Abstract: To determine whether increasing thrombectomy-capable hospitals with moderate comprehensive stroke center (CSC) capabilities is a valid alternative to centralization of those with high CSC capabilities. This retrospective, nationwide, observational study used data from the J-ASPECT database linked to national emergency medical service (EMS) records, captured during 2013–2016. We compared the influence of mechanical thrombectomy (MT) use, the CSC score, and the total EMS response time on the modified Rankin Scale score at discharge among patients with acute ischemic stroke transported by ambulance, in phases I (2013–2014, 1461 patients) and II (2015–2016, 3259 patients). We used ordinal logistic regression analyses to analyze outcomes. From phase I to II, MTs increased from 2.7 to 5.5%, and full-time endovascular physicians per hospital decreased. The CSC score and EMS response time remained unchanged. In phase I, higher CSC scores were associated with better outcomes (1-point increase, odds ratio [95% confidence interval]: 0.951 [0.915–0.989] ) and longer EMS response time was associated with worse outcomes (1-min increase, 1.007 [1.001–1.013]). In phase II, neither influenced the outcomes. During the transitional shortage of thrombectomy-capable hospitals, increasing hospitals with moderate CSC scores may increase nationwide access to MT, improving outcomes.

Abstract: What are the pregnancy outcomes after the OP timization of T hyroid function, Im munity, and U terine M ilieu (OPTIMUM) treatment strategy in patients with repeated implantation failure (RIF)? Method of study Infertile women with a history of RIF after more than three embryo transfer (ET) cycles underwent implantation testing, including a hysteroscopy, endometrial biopsy for CD138 immunostaining and bacterial culture, and serum 25‐hydroxyvitamin D 3 , interferon‐γ‐producing helper T (Th1) cell, IL‐4‐producing helper T (Th2) cell, thyroid‐stimulating hormone, thyroid peroxidase antibody, and thrombophilia screening between April 2017 and August 2018. We treated chronic endometritis with antibiotics, aberrant high Th1/Th2 cell ratios with vitamin D and/or tacrolimus intake, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low‐dose aspirin. Of the 116 RIF women, 88 women with 133 ET cycles were recruited from a questionnaire‐based survey regarding pregnancy outcomes. Fifty‐nine consecutive RIF patients without the OPTIMUM treatment strategy were also recruited as a control. Results The 116 women with RIF after the OPTIMUM treatment strategy were 38.3 ± 3.8 years old and had an implantation failure history over 5 (3‐19) ET cycles. Implantation testing identified impaired intrauterine circumstances in 75 women (64.7%), an aberrant elevated Th1/Th2 cell ratio in 56 women (48.3%), and thyroid abnormalities in 33 women (28.4%). Cumulative ongoing pregnancy rates including spontaneous pregnancy in the patients aged  〈  40 and ≥ 40 years were 72.7% and 45.5% within two ET cycles, respectively. The pregnancy outcomes in the OPTIMUM group were significantly higher than those in the control. Conclusions The OPTIMUM treatment strategy improved pregnancy outcomes in patients with RIF.

Abstract: Endometrial receptivity array (ERA) is used to determine the timing of embryo transfer (ET) synchronized with the window of implantation (WOI). The effectiveness and evaluation of ERAs in women with recurrent implantation failure remain controversial. We report the case of a patient with recurrent implantation failure that raises the issue of reproducibility of ERA tests. Case report A 36-year-old Japanese woman with secondary infertility who had previously given birth failed to conceive after three frozen-thawed embryo transfer (FET) cycles. An ERA test was conducted to confirm the WOI. The first ERA test was performed 125 h after progesterone exposure. The laboratory reported that the endometrium was in a non-receptive (post-receptive) phase, and recommended retesting 101 h after progesterone exposure. A simultaneous chronic endometritis (CE) test showed a score of 3. After the antibiotics administration to treat CE, the second ERA test was performed after 101 h of progesterone exposure. The laboratory reported that the endometrium had not reached the WOI and estimated the WOI to be 113 ± 3 h after progesterone exposure. The third ERA test was performed 113 h after progesterone exposure. The laboratory reported that the endometrium was in a non-receptive (pre-receptive) phase and estimated the WOI to be 137 ± 3 h after progesterone exposure. A CE test performed at the same time as the second and third ERA tests showed a score of 1 for the collected endometrium. According to the third ERA test results, the vitrified-warmed blastocyst was transferred at 137 h of progesterone exposure. Pregnancy was achieved and the patient had an uncomplicated vaginal delivery at 39 weeks. One year later, another pregnancy was achieved after FET at 137 h of progesterone exposure, and the patient delivered at 33 weeks due to an unexpected membrane rupture. Conclusion Because the results of the ERA test may vary in the presence of CE, CE should be diagnosed simultaneously with or before conducting ERA tests. If CE is diagnosed, ERA testing should be performed after treatment with antimicrobials or other drugs.

Abstract: Background: Isocitrate dehydrogenase (IDH)-1 and -2 are TCA cycle-involved enzymes which convert isocitrate to alpha-ketoglutarate. Mutations that alter the enzymatic activity causes accumulation of a mal-metabolite D-2-hydroxyglutarate, which results in inhibition of DNA methylation and tumorigenesis. IDH-1 and IDH-2 mutation are present in approximately 7-10% and 10% of patients with acute myeloid leukemia (AML), respectively. Recently, whole exome sequencing has been used for the next-generation sequencing of AML, and certain gene mutations have been identified in patients with AML. The treatment strategies for leukemia have undergone drastic changes with the rapid development of new drugs. However, the proper use of newly developed agents poses a major challenge in AML treatment. Genome profiling analysis can be used to select the optimal treatment for patients with newly diagnosed AML. IDH mutant-specific inhibitors such as ivosidenib and enasidenib were already approved in the US, and combination treatment with venetoclax and Azacitidine was recently approved in Japan. Methods and Results: We lunched an actionable mutation profiling multicenter study named Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233), in which a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel. The primary outcome was the frequency of each genomic alteration, as determined using F1H, which is a comprehensive genome profiling test based on next-generation sequencing, in the AML specimens. The secondary outcome was the association between each genomic alteration and the clinicopathological characteristics, prognosis, and quality of specimens used in the genetic analysis. The eligibility criteria were as follows: 1) histological diagnosis of AML through bone marrow aspiration; 2) fulfillment of either of the following conditions: i) newly diagnosed AML unfit for standard treatment (ND-unfit AML) or ii) R/R-AML; 3) sufficient sample collection via bone marrow aspiration; 4) Age of participants 20 years or above during registration; 5) provision of written informed consent by participants. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. The median turnaround time was 13 days (minimum 8 days). We found 13 patients (7.3%) with IDH1 mutation and 17 patients (9.6%) with IDH2 mutation out of 177 patients who joined this study and the F1H report was successfully returned. Only one patient had both mutations, and each mutation was mutually exclusive in all the other patients (Figure 1). The major amino acid alteration of IDH1 and IDH2 were R132C/G/H/L and R140Q/W, respectively. Frequently co-occurring mutations include FLT3 (44.8%), NPM1 (34.5%), DNMT3A (31.0%) and RUNX1 mutation (20.7%). Mutations of RAS pathway-related genes (e.g., KRAS, NRAS and PTPN11) were seen in 6 patients (20.7%). Any gene alterations didn't show statistically significant co-occurrence with IDH1 and IDH2 mutation. Serial genome profiling analyses were performed to evaluate the time-dependent changes in the genome profiles of patients administered FLT3 inhibitors, gilteritinib, and quizartinib for treating FLT3-mutated AML. Also in this cohort, we are examining the properties and distribution of IDH1/2 mutations during treatment with FLT3 inhibitors. In the several patients, expansion and persistence of IDH mutated clones seemed to be cause of resistance (Figure 2 as the representative result). The detailed clinical outcomes of AML patients with IDH1/2 mutations are under investigation. Conclusions: In our evaluation of the suitability of F1H for HM-SCREEN-Japan 01, we successfully identified IDH-1/2 mutation that can be used as therapeutic targets in AML, which have rarely been identified thus far. Figure 1 Figure 1. Disclosures Shibayama: Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Fujimoto: Honoraria; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Mundi Pharma: Honoraria; Essentia Pharma Japan: Research Funding. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Pfizer: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Abbvie: Honoraria. Yamamoto: AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria. Kuroda: Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Astellas: Research Funding, Speakers Bureau; Abbvie: Research Funding; Gilead: Research Funding; Symbio: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Nippon Boehringer Ingelheim: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau; Mundipharma: Research Funding. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Asahi kasei: Research Funding; Eli Lilly: Research Funding; MSD: Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Kyowa Kirin: Other: Personal fees, Research Funding; Ono Pharmaceutical: Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Huya Japan: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding. Ono: Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Celgene: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Takahashi: Toyamakagaku: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Eizai: Research Funding. Iyama: Alexion Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Genmab: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Chugai: Honoraria, Research Funding; Symbio: Honoraria; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Minami: Novartis Pharma KK: Honoraria; Ono: Research Funding; Pfizer Japan Inc.: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; CMIC: Research Funding.

Abstract: The early to mid-Aptian was punctuated by episodic phases of organic-carbon burial in various oceanographic settings, which are possibly related to massive volcanism associated with the emplacement of the Ontong Java, Manihiki, and Hikurangi oceanic plateaus in the southwestern Pacific Ocean, inferred to have formed a single plateau called Ontong Java Nui. Sedimentary osmium (Os) isotopic compositions are one of the best proxies for determining the timing of voluminous submarine volcanic episodes. However, available Os isotopic records during the age are limited to a narrow interval in the earliest Aptian, which is insufficient for the reconstruction of long-term hydrothermal activity. We document the early to mid-Aptian Os isotopic record using pelagic Tethyan sediments deposited in the Poggio le Guaine (Umbria-Marche Basin, Italy) to precisely constrain the timing of massive volcanic episodes and to assess their impact on the marine environment. Our new Os isotopic data reveal three shifts to unradiogenic values, two of which correspond to black shale horizons in the lower to mid-Aptian, namely the Wezel (herein named) and Fallot Levels. These Os isotopic excursions are ascribed to massive inputs of unradiogenic Os to the ocean through hydrothermal activity. Combining the new Os isotopic record with published data from the lowermost Aptian organic-rich interval in the Gorgo a Cerbara section of the Umbria-Marche Basin, it can be inferred that Ontong Java Nui volcanic eruptions persisted for ∼5 m.y. during the early to mid-Aptian.

Abstract: ARM‐normalized relative paleointensity is inversely correlated with the proportion of biogenic magnetite in the studied sediments The estimated relative paleointensity recording efficiency of biogenic magnetite is lower than that of terrigenous magnetic minerals Varying abundances of magnetic inclusions might cause contrasting recording efficiencies for biogenic magnetite between different studies