Secondary Stroke Prevention Among Filipinos Compared with Other Racial Groups in Hawaii

Purpose/Background: As the fifth leading cause of death in the United States and a main cause of disability, stroke results in immense health and economic burden. Filipinos (FI) were found to have the highest mortality due to major CVD and stroke in Hawaii, and it is unclear whether the increased stroke risk among FI might be reduced by increasing the use of guideline recommended medications for secondary stroke prevention. Additionally, the attitudes and concerns of FI patients in Hawaii regarding stroke prevention have not been studied. The purpose of this study is to utilize a mixed-method approach to elucidate health disparities in FI after stroke compared with other racial groups in Hawaii, Whites, other Asians, Native Hawaiian and other Pacific Islanders (NHOPI) and other race. Materials & Methods: The Get With the Guidelines – Stroke (GWTG-Stroke) data from The Queenʼs Medical Center (QMC) will be used to identify patients hospitalized for stroke from years 2006-2016. Subjects will be excluded if diagnosed with non-ischemic stroke and with disposition other than home. Multivariable logistic regression models will examine differences in appropriate medication use at discharge related to race/ethnicity, controlling for age, sex, insurance, prior use of medications, and stroke risk factors. Additionally, semi-structured key informant interviews will be conducted among FI and other stroke patients from QMC. Transcripts from the interviews will be reviewed, coded, and interpreted for congruent themes. Results: Preliminary results from the GWTG-Stroke 2013 to 2016 data identified a total of 3574 stroke patients. After meeting inclusion criteria, a total of 1489 subjects were identified. The subjects included 398 Whites, 191 FI, 528 other Asian, 346 NHOPI, and 26 other race. At baseline, there was no difference in the average age of FI compared with Whites (66 vs 67 years old, respectively, P=0.15); however, other Asians (70 years old, P=0.002) were older, and NHOPI (60 years old, P\u3c0.001) were younger than Whites. Furthermore, FI, other Asians, and NHOPI had significantly higher rates of hypertension, diabetes mellitus, and dyslipidemia than Whites. Multivariable logistic regression results showed no statistically significant racial difference in prescribing of antithrombotics or statins at discharge. Age [OR=0.97; 95% CI (0.95, 0.995)], however, was a negative predictor of antithrombotic prescription, and being female [OR=0.68; 95% CI (0.51, 0.90)] was associated with lower rates of statin prescription on discharge (Table 1). Discussion/Conclusion: Analyses of data from a large hospital in Hawaii from 2013 to 2016 found race was not associated with prescribing differences for the guideline recommended medications for secondary stroke prevention. Further study is needed to better understand why female gender was associated with fewer statin prescriptions. The pending results of the key informant interviews may shed light on the attitudes and concerns regarding stroke prevention among FI and other racial groups in Hawaii

Effect of Students’ Reflection on their Teaching Practice Experiences: Discussions during Case Conferences in Teaching Practice

The purpose of this study was to clarify the effect of reflecting by student A, who participated in a teaching practice. As a result, the following three points were clarified. First, student A made more comments at case conferences than student teacher B. Moreover, student A made more comments concerning “alternatives” in which students’ reflections appear in case conferences than student teacher B. Second, the students’ reflections at case conferences revealed a commonly shared viewpoint on “teaching skills”. Student A also held the viewpoint of an “approach to the objective” and that the content of the class was appropriate to the goal of the lesson. Regarding the difference between student A and student teacher B, it was suggested that the mentoring received by student A from mentor D during the teaching practice had some degree of influence. Third, both student A and student teacher B has difficulties with “schoolchild understanding” despite mentor D talking at case conferences about this issue. Based on these findings, it is suggested that it is difficult to engage in reflection that enables student to comprehend “schoolchild understanding” in teaching practice

Genomic Control of Upregulation of GRP78 Expression for Promotion of Neurite Elongation and Attenuation of Cell Death via PKA-Mediated Signaling in PC12 Cells

Neurodegeneration occurs due to neuronal cell death and subsequently disrupts neuronal networks. In current medicine, methods for interruption of neuronal cell death and avoidance of disruption of neuronal networks have potential as therapy for neurodegenerative disorders. Development of this therapy requires analysis of the molecular mechanism of neurite extension that leads to network formation. Here, we show that forskolin (fsk), an activator of adenylate cyclase, increases the intracellular cAMP concentration and induces neurite outgrowth in PC12 cells. The effect of fsk on neurite outgrowth was diminished by H89, an inhibitor of protein kinase A (PKA), and by PD98059 and U0126, which are inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway. With fsk treatment in the presence of tunicamycin, an inducer of cell death, the activity of the glucose-regulated protein 78 (GRP78) promoters was upregulated. Interestingly, this effect was completely abolished by H89 and by PD98059 and U0126. This phenomenon was confirmed using a dominant-negative PKA-expressing PC12 cell line, in which the PKA-mediated signaling pathway was completely eliminated. These lines of evidence suggest that GRP78 promotes neuronal elongation that is regulated by fsk and mediated by PKA.This work was supported by SENRYAKU (2013-2017) and KAKENHI (25340104) grants-in-aid from MEXT (Ministry of Education, Culture, Sports, Science and Technology of Japan), and by a Kansai University Grant-in- Aid for Encouragement of Scientists (2014)

急性期虚血性脳卒中患者から機械的血栓回収術で得られた血栓の年齢と組成は血栓回収術転帰および臨床転帰と関連していた

Introduction: Understanding the composition of stroke thrombi retrieved by mechanical thrombectomy is essential to clarify the pathogenesis of stroke. However, it is difficult to evaluate thrombus composition precisely and objectively. Immunohistochemical staining was used to evaluate thrombus composition and age. Materials and methods: Consecutive thrombi (n = 108) retrieved from patients who underwent mechanical thrombectomy for acute large-vessel ischemic stroke were retrospectively analyzed. Lytic features of granulocytes and CD163 were estimated as indicators of the age of the cardioembolic (CE) thrombus. Results: The stroke subtypes were as follows: CE, 74 cases; large artery atherosclerosis, 11; undetermined etiology, 12; and other determined etiology, 11. There were no statistical differences in thrombi composition according to stroke subtypes. The fibrin area was positively correlated with the red blood cell (RBC) and platelet areas. The following analysis was performed using CE only. Regarding age, the thrombus was judged as fresh in 30.0 % and older in 70.0 % based on the lytic features. The RBC areas of older thrombi were smaller than those of fresh thrombi. The puncture-to-reperfusion time of older thrombi was longer than that of fresh thrombi. Platelet-rich thrombi were associated with a greater number of maneuvers, a smaller prevalence of TICI 3, and unfavorable functional outcomes compared to platelet-poor thrombi. The number of CD163 positive cells in thrombi with anticoagulants was higher than in those without anticoagulants. Conclusion: Thrombus composition correlated with revascularization and clinical outcomes. The composition of an acute ischemic thrombus may reflect the pathophysiology of stroke and influence treatment efficacy.博士（医学）・甲第855号・令和4年12月22日Copyright © 2022 Elsevier Ltd. All rights reserved

Fundamental Parameters of the Milky Way Galaxy Based on VLBI astrometry

We present analyses to determine the fundamental parameters of the Galaxy based on VLBI astrometry of 52 Galactic maser sources obtained with VERA, VLBA and EVN. We model the Galaxy's structure with a set of parameters including the Galaxy center distance R_0, the angular rotation velocity at the LSR Omega_0, mean peculiar motion of the sources with respect to Galactic rotation (U_src, V_src, W_src), rotation-curve shape index, and the V component of the Solar peculiar motions V_sun. Based on a Markov chain Monte Carlo method, we find that the Galaxy center distance is constrained at a 5% level to be R_0 = 8.05 +/- 0.45 kpc, where the error bar includes both statistical and systematic errors. We also find that the two components of the source peculiar motion U_src and W_src are fairly small compared to the Galactic rotation velocity, being U_src = 1.0 +/- 1.5 km/s and W_src = -1.4 +/- 1.2 km/s. Also, the rotation curve shape is found to be basically flat between Galacto-centric radii of 4 and 13 kpc. On the other hand, we find a linear relation between V_src and V_sun as V_src = V_sun -19 (+/- 2) km/s, suggesting that the value of V_src is fully dependent on the adopted value of V_sun. Regarding the rotation speed in the vicinity of the Sun, we also find a strong correlation between Omega_0 and V_sun. We find that the angular velocity of the Sun, Omega_sun, which is defined as Omega_sun = Omega_0 + V_sun/R_0, can be well constrained with the best estimate of Omega_sun = 31.09 +/- 0.78 km/s/kpc. This corresponds to Theta_0 = 238 +/- 14 km/s if one adopts the above value of R_0 and recent determination of V_sun ~ 12 km/s.Comment: 14 pages, 6 figures, PASJ in pres

ATR阻害は非相同末端結合および相同組換え修復と非依存的に5-FUを増感する

The anticancer agent 5-fluorouracil (5-FU) is cytotoxic and often used to treat various cancers. 5-FU is thought to inhibit the enzyme thymidylate synthase, which plays a role in nucleotide synthesis and has been found to induce single- and double-strand DNA breaks. ATR Ser/Thr kinase (ATR) is a principal kinase in the DNA damage response and is activated in response to UV- and chemotherapeutic drug-induced DNA replication stress, but its role in cellular responses to 5-FU is unclear. In this study, we examined the effect of ATR inhibition on 5-FU sensitivity of mammalian cells. Using immunoblotting, we found that 5-FU treatment dose-dependently induced the phosphorylation of ATR at the autophosphorylation site Thr-1989 and thereby activated its kinase. Administration of 5-FU with a specific ATR inhibitor remarkably decreased cell survival, compared with 5-FU treatment combined with other major DNA repair kinase inhibitors. Of note, the ATR inhibition enhanced induction of DNA double-strand breaks and apoptosis in 5-FU-treated cells. Using gene expression analysis, we found that 5-FU induced the activation of the intra-S cell-cycle checkpoint. Cells lacking BRCA2 were sensitive to 5-FU in the presence of ATR inhibitor. Moreover, ATR inhibition enhanced the efficacy of the 5-FU treatment, independently of the nonhomologous end-joining and homologous recombination repair pathways. These findings suggest that ATR could be a potential therapeutic target in 5-FU-based chemotherapy.博士（医学）・甲第791号・令和3年3月15日© 2020 Ito et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.This is an Open Access article under the CC BY license(https://creativecommons.org/licenses/by/4.0/)

VLBI Astrometry of AGB Variables with VERA -- A Semiregular Variable S Crateris --

We present a distance measurement for the semiregular variable S Crateris (S Crt) based on its annual parallax. With the unique dual beam system of the VLBI Exploration for Radio Astrometry (VERA) telescopes, we measured the absolute proper motion of a water maser spot associated with S Crt, referred to the quasar J1147-0724 located at an angular separation of 1.23$^{\circ}$. In observations spanning nearly two years, we have detected the maser spot at the LSR velocity of 34.7 km s$^{-1}$, for which we measured the annual parallax of 2.33$\pm$0.13 mas corresponding to a distance of 430$^{+25}_{-23}$ pc. This measurement has an accuracy one order of magnitude better than the parallax measurements of HIPPARCOS. The angular distribution and three-dimensional velocity field of maser spots indicate a bipolar outflow with the flow axis along northeast-southwest direction. Using the distance and photospheric temperature, we estimate the stellar radius of S Crt and compare it with those of Mira variables.Comment: 9 pages, 4 figures, accepted for publication in PASJ (Vol.60, No.5, October 25, VERA special issue

27ヒドロキシコレステロールはエストロゲン受容体を介してヒトSLC22A12の発現を制御する

The excretion and reabsorption of uric acid both to and from urine are tightly regulated by uric acid transporters. Metabolic syndrome conditions, such as obesity, hypercholesterolemia, and insulin resistance, are believed to regulate the expression of uric acid transporters and decrease the excretion of uric acid. However, the mechanisms driving cholesterol impacts on uric acid transporters have been unknown. Here, we show that cholesterol metabolite 27-hydroxycholesterol (27HC) upregulates the uric acid reabsorption transporter URAT1 encoded by SLC22A12 via estrogen receptors (ER). Transcriptional motif analysis showed that the SLC22A12 gene promoter has more estrogen response elements (EREs) than other uric acid reabsorption transporters such as SLC22A11 and SLC22A13, and 27HC-activated SLC22A12 gene promoter via ER through EREs. Furthermore, 27HC increased SLC22A12 gene expression in human kidney organoids. Our results suggest that in hypercholesterolemic conditions, elevated levels of 27HC derived from cholesterol induce URAT1/SLC22A12 expression to increase uric acid reabsorption, and thereby, could increase serum uric acid levels.博士（医学）・甲第772号・令和3年3月15日© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License(https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset

This prespecified subanalysis of the global, randomized controlled phase Ill KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFRIALK alterations and a PD-L1 tumor proportion score of 50% or greater

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738