Introduction

Forum Modernisation, Women and Children : ‘child removal’ in Britain and beyond : a lifecourse approac

Use of iGlarLixi for Management of Type 2 Diabetes in Japanese Clinical Practice : SPARTA Japan, a Retrospective Observational Study

Introduction: Many individuals with type 2 diabetes (T2D) experience suboptimal glycemic control. Treatment intensification options include fixed-ratio combination products containing a basal insulin and a glucagon-like peptide-1 receptor agonist, such as iGlarLixi (insulin glargine 100 U/mL and lixisenatide). This study aimed to provide real-world evidence of the effect of iGlarLixi in Japanese clinical practice. Methods: SPARTA Japan was a non-comparative, observational study conducted at 27 institutions in Japan. Anonymized individual-level data from adults with T2D receiving iGlarLixi in routine clinical practice were retrospectively collected. The primary study objective was to assess the impact of iGlarLixi on the change in glycated hemoglobin (HbA1c) at 6 months’ post-treatment initiation, with preplanned subanalyses to determine the influence of baseline characteristics. Secondary and exploratory endpoints included assessment of the proportion of individuals achieving HbA1c targets, change in body weight, and incidence and severity of hypoglycemia and gastrointestinal events. Results: The full analysis set included 432 individuals, with data available at 6 months for 426. Of the 432 individuals, the mean (SD) age at baseline was 61.6 (12.8) years and the majority had a T2D duration of ≥ 10 years [mean (SD) 13.3 (10.4) years]. At 6 months, HbA1c had significantly decreased versus baseline ( –0.85%; P < 0.0001), with a greater decrease in those aged < 65 years, with a shorter duration of T2D and higher baseline HbA1c. A significant increase in the proportion of participants achieving age-specific HbA1c versus baseline was observed. Mean body weight decreased by 0.5 kg (P = 0.0034 versus baseline). There were few hypoglycemia and gastrointestinal events (in individuals with HbA1c data); no severe hypoglycemic events were reported. Conclusions: The results of this real-world study indicate that iGlarLixi may improve glycemic control without serious adverse events in Japanese individuals with T2D who have suboptimal glycemic control on current treatment regimens and switch to iGlarLixi

Use of iGlarLixi for the Management of Type 2 Diabetes in Japanese Clinical Practice : Prior Treatment Subgroup Analysis of the SPARTA Japan Study

Introduction: iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, is one option for treatment intensification in individuals with type 2 diabetes (T2D) who are unable to achieve targeted glycaemic control with their current glucose-lowering agent. Real-world data on the impact of prior treatment on the effectiveness and safety of iGlarLixi may be useful to guide individualised treatment decisions. Methods: This analysis of the 6-month, retrospective, observational SPARTA Japan study compared glycated haemoglobin (HbA1c), body weight and safety for pre-specified subgroups defined by prior treatment: post oral antidiabetic agent (OAD), GLP-1 RA, basal insulin (BI) + OADs (BOT), GLP-1 RA + BI or multiple daily injections (MDI). The post BOT and MDI subgroups were further divided on the basis of prior dipeptidyl peptidase 4 inhibitor (DPP-4i) use, and the post MDI group was divided on the basis of whether participants continued bolus insulin. Results: Of the 432 participants in the full analysis set (FAS), 337 were included in this subgroup analysis. Across subgroups, mean baseline HbA1c ranged from 8.49% to 9.18%. iGlarLixi significantly (p < 0.05) reduced mean HbA1c from baseline in all but the post GLP-1 RA + BI group. At 6 months, these significant reductions ranged from 0.47% to 1.27%. Prior DPP-4i exposure had no impact on the HbA1c-lowering effect of iGlarLixi. Mean body weight decreased significantly in the FAS (0.5 kg) and the post BOT (1.2 kg) and MDI (1.5 and 1.9 kg) subgroups but increased in the post GLP-1 RA subgroup (1.3 kg). iGlarLixi treatment was generally well tolerated, with very few participants discontinuing because of hypoglycaemia or gastrointestinal events. Conclusion: In participants with suboptimal glycaemic control on various regimens, 6 months of iGlarLixi treatment improved HbA1c in all but one prior treatment subgroup (GLP-1 RA + BI), and was generally well tolerated

コンバラトキシンによる凝固亢進における単球由来組織因子陽性細胞外小胞の関与

Objectives: Convallatoxin (CNT) is a natural cardiac glycoside extracted from lily of the valley (Convallaria majalis). Although it is empirically known to cause blood coagulation disorders, the underlying mechanism remains unclear. CNT exerts cytotoxicity and increases tissue factor (TF) expression in endothelial cells. However, the direct action of CNT on blood coagulation remains unclear. Therefore, herein, we investigated the effects of CNT on whole blood coagulation system and TF expression in monocytes. Methods: Blood samples were collected from healthy volunteers to measure plasma thrombin–antithrombin complex (TAT) concentration using ELISA and to perform rotational thromboelastometry (ROTEM) and whole-blood extracellular vesicle (EV)-associated TF (EV-TF) analysis. The effects of CNT were also investigated using the monocytic human cell line THP-1. Quantitative real-time PCR and western blotting were performed, and PD98059, a mitogen-activated protein kinase (MAPK) inhibitor, was used to elucidate the action mechanism of CNT-mediated TF production. Results: CNT treatment increased EV-TF activity, shortened the whole blood clotting time in rotational thromboelastometry analysis, and increased TAT levels, which is an index of thrombin generation. Furthermore, CNT increased TF mRNA expression in THP-1 cells and EV-TF activity in the cell culture supernatant. Therefore, CNT may induce a hypercoagulable state with thrombin generation, in which elevated EV-TF activity derived from monocytes might be involved. These procoagulant effects of CNT were reversed by PD98059, suggesting that CNT-induced TF production in monocytes might be mediated by the MAPK pathway. Conclusions: The findings of the present study have further clarified the procoagulant properties of CNT.本文は発行元が定める公開猶予期間終了後に公開

L-Qモデルは転移性脳腫瘍の定位放射線照射に適用可能か?

The biologically effective dose (BED) based on the linear-quadratic (LQ) model has been commonly used to evaluate the dose-effect relationships among the different fractionation schedules, but whether the LQ model is appropriate for hypofractionated (HF) high-dose stereotactic irradiation (STI) is uncertain. The validity of the model at high doses per fraction has been critically examined. In this study, STI of metastatic brain tumors was evaluated to suggest the applicability of the LQ model to HF high-dose radiotherapy. No significant difference was found between stereotactic radiosurgery (SRS) and HF stereotactic radiotherapy (SRT) in the analyses of 151 tumors. Furthermore, no significant differences were found among SRS, HF-SRT, and non-HF SRT in 117 metastatic lung adenocarcinomas. The results of this study suggest that BED calculation is a reasonable approach for careful dose-effect evaluation based on the LQ model for HF high-dose radiotherapy for metastatic brain tumors, especially lung adenocarcinomas.博士（医学）・甲第688号・平成30年9月26

中枢神経系原発悪性リンパ腫の放射線治療個別化の妥当性と有用性：画像評価を用いた治療効果に基づく放射線治療計画

Background: To assess the feasibility and efficacy of individualized treatment selection in radiation therapy (RT) for primary central nervous system lymphoma (PCNSL) according to treatment response by radiographic assessment. Methods: The details of recurrence and change in performance status (PS) were assessed in 31 patients with histologically confirmed PCNSL treated between 2000 and 2016. During the treatment period, radiographic assessment was conducted, and RT planning (RTP) was determined individually by treatment response. Results: At a median follow-up of 28.2 months, 9 patients were alive and 7 of whom were relapse-free. Two-year overall survival (OS) and progression-free survival (PFS) rates were 69.3% and 52.7%, with median survival times (MSTs) of 36.5 months and 24.4 months, respectively. Two-year local recurrence rate was 40.5% and the median time to local recurrence from treatment initiation was 27.9 months. All patients were scheduled to receive whole-brain RT (WBRT) and subsequent partial-brain RT(PBRT), with a median total dose to the tumor bed of 46 Gy and median WBRT dose of 30 Gy. Eight patients received reduced-dose WBRT (rd-WBRT) (<30 GY), and 13 patients who could not achive a complete response (CR) during the RT period received additional boost radiation after WBRT and PBRT, with a median dose of 6 Gy. Over 70% of local recurrence occurred within areas in which only WBRT was conducted (median dose of 30.3 Gy). Two-year occurrence rate of neurotoxicity over grade 2 was 49.5%. PS at 24 months after RT was maintained in 12 patIents. Conclusions: lndividual RTP using radiographic assessment led to reasonable survival and disease control rates with mild treatment-related toxicity. For patients not receiving chemotherapy or lacking a CR after chemotherapy and WBRT, WBRT followed by PBRT and additional boost radiation for poor RT responders might be effective. However, even for patients with CR after chemotherapy, a WBRT dose of 30 Gy or higher might be necessary for local control.博士（医学）・甲第705号・平成31年3月15

Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke

Abstract: Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Int. J. Mol. Sci. 2013, 14 18900 Therefore, antihypertensive treatments are recommended for the prevention of stroke. Thre

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The synthesis of 2,4,6-Pyridine tricarboxylic acid has been using 2,4,6-collidine as a key starting materal