The myocardial fractional flow reserve （FFR） is a useful measure of physiological stenosis in the coronary artery. Previous reports have identified peripheral FFR （pFFR） as another useful measure in peripheral artery disease （PAD）; however, the vasodilators used to obtain maximal hyperemia varied among studies. The present study was conducted to identify the ideal vasodilator and vasodilator dose for pFFR assessment. We enrolled 24 patients with 26 lesions, comprising 14 lesions of the iliac artery and 12 lesions of the superficial femoral artery （SFA）. After measuring the mean aortic pressure （Pa）, the guidewire was advanced across the lesion and the mean distal pressure （Pd） was measured at the baseline Pd/Pa. A 100-µg dose of adenosine 5’-triphosphate （ATP） was then administered to obtain a pFFR with a washout interval of 5 to 10 minutes. Next, 200µg of ATP, 10mg of papaverine hydrochloride, or 1.5mg of isosorbide dinitrate was administered before the final pFFR measurement. The baseline Pd/Pa （0.88±0.08） was significantly decreased after each vasodilator （P＜0.0001）, but there was no significant difference in pFFR among vasodilators （P＝0.7569）. The study was discontinued in two patients with SFA lesions due to decreased systemic blood pressure after vasodilator administration. The hyperemic efficacy of 100µg of ATP administered intra-arterially was similar to the efficacies of 200µg of ATP, 10mg of papaverine hydrochloride, and 1.5mg of isosorbide dinitrate. Given the milder side effects of ATP versus other vasodilators, an intra-arterial dose of ATP 100µg may be optimal as a first-line agent for pFFR measurement.

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The aim of the present study was to assess the overall efficacy and safety of long-acting beta-2 agonist （LABA） and long-acting muscarinic antagonist （LAMA） combination therapies （LABA/LAMA） versus monotherapies or placebo in patients with chronic obstructive pulmonary disease （COPD）. The overall efficacy and safety of LABA/LAMA versus LABA, LAMA, or placebo in patients with COPD were assessed by meta-analysis of Phase 3 trials. Primary efficacy outcomes included changes in forced expiratory volume in 1 second （FEV₁₀） from baseline and responder rates using St. George’s Respiratory Questionnaire （SGRQ）. The incidence of serious adverse events （SAEs） was the primary safety outcome. Pooled estimates are presented as standard mean differences （SMD）, odds ratios （ORs）, or risk differences （RDs） with 95% confidence intervals （CIs）. Eleven articles reporting on 13 randomized controlled trials of LABA/LAMA met the criteria for inclusion in the present study. Comparing LABA/LAMA with LAMA, LABA, and placebo, the SMD （95% CI） for a change in FEV₁₀ from baseline was 0.08 （0.06-0.09）, 0.09 （0.07-0.11）, and 0.24 （0.19-0.30）, respectively; the corresponding ORs （95% CI） for changes in SGRQ score were 1.39 （1.24-1.57）, 1.39 （1.06-1.83）, and 1.80 （1.47-2.19）, respectively. The RDs （95% CIs） for SAEs with LABA/LAMA compared with LAMA, LABA, and placebo were －0.01 （－0.02, 0.00）, －0.01 （－0.03, 0.00）, and 0.01 （－0.01, 0.02）, respectively. Pulmonary function and health-related quality of life were significantly higher for LABA/LAMA, and the risk of SAEs did not increase significantly with combination therapy. These results indicate the overall efficacy and safety of LABA/LAMA in patients with COPD.

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A high-throughput method was developed to analyze five barbiturates （phenobarbital, cyclobarbital, amobarbital, secobarbital, and thiopental） and a metabolite in human body samples using a new Monolithic C₁₈ gel-packed Spin Tip and ultra-performance liquid chromatography （UPLC）-quadrupole-time-of-flight （Q-ToF） mass spectrometry （MS）. Plasma （20µl） or urine （100µl） samples spiked with the five barbiturates and 5-（4-methylphenyl）-5-phenylhydantoin （internal standard, IS） were mixed with distilled water. The mixture was extracted using the Monolithic C₁₈ Spin Tip, and the analytes retained on the C₁₈ phase were then eluted with methanol. The eluate was injected directly into an analytical column （Waters Acquity BEH C₁₈, 50mm×2.1mm i.d., particle size 1.7µm）, and quantified by Q-ToF-MS with negative-ion electrospray ionization （ESI）. Good separation and clear peak shapes of the five drugs were achieved within an analysis time of 6min, including the extraction time. All drugs spiked in the plasma showed recoveries of 86-98％. The regression equations for the five drugs showed excellent linearities in the range of 5-500ng/20µl of plasma, with limits of detection and i-Fit of 1ng/20µl. The method was also successfully applied to determine the level of amobarbital and its metabolite in human plasma and urine, respectively, after oral administration to a volunteer. This new method could be applied widely in the clinical and forensic fields for the quantitative determination of drugs and metabolites.

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The efficacy and safety of dupilumab, a humanized interleukin （IL）-4 receptor alfa monoclonal antibody （mAb） that inhibits the signaling of the type 2 cytokines IL-4 and IL-13, for the treatment of uncontrolled eosinophilic asthma remains to be fully characterized, particularly in comparison to other therapeutic mAbs. Therefore, we conducted a meta-analysis of randomized controlled trials （RCTs） to indirectly compare the efficacy and safety of dupilumab with those of mepolizumab, a humanized anti-IL-5 mAb, in patients with uncontrolled eosinophilic asthma. Comparisons were made using the Bayesian statistical method. This meta-analysis complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses （PRISMA） guidelines. Six RCTs were eligible for this study: two RCTs focused on dupilumab and four on mepolizumab. The primary efficacy outcome was a change in the forced expiratory volume at 1.0 second （FEV1.0）, and the primary safety outcome was the incidence of severe adverse effects （SAE）. The mean difference in changes in the FEV1.0 following treatment with dupilumab versus mepolizumab was 0.133 （95% CI, 0.016-0.252）. There was no significant difference between these two agents in the incidence of SAE （OR, 1.99; 95% CI, 0.19-11.16）. These results strongly indicate that dupilumab is more effective than mepolizumab and is generally well-tolerated in patients with uncontrolled eosinophilic asthma.

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Adrenocortical hormones are effective in many, but not all, cases of autoimmune pancreatitis （AIP）. While effective treatment for refractory and recurrent cases of AIP has not been established, immunomodulators are sometimes used. We examined the therapeutic effect of the immunomodulator FK506 against AIP using an animal model: aly/aly male mice. Mice were divided into three groups based on FK506 dose: 1mg/kg, 2mg/kg, and non-administration （pancreatitis） groups. Pancreatic exocrine gland injury was regarded as pancreatitis and pancreatic endocrine injury was regarded as insulitis. Histological evaluation of pancreatic tissue at 16 and 24 weeks of age was performed quantitatively using ImageJ software, and the three groups were compared. The pancreatitis group developed pancreatitis at 24 weeks of age, but onset of pancreatitis was suppressed in the 1mg group. However, pancreatitis development was not suppressed in the 2mg group, and pancreatitis developed from as early as 16 weeks of age. In the pancreatitis group, insulitis resulted in morphological changes such as shrinkage of pancreatic islets of Langerhans as inflammatory cell infiltration into pancreatic acinar cells became stronger. No significant difference was observed between the 1mg group and the pancreatitis group in the islet area but, in the 2mg group, there was significant reduction in area compared to the pancreatitis group and the 1mg group. Although administration of FK506 at a low dose had an effect of suppressing the onset of pancreatitis, administration at a higher dose appeared to exacerbate pancreatitis.

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Alzheimer’s disease （AD） is one of the most common causes of dementia, characterized by the accumulation of amyloid-β （Aβ） peptide deposits in the brain. Within an aging society, elderly patients with preoperative dementia, or those who are affected by postoperative cognitive impairment, are a major health problem. Although inhalation anesthetics induce accumulation of Aβ protein and progression of AD, propofol, a short-acting intravenous anesthetic, has gained increasing attention for its neuroprotective effects following cerebral ischemia. However, the protective action of propofol against Aβ-induced neuronal damage remains unclear. Therefore, the aim of this study was to elucidate the mechanisms underlying the protective effect of propofol against Aβ-induced neurotoxicity. Neural damage was induced in human neuroblastoma cells （SH-SY5Y） using 2.5µM Aβ（1–42）. Cells were pretreated with propofol （1µM） for 1h, followed by further treatment with propofol for 20h in combination with Aβ. In Aβ（1–42）-induced neural damage, caspase-3 activation was increased, as was phosphorylation of p38 mitogen-activated protein kinase （MAPK） and tau. Moreover, cell viability and the phosphorylation of Akt, cAMP response element-binding protein, and Bcl-2 decreased significantly with Aβ treatment. However, these responses were reversed by pretreatment with propofol and p38MAPK inhibitor. The Aβ（1–42）-induced increase in reactive oxygen species generation was inhibited by propofol pretreatment, but remained unchanged following pretreatment with the p38MAPK inhibitor. Furthermore, Aβ（1–42）-treated cells exhibited a significant increase in cytosolic Ca^2＋（［Ca^2＋］_i）, but propofol pretreatment resulted in a significant decrease in ［Ca^2＋］_i starting 30s after exposure to Aβ（1–42）. Our results indicate that the mechanism underlying the protective effect of propofol against Aβ-induced neurotoxicity is a decrease in ［Ca^2＋］_i, which subsequently suppresses oxidative stress, along with p38MAPK and tau phosphorylation. Thus, these findings suggest that propofol, at clinically relevant concentrations, is likely to be safe in elderly patients and in those with risk factors for AD.

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Traditionally, cervical brachytherapy has been prescribed to point A. However, since the Groupe Européen de Curiethérapie and European Society for Radiotherapy＆ Oncology guidelines were published, image-guided brachytherapy has become an emerging technique. The purpose of this study was to evaluate the high-risk clinical target volume （HR-CTV） coverage and analyze dose-volume histograms for organs at risk in point A prescription of high-dose-rate brachytherapy. A total of 68 patients with locally advanced cervical cancer were treated with three-dimensional conformal external beam radiation therapy and brachytherapy from December 2012 to March 2017. Fractions of 6Gy for a total of 12-24Gy were delivered at point A by brachytherapy to all patients. Following each brachytherapy application, a pelvic computed tomography scan was performed and imported into a three-dimensional brachytherapy treatment planning system. In this study, the HR-CTV, bladder, and rectum were re-delineated according to Report 89 of the International Commission on Radiation Units and Measurements using the magnetic resonance images at the time of diagnosis, and the dose-volume histogram of each structure was analyzed. The median age of patients at diagnosis was 67 years （range, 31-91 years）. Mean HR-CTV D₉₀ for all patients was 558.3cGy （range, 228.7-1005.1cGy） and the mean HR-CTV D₉₀ within each clinical T stage was: Ib, 646.4cGy; 2a, 579.3cGy; 2b, 545.2cGy; 3a, 556.6cGy; 3b, 451.3cGy; and 4, 497.9cGy. HR-CTVD₉₀ was correlated with HR-CTV. The mean D2cm³ was 678.1cGy for the bladder and 511.9cGy for the rectum. Using point A-based dose prescription, HR-CTV coverage was insufficient, especially in cases with a large tumor volume or a high T stage. Image-guided brachytherapy is expected to improve HR-CTV coverage while keeping rectal and bladder doses within acceptable levels.

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Healthy Parents and Children 21 （Phase 1）, and also Healthy Japan 21 （Phase 1）, are the first national health promotion campaigns in Japan to have concrete numerical targets; however, the national review of these programs mainly considers changes in each numerical target. Care for infants & environmental preparation system for continuous maternal care are emphasized in the 2^nd Healthy Parents and Children 21. Herein, two new investigations were performed mainly for the 1^st. The index framework that contributed to the policy effect was investigated using ordered multivariate, multilevel and multinominal logistic regression analysis （mixed model）. Considering the first basic task on adolescent healthcare, the contribution of the health standard index framework to the administrative effort index was very low （odds ratio＝0.041, 95％ CI: 0.002-0.703）. In the third basic task on improving the environment for children, the framework of the citizen’s behavioral index was negatively associated （i.e., disassociated） with the change in each indicator （parameter estimate＝－1.63, 95％ CI: －2.64-0.62）. Promoting adolescent healthcare was selected as the 2018 task of the Japan Agency for Medical Research and Development. The assimilation points were also suggested under the forensic view, but not included in this health promotion effort. The degree to which the indicators accurately reflected reality is defined here as assimilation. Disassociation was also recognized among the indicators concerning child abuse, including the number of deaths caused by child abuse reported by Healthy Parents and Children 21 and by the National Police Agency, （Jonckheere-Terpstra test P＝0.02 in the contingency table）. Further, the constitution of the subjective indicators concerning child abuse was confirmed to be different by cluster analysis, Mantel-Henzel χ² analysis （P＝0.02）, and logistic regression analysis （odds ratio＝1.44, 95％ CI: 1.02-2.50）.

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Rituximab （RTX） is an anti-CD20 human-mouse chimeric monoclonal antibody that exhibits antibody-dependent, cell-mediated cytotoxicity and complement-dependent cytotoxicity, resulting in an antitumor effect with immune cells or complement. RTX is approved for the treatment of many diseases including B cell lymphoma and rheumatoid arthritis. We examined whether combined RTX and gamma interferon （IFNγ） therapy provides a higher antitumor effect than RTX single therapy using B-cell lymphoma cells. In addition, we investigated the mechanisms underlying the antitumor effect. We treated tumor-derived cell lines with RTX alone, IFNγ alone, or a combination of RTX and IFNγ（RTX-IFNγ）. Untreated cells served as controls. We experimentally examined in vitro cell proliferation, conducted apoptosis and cell cycle assays, performed Western blotting to identify changes in the levels of proteins related to the cell cycle, and investigated tumor growth in a mouse xenograft experiment. Cell proliferation experiments indicated that RTX or IFNγ alone did not significantly suppress cell growth compared with the control, whereas treatment with RTX-IFNγ significantly suppressed cell proliferation. In vivo mouse experiments also showed that the administration of RTX-IFNγ significantly suppressed tumor growth compared to the single therapies. Some tumors in mice treated with RTX-IFNγ were completely resolved. The cell cycle assays revealed a significantly increased rate of cells in the G0/G1 phase following treatment with RTX-IFNγ compared with the other groups, and the levels of p27^kip1 increased and the levels of cyclin E and Cdk 2 decreased in cells treated with RTX-IFNγ. Our findings suggested that RTX-IFNγ combined therapy directly affects cells by arresting the cell cycle at the G1/S checkpoint and had a synergistic antitumor effect compared to RTX single treatment of B-cell lymphomas. This combined therapy may change the mortality rate for B-cell lymphomas.

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We have been conducting medical collaboration programs for cleft lip and palate in the Republic of Madagascar for seven years, from 2011 to 2017. The purpose of this study was to investigate the incidence of fistula after primary palatoplasty in the Republic of Madagascar, which is a developing country. A further objective was to determine if the group of patients in Madagascar had an increased incidence of palatal fistula compared to a similar group of patients in Japan, and to examine the factors that might be involved in any increase. We conducted a survey of the cleft type, age at time of surgery, and fistula incidence in 44 patients （28 males and 16 females） in Madagascar. The age at the time of surgery was 11 months to 29 years （average, 7 years and 8 months）, and the cleft types were 0 class Ⅰ, 14 class Ⅱ, 18 class Ⅲ, and 12 class Ⅳ, by the Veau classifi­cation. We used a modified two-flap palatoplasty for palatal closure. In addition to the selection of surgical technique, the factors which are suggested to influence the incidence of fistula include the experience of the surgeon, and the extent of the cleft. The incidence of postoperative fistula complication in these patients was zero. In medical collaboration settings in developing countries, there are factors which may delay wound healing, such as poor oral hygiene, poor nutrition, and instability of the flap blood flow. Understanding such factors in surgery is important to avoid palatal fistula. We report that a palatal fistula incidence rate of 0% can be achieved by avoiding those factors which contribute to fistula formation.

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Treatment for chemotherapy-induced nausea and vomiting （CINV） has improved significantly with the development of antiemetic drugs. We conducted a prospective observational study to clarify the quality of life （QOL） impact of antiemetic therapy recommended by the Japanese Cancer Therapy Association （JSCO） guidelines for Japanese breast cancer patients receiving an anthracycline plus cyclophosphamide regimen （ACR）. This was an open, single-center, prospective observational study conducted in Yokohama City University Medical Center. Antiemetic therapy recommended by the JSCO guidelines was implemented for all cases treated therein （i.e., aprepitant, dexamethasone, and palonosetron）. The primary endpoint was no impact on daily living （NIDL） rate during a 120-hour period following chemotherapy （i.e., overall phase）. We use the Japanese version of the Functional Living Index–Emesis （FLIE） to evaluate the impact of CINV on QOL. There were 118 analyzable cases. The NIDL rate during the overall phase was 44.9％, and was significantly lower than the complete response （CR） rate of 58.5％ （i.e., no emetic responses and no rescue medication; P＝0.037）. Age＜55 years （P＝0.008） and a history of morning sickness （P＝0.005） were identified as independent risk factors of NIDL （P＜0.05）. Among Japanese breast cancer patients receiving ACR and a combination of aprepitant, dexamethasone, and palonosetron, the NIDL rate was relatively low at approximately 45％. A more effective antiemetic therapy should therefore be developed for patients’ QOL that takes NIDL risk factors into account. In addition, our results suggested that the CR rate is insufficient for evaluating the effect of antiemetic therapy on a patient’s QOL.

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The overall efficacy of therapeutic monoclonal antibodies （mAbs） for asthma control in patients with uncontrolled eosinophilic asthma remains to be fully characterized. We conducted a meta-analysis of randomized controlled trials （RCTs） to analyze the efficacies of new therapeutic mAbs, such as anti-interleukin （IL）-13 therapies, anti-IL4/13 therapies, and anti-IL-5 therapies, compared with that of a placebo in patients with uncontrolled asthma. This meta-analysis complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses （PRISMA） guidelines. The primary efficacy outcome was asthma control as assessed by Asthma Control Questionnaire （ACQ） scores. Pooled estimates are presented as standardized mean differences （Std MDs） with 95% confidence intervals （CIs）. Seven RCTs of therapeutic mAbs, including anti-IL-13, anti-IL-4/13, and anti-IL-5, met the criteria for study inclusion. The overall Std MD of changes in the ACQ score was －0.31 （95% CI, －0.45 to －0.17; P＜0.0001）. These results strongly indicate that therapeutic mAbs are effective in controlling asthma in patients with uncontrolled eosinophilic asthma.

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The safety and efficacy profiles of alectinib versus crizotinib for patients with previously untreated anaplastic lymphoma kinase （ALK）-positive advanced non-small cell lung cancer still remains to be elucidated. We compared the overall efficacies of alectinib and crizotinib for previously untreated ALK-positive advanced non-small cell lung cancer through a meta-analysis of randomized controlled trials. The primary outcome was progression-free survival （PFS）. Pooled estimates were calculated as hazard ratios with 95％ confidence intervals. Two studies on alectinib met the inclusion criteria for this meta-analysis. The hazard ratio （95％ confidence interval） of alectinib for PFS, relative to crizotinib, was 0.41 （0.28-0.60）, demonstrating a superior overall efficacy of alectinib over crizotinib, in terms of PFS.

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