at different evolutionary stages and analyzed by ex situ transmission electron microscopy (TEM). Needle-shaped molybdenum oxide (MoO 3 ) nanoparticles were formed within ∼0.1 s after homogeneous nucleation from a highly supersaturated vapor. Over one second, the needle particles gradually evolved into a cubic shape by fusion in a crystallographically favored orientation in a free-flying state in vapor. The similar sizes of the elongated axes of the needle and cubic structures suggest an additional growth stage, in which the needle particles become the growth units of the cubic particles. The morphology of a final crystal should reflect the formation environment of the particle because growing crystals are sensitive to the formation conditions such as temperature, concentration, and impurities. Although nucleation under very high supersaturation induces the anisotropic growth of the needle particles, this information of the initial nucleation environment is lost in the final cubic crystal. These findings enrich our understanding of pathways in the nucleation and growth of nanoparticles and provide new insights into the growth stages driven by oriented attachment.