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Takayoshi Kiba,1 Nao Morii,2,3 Hirotoshi Takahashi,2 Shinji Ozaki,2 Misao Atsumi,4 Fumi Masumoto,4 Hiroyasu Yamashiro,2,31Division of Modern Medical Technology, Institute for Clinical Research, 2Department of Breast Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan; 3Department of Breast Surgery, Tenri Hospital, Tenri, Nara, Japan; 4Clinical Trial Management Office, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, JapanAbstract: We recently reported that neoadjuvant 5-FU, epirubicin, and cyclophosphamide (FEC) followed by weekly paclitaxel and/or trastuzumab induced a high pathological complete response (pCR) rate in hormone-negative patients. The present study examined the therapeutic efficacy of neoadjuvant FEC followed by triweekly docetaxel and/or trastuzumab in the treatment of hormone-positive patients. Between February 2012 and December 2013, 16 hormone-positive patients with local breast cancer (luminal A type: six patients; luminal B type: two patients; luminal HER2 type: eight patients) were included in the study. The histological type of the primary cancer was invasive ductal carcinoma in all patients. The cancer stages in the 16 women who received this regimen were stage I in five (31.3%), IIA in four (25.0%), IIB in five (31.3%), IIIB in one (6.3%), and IIIC in one (6.3%). Regarding clinical TNM classification, five patients were T1N0M0, one was T1N1M0, three were T2N0M0, five were T2N1M0, one was T3N2M0, and one was T4N0M0. The pCR was evaluated using resected tissue after neoadjuvant chemotherapy according to the evaluation criteria of the Japanese Breast Cancer Society. Patients were classified into pathologic responders (grade 2: 50.0% of all patients: 2/6 of luminal A type; 6/8 of Luminal HER2 type) and nonresponders (grades 0 and 1: 50.0% of all patients: 4/6 of luminal A type; 2/2 of luminal B type; 2/8 of luminal HER2 type) according to the grade of the tumor. The pCR rate was 0%. Hematologic and nonhematologic toxicity was reversible and manageable. This study demonstrated that neoadjuvant FEC followed by triweekly docetaxel and/or trastuzumab did induce a high pathologic response in luminal HER2 type, but not in luminal A and B types, and did not induce a high pCR rate in the hormone-positive patients.Keywords: luminal type, surgery, therapeutic efficacy

Abstract Ulcerative colitis (UC) is a refractory inflammatory bowel disease, which is known to cause psychiatric disorders such as anxiety and depression at a high rate in addition to peripheral inflammatory symptoms. However, the pathogenesis of these psychiatric disorders remains mostly unknown. While prior research revealed that the Enterococcus faecalis 2001 (EF-2001) suppressed UC-like symptoms and accompanying depressive-like behaviors, observed in a UC model using dextran sulfate sodium (DSS), whether it has an anxiolytic effect remains unclear. Therefore, we examined whether EF-2001 attenuates DSS-induced anxiety-like behaviors. Treatment with 2% DSS for seven days induced UC-like symptoms and anxiety-like behavior through the hole-board test, increased serum lipopolysaccharide (LPS) and corticosterone concentration, and p-glucocorticoid receptor (GR) in the prefrontal cortex (PFC), and decreased N-methyl-d-aspartate receptor subunit (NR) 2A and NR2B expression levels in the PFC. Interestingly, these changes were reversed by EF-2001 administration. Further, EF-2001 administration enhanced CAMKII/CREB/BDNF-Drebrin pathways in the PFC of DSS-treated mice, and labeling of p-GR, p-CAMKII, and p-CREB showed colocalization with neurons. EF-2001 attenuated anxiety-like behavior by reducing serum LPS and corticosterone levels linked to the improvement of UC symptoms and by facilitating the CAMKII/CREB/BDNF-Drebrin pathways in the PFC. Our findings suggest a close relationship between UC and anxiety.

Background: The Japanese drug use system allowed the once-daily use of inhaled corticosteroid fluticasone furoate (FF) combined with a long-acting beta-2 agonist vilanterol (VI) and a long-acting muscarinic antagonist umeclidinium (UMEC) against asthma on 18 February 2021. We investigated the real-world effects of these drugs (FF/UMEC/VI) mainly on lung function tests.Methods: This was an open-label, uncontrolled, within-group time-series (before-after) study. Prior asthma treatment (inhaled corticosteroid with/without a long-acting beta-2 agonist with/without a long-acting muscarinic antagonist) was switched to FF/UMEC/VI 200/62.5/25 μg. Subjects were evaluated by lung function tests prior to, and 1–2 months after, initiation of FF/UMEC/VI 200/62.5/25 μg. Patients were asked questions regarding the asthma control test and preference for drugs.Results: Overall, 114 asthma outpatients (97% Japanese) were enrolled from February 2021 to April 2022: 104 subjects completed the study. Forced expiratory volume in 1 s, peak flow, and asthma control test score of FF/UMEC/VI 200/62.5/25 μg-treated subjects were significantly increased (p < 0.001, p < 0.001, and p < 0.01, respectively). In contrast with FF/VI 200/25 μg, instantaneous flow at 25% of the forced vital capacity and expiratory reserve volume were significantly increased by FF/UMEC/VI 200/62.5/25 μg (p < 0.01, p < 0.05, respectively). Sixty-six percent of subjects declared they wanted to continue FF/UMEC/VI 200/62.5/25 μg in the future. Adverse effects, mainly local, were seen in 30% of patients, but no serious adverse effects were seen.Conclusion: Once-daily FF/UMEC/VI 200/62.5/25 μg was effective against asthma without serious adverse events. This is the first report that demonstrated FF/UMEC/VI dilated peripheral airways using lung function tests. This evidence on drug effects may improve our understanding of pulmonary physiology and the pathophysiology of asthma.

The US OHSA PSM and the CCPS RBPS clarifies the requirements for the operation and asset management elements related to process safety. Since different departments are in charge of these elements across organizations and sometimes tend toward organizational silo of operation-maintenance-safety, the ability to organize process safety information across departments becomes important. The Strategic PSM (SPSM) Research Group was established through industry-government-academia collaboration to propose an effective implementation of the risk-based approach for process safety management for Japanese industry. This is since Japanese Safety Regulation systems had been moving from a prescriptive approach to emphasizing operator’s accountability and risk-based approach.

Safety valves are installed on process equipment where pressure-rise would occur to prevent rupture of them in chemical plants. However, it is difficult to analyze pressure-rise behavior quantitatively during reaction runaway, especially, in case of occurrence of two-phase flow. It is necessary to apply experimental and analytical technical knowledge for the vent sizing. The vent sizing method for two-phase flow by reaction runaway has been developed by the Design Institute for Emergency Relief Systems (DIERS) established in 1987, and then ISO 4126-10 was published in 2010 and it got the global standard. However, the ISO model is assumed conservative analysis condition to prevent underestimation, and sometimes unrealistic results are obtained. In this study, detailed process dynamic simulation model to estimate accurate vent size was constructed in Aspen Dynamics, process simulation software. In order to construct dynamic simulation model, it is necessary to define reaction rates, mass balance including chemical reactions and flow rate from vent or exhaust gas line, and heat balance between before and after chemical reactions. These parameters regarding the runaway reaction were obtained through Advanced Reactive System Screening Tool (ARSST) experiments. As ISO-omega model is not contained in Aspen Dynamics, ISO-omega model constructed by Aspen Custom Modeler is coupled with Aspen Dynamics as a subroutine program. Process parameters such as temperature, pressure and liquid level in process equipment are calculated comprehensively, and effect of exhaust gas line is also considered in this model. In order to confirm the validation of the results of detailed simulation model, a 40-mL-scale small test apparatus with a safety valve was developed. The maximum pressure with each diameter of safety valve was observed experimentally and they were good corresponding to the results of detailed simulation. Furthermore, this experimental method would be expected to estimate the vent size directly without the complicated analysis such as the ISO method or a detailed simulation model. The combination of case studies of the experiment and simulation also provides various additional knowledge, such as identification of the composition in a reactor in which a less violent runaway reaction occurs or the process condition for which a runaway reaction does not inherently occur. This study would contribute to the design of resilient processes for process upsets and will lead to sustainable and economical design.

Hydrogen refuelling stations (HRSs) have attracted widespread attention in Japan. The Ministry of Economy, Trade, and Industry in Japan set a goal for the construction of HRSs in a strategic roadmap. Owing to the explosive and fire hazards associated with HRSs, a considerable amount of safety studies for HRSs has been conducted for several years; however, the safety studies conducted in Japan are yet to be reviewed. This study aimed to comprehensively review the safety studies conducted in Japan, particularly the risk assessment (RA) of HRSs, and to provide useful insights on the direction of future studies on the safety of HRSs. To this end, a comprehensive review of international and Japanese safety studies for HRSs was presented by adopting a bibliometric analysis approach and an overview of Japanese safety studies for HRSs was presented based on the type of HRSs. The results revealed that it is essential to conduct the RA of HRSs, particularly for HRSs yet to be assessed, to contribute to the decision-making process for the social implementation of HRSs in the future.

BackgroundThe oxidized high-density lipoprotein (oxHDL) is a possible marker for cardiovascular diseases. This study investigated the effects of smoking cessation with varenicline (a partial agonist of nicotinic acetylcholine receptors) on the levels of oxHDL in the serum of subjects compared with those of high-density lipoprotein cholesterol (HDL-C).MethodsData of 99 nicotine-dependent adult subjects who visited the smoking cessation outpatient services at International University of Health and Welfare Shioya Hospital were reviewed. Each subject was treated with varenicline titrated up to 1.0 mg twice daily for 12 weeks. Serum levels of oxHDL and HDL-C were repeatedly measured by enzyme-linked immunosorbent assay and enzymatic method, respectively.ResultsThe serum levels of oxHDL were significantly decreased from 163.2 ± 96.6 to 148.3 ± 80.7 U/mL (p = 0.034, n = 99). This effect was more prominent when the data of subjects in whom the treatment was objectively unsuccessful (exhaled carbon monoxide at 3 months ≥ 10 ppm) were omitted (from 166.6 ± 98.4 to 147.4 ± 80.6 U/mL; p = 0.0063, n = 93). In contrast, the serum levels of HDL-C were significantly increased (p = 0.0044, n = 99). There was a close relationship between the baseline levels of oxHDL and HDL-C (R = 0.45, p < 0.0001, n = 99). Changes in the levels of oxHDL were closely associated with changes in the levels of exhaled carbon monoxide in subjects in whom smoking cessation with varenicline was very effective (decrease in exhaled carbon monoxide by ≥ 15 ppm after treatment with varenicline; R = 0.42, p = 0.0052, n = 43).ConclusionsAlthough there was a close relationship between the baseline serum concentrations of oxHDL and HDL-C, smoking cessation decreased oxHDL and increased HDL-C. This effect on oxHDL may be associated with the effectiveness of smoking cessation.

Obstructive sleep apnea (OSA) patients are at risk for increased blood pressure and carotid intima-media thickness (IMT), with pulmonary hypertension and right-sided heart failure potentially developing as well. Chronic intermittent hypoxia (IH) has been used as an OSA model in animals, but its effects on vascular beds have not been evaluated using objective unbiased tools. Previously published and current experimental data in mice exposed to IH were evaluated for IMT in aorta and pulmonary artery (PA) after IH with or without normoxic recovery using software for meta-analysis, Review Manager 5. Because IMT data reports on PA were extremely scarce, atherosclerotic area percentage from lumen data was also evaluated. IH significantly increased IMT parameters in both aorta and PA as illustrated by Forest plots (P < 0.01), which also confirmed that IMT values after normoxic recovery were within the normal range in both vascular beds. One-sided scarce lower areas in Funnel Plots were seen for both aorta and PA indicating the likelihood of significant publication bias. Forest and Funnel plots, which provide unbiased assessments of published and current data, suggest that IH exposures may induce IMT thickening that may be reversed by normoxic recovery in both aorta and PA. In light of the potential likelihood of publication bias, future studies are needed to confirm or refute the findings. In conclusion, OSA may induce IMT thickening (e.g., aorta and/or PA), but the treatment (e.g., nasal continuous positive airway pressure) will likely lead to improvements in such findings.

In the field of respiratory clinical practice, the importance of measuring carbon dioxide (CO2) concentrations cannot be overemphasized. Within the body, assessment of the arterial partial pressure of CO2 (PaCO2) has been the gold standard for many decades. Non-invasive assessments are usually predicated on the measurement of CO2 concentrations in the air, usually using an infrared analyzer, and these data are clearly important regarding climate changes as well as regulations of air quality in buildings to ascertain adequate ventilation. Measurements of CO2 production with oxygen consumption yield important indices such as the respiratory quotient and estimates of energy expenditure, which may be used for further investigation in the various fields of metabolism, obesity, sleep disorders, and lifestyle-related issues. Measures of PaCO2 are nowadays performed using the Severinghaus electrode in arterial blood or in arterialized capillary blood, while the same electrode system has been modified to enable relatively accurate non-invasive monitoring of the transcutaneous partial pressure of CO2 (PtcCO2). PtcCO2 monitoring during sleep can be helpful for evaluating sleep apnea syndrome, particularly in children. End-tidal PCO2 is inferior to PtcCO2 as far as accuracy, but it provides breath-by-breath estimates of respiratory gas exchange, while PtcCO2 reflects temporal trends in alveolar ventilation. The frequency of monitoring end-tidal PCO2 has markedly increased in light of its multiple applications (e.g., verify endotracheal intubation, anesthesia or mechanical ventilation, exercise testing, respiratory patterning during sleep, etc.).

Following major accidents, such as the Seveso and the Piper Alpher, design phase process safety performance has been improved by applying a "risk based' regulations (e.g. safety case regulations) and Plant Owner Company standards as efforts to enhance safety in the oil and gas industry. However, major accident events continue to occur. This is inevitable, since risk cannot be nil if hazardous materials are being handled. A potential area for further improvement of the process safety performance, especially in the design phase, is the a "quality' of process safety information, which is the foundation of the safety management system of the operational process. Thus, managing process safety activities, which requires establishing high-quality process safety information, is the ultimate objective of process safety management in the design phase. In this paper, the following aspects are discussed and suggested:Some important elements of Process Safety Management (PSM) System in design phase are discussed, such as approach evaluating difficulties/ characteristics of technical Process Safety requirements in project, Process Safety organization structure types depending on level of technical Process Safety requirements, and approach developing effective communication channel with related engineering disciplines. Design process safety Key Performance Indicator (KPI) tiers are proposed, which are not available as industrial practice differently from Operation Phase PS-KPI. Since the evaluation of design process safety management performance is not straightforward, as records of process safety incidents are applicable only during the operational phase. A simple model allowing numerical indications of design PS KPI performance evaluation is proposed using a Markov model. Where no numerical indicator is available, the review or monitoring of Plan-Do-Check-Act (PDCA) is not effective and does not fully capture specific remedial action plans. Based on reference data from actual project, a sensitivity study has been conducted in order to identify effective Design Phase PSM performance improvement parameters.

Objective: The Japanese drug use system allowed the “once-daily use” of inhaled corticosteroid (ICS) fluticasone furoate (FF) combined with a long acting beta-2 agonist (LABA) vilanterol (VI) against asthma for the first time in 2013. Until then, patients with asthma had to use ICS at least twice-daily. We investigated the real-world efficacy and problems of this drug (FF/VI). Methods: This was an open-label, uncontrolled, within-group time-series (before-after) design. Prior treatments of asthma (twice-daily use of ICS with or without LABA) were switched to once-daily use of FF/VI (200 μg/25 μg). Subjects were evaluated by lung function tests prior to, and 2–3 months after, the initiation of FF/VI. Questions on the asthma control test (ACT) and preference of drugs were asked to patients. Results: One hundred and twenty-eight Japanese asthma outpatients were enrolled from 2014–2018 and 107 subjects completed the study. Peak flow, instantaneous flow at 75% of the forced vital capacity (V75), V50, maximum mid-expiratory flow rate, forced expiratory volume in 1 s, and ACT score in FF/VI-using subjects were significantly increased (all p

In response to kidney damage, osteocytes increase the production of several hormones critically involved in mineral metabolism. Recent studies suggest that osteocyte function is altered very early in the course of chronic kidney disease. In the present study, to clarify the role of osteocytes and the canalicular network in mineral homeostasis, we performed four experiments. In Experiment 1, we investigated renal and intestinal Pi handling in osteocyte-less (OCL) model mice [transgenic mice with the dentin matrix protein-1 promoter-driven diphtheria toxin (DT)-receptor that were injected with DT]. In Experiment 2, we administered granulocyte colony-stimulating factor to mice to disrupt the osteocyte canalicular network. In Experiment 3, we investigated the role of osteocytes in dietary Pi signaling. In Experiment 4, we analyzed gene expression level fluctuations in the intestine and liver by comparing mice fed a high Pi diet and OCL mice. Together, the findings of these experiments indicate that osteocyte ablation caused rapid renal Pi excretion (P

Onshore LNG Plant development projects start from the “Concept Definition” phase, where financial feasibility is first estimated and major conditions such as site location and development area extent are decided. Current industrial practice applies “risk” for the evaluation of design options once detailed design data is available. Due to the limited flexibility for “change” during the detailed design phase, safety measures tend towards the application of active safeguarding systems (such as automated depressuring by fire and gas detection). Consequently, it is difficult to apply ideal inherently safer design, e.g., separation distances, during the “Design” phase of a project. Further, modularized LNG plants require large, complex structures (modules) to support LNG process equipment and to allow sea and land transportation. This results in excessive congestion and the existence of large voids under the module-deck, which are confined by large girders. As such, in the event of leakage, it is critical for plant safety to install adequate ventilation to reduce the accumulation of flammable gas and potential for subsequent explosions. In order to reduce the potential of such hazards, it is important to consider an inherently safer layout to enhance ventilation, e.g., direction or separation. Implementation of an inherently safer layout during the early design phase requires a strategic approach, such as setting targets for accidental event sizes which avoid escalation events via the separation distance and/or pre-defining the separation distances themselves. This paper proposes a strategy for the implementation of inherently safer design in the plant overall plot plan and pre-defined separation distances for modules within the process train, based on the evaluation of layout options in view of Air-Fin-Cooler induced air flow in modularized LNG plants by quantifying its effects as Air Change per Hour (ACH) and flammable gas cloud volumes through Computational Fluid Dynamics (CFD) analysis.