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Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444

HNCO and SiO are well known shock tracers and have been observed in nearby galaxies, including the nearby (D=3.5 Mpc) starburst galaxy NGC 253. The simultaneous detection of these two species in regions where the star formation rate is high may be used to study the shock history of the gas. We perform a multi-line molecular study using these two shock tracers (SiO and HNCO) with the aim of characterizing the gas properties. We also explore the possibility of reconstructing the shock history in NGC 253's Central Molecular Zone (CMZ). Six SiO transitions and eleven HNCO transitions were imaged at high resolution $1''.6$ (28 pc) with the Atacama Large Millimeter/submillimeter Array (ALMA) as part of the ALCHEMI Large Programme. Both non-LTE radiative transfer analysis and chemical modelling were performed in order to characterize the gas properties, and to investigate the chemical origin of the emission. The non-LTE radiative transfer analysis coupled with Bayesian inference shows clear evidence that the gas traced by SiO has different densities and temperatures than that traced by HNCO, with an indication that shocks are needed to produce both species. Chemical modelling further confirms such a scenario and suggests that fast and slow shocks are responsible for SiO and HNCO production, respectively, in most GMCs. We are also able to infer the physical characteristics of the shocks traced by SiO and HNCO for each GMC. Radiative transfer and chemical analysis of the SiO and HNCO in the CMZ of NGC 253 reveal a complex picture whereby most of the GMCs are subjected to shocks. We speculate on the possible shock scenarios responsible for the observed emission and provide potential history and timescales for each shock scenario. Higher spatial resolution observations of these two species are required in order to quantitatively differentiate between scenarios.

3-1. Research Activities in 2021

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CO CV CM CI Ryugu A Ryugu C 0.0 0.5 1.0 1.5 44/40CaSRM915a (age corrected) The Hayabusa2 spacecraft has returned samples from the Cb-type asteroid (162173) Ryugu to Earth. Previous petrological and chemical analyses support a close link between Ryugu and CI chondrites that are presumed to be chemically the most primitive meteorites with a solar-like composition. However, Ryugu samples are highly enriched in Ca compared to typical CI chondrites. To identify the cause of this discrepancy, here we report stable Ca isotopic data (expressed as delta 44/40CaSRM915a) for returned Ryugu samples collected from two sites. We found that samples from both sites have similar delta 44/40CaSRM915a (0.58 +/- 0.03 parts per thousand and 0.55 +/- 0.08 parts per thousand, 2 s.d.) that fall within the range defined by CIs. This isotopic similarity suggests that the Ca budget of CIs and Ryugu samples is dominated by carbonates, and the variably higher Ca contents in Ryugu samples are due to the abundant carbonates. Precipitation of carbonates on Ryugu likely coincided with a major episode of aqueous activity dated to have occurred similar to 5 Myr after Solar System formation. Based on the pristine Ryugu samples, the average delta 44/40CaSRM915a of the Solar System is defined to be 0.57 +/- 0.04 parts per thousand (2 s.d.).

Jun Aoki,1 Kazuhiro Sakamoto,1 Rina Takahashi,1 Koichiro Niwa,1 Shun Ishiyama,1 Kiichi Sugimoto,1 Hirohiko Kamiyama,1 Makoto Takahashi,1 Yutaka Kojima,1 Michitoshi Goto,1 Yuichi Tomiki,1 Toshiaki Iba21Department of Coloproctological Surgery, Juntendo University, Faculty of Medicine, Tokyo, Japan; 2Department of Emergency and Disaster Medicine, Juntendo University, Faculty of Medicine, Tokyo, JapanBackground: There is a high incidence of venous thromboembolism (VTE) during the perioperative period for cancer. Therefore, there is an urgent need to elucidate the perioperative onset and appropriate prophylaxis for VTE.Purpose: VTE during the perioperative period for colorectal cancer was evaluated by lower limb venous ultrasonic examinations (lower limb echo) under enoxaparin prophylaxis. We also examined the relationship between hemorrhagic adverse events and anti-Xa factor activity.Patients and methods: Eighty-three subjects who underwent lower limb echo during the perioperative period for colorectal cancer were prospectively included. Enoxaparin was administered for 5 days, from day 1 to day 5 after surgery. Lower limb echo was performed before surgery and on day 5 after surgery. The activated partial thromboplastin time, D-dimer levels, and anti-Xa factor activity were measured before surgery and on days 1, 3, 5, 7, and 9 after surgery.Results: VTEs before surgery were observed on lower limb echo for 16 patients (19.2%). Three patients (3.6%) had a new thrombus during the perioperative period. The preoperative D-dimer level was an independent prognostic factor for newly formed postoperative VTEs (p=0.0036; odds ratio, 19.37). Three patients (3.6%) had hemorrhagic events; however, there was no significant trend for anti-Xa factor activity.Conclusion: VTE prevention using enoxaparin was relatively safe, and D-dimer measurements before surgery were useful for predicting perioperative VTE.Keywords: postoperative complications, pulmonary thromboembolism, deep vein thrombosis, D-dimer, anti-Xa factor activity

To evaluate the clinical outcomes of surgical repair of an extracardiac total anomalous pulmonary venous connection (TAPVC) in a functional single-ventricle (f-SV) strategy. This was a retrospective analysis of 48 consecutive cases of extracardiac TAPVC repair, from 1998 to 2015. Demographic and clinical variables were as follows: median age, 24 (range 0–744) days; median weight, 3.1 (range 2.0–9.6) kg; type of TAPVC—supracardiac, 21 patients, infracardiac, 8, and mixed, 19; right atrial isomerism, 45 patients; pulmonary atresia, 24 patients; and obstructed TAPVC, 30 patients. Concomitant procedures included systemic-to-pulmonary shunting in 15 patients, pulmonary artery banding in 12, ventricle-to-pulmonary artery shunting in 2, a Norwood procedure in one, a bidirectional Glenn procedure in 16, and a Fontan procedure in 1. The 1- and 5-year cumulative survival rates were 66.0% and 58.0%, respectively. Of the 28 survivors, 22 (78.6%) underwent Fontan completion and 4 (14.3%) a bidirectional Glenn procedure, and 1 (3.6%) was awaiting a bidirectional Glenn procedure. Recurrent pulmonary venous stenosis (PVS) was observed in 17 patients, with a 1- and 5-year rates of freedom from recurrent PVS 59.8% and 53.5%, respectively. Of the 20 post-operative deaths, only 4 were PVS related. Only pre-operative pulmonary atresia was identified as an independent risk factor of mortality after TAPVC repair. The midterm surgical outcomes of f-SV with extracardiac TAPVC were acceptable. Moreover, among survivors, Fontan completion can be sufficiently expected. Further improvement, with the development of a comprehensive treatment strategy, is required for this patient group.

Stray millimeter-wave radiation from a 70-GHz electron cyclotron heating and current drive (ECH/ECCD) system has been measured in the Heliotron J helical device. Two rotatable diode detectors located at the out- board side ports are used to pick up the stray radiation: one is installed at the ECH launcher port and the other is installed at a toroidal angle of 135 deg far from the ECH launcher port. Both detectors are rotated to measure the polarization of the stray radiation. The results show that at the toroidal position far from the ECH launcher, the polarization is not fully randomized before plasma breakdown, whereas the polarization is uniform after a quasi- stationary plasma is generated. The polarization near the ECH launcher is not uniform even in a quasi-stationary plasma. Plasma experiments scanning the electron density indicate that the EC power absorption estimated from the stray radiation at the toroidal position far from the ECH launcher is correlated with the single-pass ab- sorption rate calculated by the TRAVIS ray-tracing code. These results indicate that the diagnostic using a simple diode detector can be used as a real-time monitor of EC power absorption only when the plasma with finite density is produced and the detector is placed far from the ECH launcher port.

Background: A novel oral hypoglycemic agent (OHA) would be imeglimin (Twymeeg) as tetrahydrotriazine-containing drug. Case presentation: The patient is 93-year-old female and developed appetite loss and slower vocal response in March, 2022. Result: She was transferred to our hospital, and diagnosed as T2DM with HbA1c 8.4% and small lacunar infarction in bilateral white matter by MRI. Then, imeglimin 2000mg/day was started and HbA1c was decreased to 6.2% in April, 2020. Discussion: Imeglimin has dual function for increasing insulin secretion and decreasing insulin resistance. It seems to be effective for elderly case, and will be used widely in the future.

Background: Oral semaglutide (imeglimin) has been prescribed for patients with type 2 diabetes (T2D) as Twymeeg. Case presentation: The patient is 77-year-old male with hypertension, previous cerebral vascular accident (CVA). He continued unbalanced meal with preference of much carbohydrate. In Sept 2021, he became diabetic with HbA1c 8.8%. Results: Imeglimin 2000mg/day was started improving to 6.7% for 2 months. Discussion: Complete blood count (CBC) showed decreased Hb and increased MCV, suggesting macrocytic anemia for lack of vegetables. Much carbohydrate intake may bring T2D. Remarkable diabetic improvement may be from dual mechanisms for increasing insulin secretion and decreasing insulin resistance.

We discuss the relativistic ion acceleration by irradiating a nanostructure target with ultra- intense laser. The nanostructure target is mounted on a large-area suspended graphene (LSG), which is a novel solid target with remarkable features such as the thinnest, lightest, strongest, transparent, and reasonable, for laser ion acceleration. We have developed various types of targets such as nanometer thin gold, and other materials on LSG, and now carbon nanotube on LSG. This will enable us to access the unexplored regime, relativistic ions., 日本物理学会 2020年秋季大会

We present spatial variations of the CO J=2-1/1-0 line ratio in M83 using Total Power array data from ALMA. While the intensities of these two lines correlate tightly, the ratio varies over the disk, with a disk average ratio of 0.69, and shows the galactic center and a two-arm spiral pattern. It is high (>0.7) in regions of high molecular gas surface density, but ranges from low to high ratios in regions of low surface density. The ratio correlates well with the spatial distributions and intensities of FUV and IR emissions, with FUV being the best correlated. It also correlates better with the ratio of IR intensities (70/350mic), a proxy for dust temperature, than with the IR intensities. Taken together, these results suggest either a direct or indirect link between the dust heating by the interstellar radiation field and the condition of GMCs, even though no efficient mechanism is known for a thermal coupling of dust and bulk gas in GMCs., Accepted for ApJ Letters

Submillimetre and millimetre line and continuum observations are important in probing the morphology, column density, and dynamics of the molecular gas and dust around obscured active galactic nuclei (AGNs) and their mechanical feedback. With very high-resolution (0.′′ ″02 × 0.′′ ″03 (2 × 3 pc)) ALMA 345 GHz observations of CO 3-2, HCO+ 4-3, vibrationally excited HCN 4-3 ν2 = 1f, and continuum we have studied the remarkable, extremely radio-quiet, molecular jet and wind of the lenticular galaxy NGC 1377. The outflow structure is resolved, revealing a 150 pc long, clumpy, high-velocity (∼600 km s-1), collimated molecular jet where the molecular emission is emerging from the spine of the jet with an average diameter of 3-7 pc. The jet widens to 10-15 pc about 25 pc from the centre, which is possibly due to jet-wind interactions. A narrow-angle (50°-70°), misaligned and rotating molecular wind surrounds the jet, and both are enveloped by a larger-scale CO-emitting structure at near-systemic velocity. The jet and narrow wind have steep radial gas excitation gradients and appear turbulent with high gas dispersion (σ > 40 km s-1). The jet shows velocity reversals that we propose are caused by precession, or more episodic directional changes. We discuss the mechanisms powering the outflow, and we find that an important process for the molecular jet and narrow wind is likely magneto-centrifugal driving. In contrast, the large-scale CO-envelope may be a slow wind, or cocoon that stems from jet-wind interactions. An asymmetric, nuclear r ∼ 2 pc dust structure with a high inferred molecular column density N(H2) ∼ 1.8 × 1024 cm-2 is detected in continuum and also shows compact emission from vibrationally excited HCN. The nuclear dust emission is hot (Td > 180 K) and its luminosity is likely powered by a buried AGN. The lopsided structure appears to be a warped disk, which is responsible for a significant part of the nuclear obscuration and possibly formed as a result of uneven gas inflows. The dynamical mass inside r = 1.4 pc is estimated to 9-3+2 × 106 M, implying that the supermassive black hole (SMBH) has a high mass with respect to the stellar velocity dispersion of NGC 1377. We suggest that the SMBH of NGC 1377 is currently in a state of moderate growth, at the end of a more intense phase of accretion and also evolving from a state of more extreme nuclear obscuration. The nuclear growth may be fuelled by low-angular momentum gas inflowing from the gas ejected in the molecular jet and wind. Such a feedback-loop of cyclic outflows and central accretion could explain why there is still a significant reservoir of molecular gas in this ageing, lenticular galaxy. A feedback-loop would be an effective process in growing the nuclear SMBH and thus would constitute an important phase in the evolution of NGC 1377. This also invites new questions as to SMBH growth processes in obscured, dusty galaxies. © 2020 ESO.

Background: As a novel oral hypoglycemic agent (OHA), imeglimin has been recently applied for patients with type 2 diabetes mellitus (T2DM) as Twymeeg. It has beneficial twin mechanisms associated with increasing insulin secretion, and decreasing insulin resistance. It has a triazine ring and become the first OHA for tetrahydrotriazine-containing agent in the category of the glimins. Case presentation: The case is 84-year-old female with T2DM and mild cognitive impairment (MCI). Her HbA1c was 9.3% a year ago. Results: She was begun to receive Dulaglutide 0.75mg/week and showed 1.3% HbA1c reduction for 6 months. However, HbA1c was elevated again to 8.5%, and then she was provided Twymeeg 2000mg/day. HbA1c decreased from 8.5% to 7.5% in 3 months. [Discussion and conclusion] From combined treatments of imeglimin and other agents in the previous study, mean HbA1c reduction showed single imiglimin -0.46%, DPP-4i -0.92% and GLP-1RA -0.12%. Possible reason for the difference between the latter two suggests that multiple action mechanisms of imeglimin may be present including the enhancement of glucose-stimulated insulin secretion (GSIS). In contrast, she showed satisfactory HbA1c reduction by the combination of imeglimin and GLP-1RA. The pathophysiology is not clear, and future follow up the clinical progress will be required.

Background: American Diabetes Association (ADA) presented 2022 guideline, and indicated the benefit of sodium-glucose transporter 2 inhibitor (SGLT2i) and glucagon-like peptide 1 receptor agonist (GLP-1RA). Xultophy is a combined agent of insulin degludec/liraglutide (IDegLira), which is recently clinically useful. Patient and Method: The case is 72-year-old man with type 2 diabetes mellitus (T2DM). He has been treated by some oral hypoglycemic agents (OHAs) with unstable HbA1c levels. Results: When HbA1c was 9.9% in 2018, his daily profile of blood glucose three times a day ranged 208-289 mg/dL. By starting canagliflozin, blood glucose decreased for 145-194 mg/dL. As HbA1c increased to 8.8% in 2021, blood glucose ranged 179-192 mg/dL. By starting Xultophy 12 doses per day, it decreased to normal level for 73-155 mg/dL. HbA1c was reduced to 6.7% half year later. Changes in eGFR showed the decrease from 80 to 51 mL/min/1.73 m2 during unstable HbA1c period in 2018-2019, and stable 50-60 mL/min/1.73 m2 during stable HbA1c period in 2020-2021 with Xultophy therapy. Discussion: SGLT2i, GLP-1RA and Xultophy seem to be beneficial for cardiovascular and renal function. Furthermore, these agents seem to be adequate for diabetic patients with chronic kidney disease (CKD) and/or diabetic kidney disease (DKD).

Shunta Hori, Tatsuki Miyamoto, Keiichi Sakamoto, Takuto Shimizu, Kazuki Ichikawa, Yosuke Morizawa, Daisuke Gotoh, Yasushi Nakai, Makito Miyake, Tatsuo Yoneda, Nobumichi Tanaka, Katsunori Yoshida, Kiyohide Fujimoto Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan Background: Transplant renal vein thrombosis (TRVT) is a severe vascular complication and is caused by various factors, including recipient factors, donor factors, immunosuppression regimens, and surgical techniques. Despite adequate interventions, including thrombolytic therapy or surgical thrombectomy, successful salvage of the allograft is often difficult. We observed a case of TRVT induced by compression of the renal vein immediately after intraoperative abdominal closure.Case presentation: A 41-year-old male underwent ABO-compatible living kidney transplantation. The donor was his 45-year-old sister, and her right kidney was donated. The allograft had a single artery and vein. One of the preoperative recipient problems was obesity (body mass index, 33.4kg/m2). Intraoperative Doppler ultrasonography (US) revealed sufficient blood flow throughout the allograft, and urine output was also observed. After surgery, hematuria was observed; the urine output decreased and serum creatinine levels increased to 7.0mg/dL. Doppler US showed a decrease in diastolic flow and an elevated resistive index, which were similar findings to those noted in acute rejection. Although steroid pulse therapy was initiated, allograft dysfunction was worsening. On postoperative day 4, surgical exploration revealed TRVT; consequently, thrombectomy was performed. The urine output increased, and serum creatinine levels decreased to 1.8mg/dL. The cause of TRVT development may be that the transplant renal vein was relatively short, due to the right kidney being compressed by surrounding tissues after abdominal closure, and that TRVT was gradually developing due to stagnant blood flow.Conclusion: Although TRVT is induced by multiple factors, an accurate diagnosis is often difficult. Understanding these factors, including obesity, and considering TRVT as a cause of allograft dysfunction are important during the pre-, peri-, and postoperative periods. Knowledge of TRVT can lead to early and accurate diagnosis and intervention, resulting in better outcomes for the patients with allograft dysfunction. Keywords: kidney transplantation, surgical exploration, transplant renal vein thrombosis, thrombectomy&nbsp

The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

Norihito Omote, Naozumi Hashimoto, Masahiro Morise, Koji Sakamoto, Shinichi Miyazaki, Akira Ando, Yoshio Nakahara, Yoshinori Hasegawa Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan Background: Non-small cell lung cancer (NSCLC) is the predominant cause of death in patients with COPD, and the severity of COPD in NSCLC patients is classified mainly as mild to moderate. Most advanced NSCLC patients with mild to moderate COPD are treated with chemotherapy; however, the feasibility for and prognosis after chemotherapy of these patients are not well understood. The aim of this study was to elucidate the impact of mild to moderate COPD on the feasibility for and prognosis after chemotherapy in NSCLC patients.Patients and methods: A retrospective review was performed on 268 NSCLC patients who received first-line chemotherapy from 2009 to 2014 in our institution. Finally, 85 evaluable patients were included in this study. The clinical characteristics, toxicity profile, objective response rate, and prognosis were analyzed and compared between patients with mild to moderate COPD and those without COPD (non-COPD).Results: Forty-three patients were classified as COPD (27 cases mild and 16 cases moderate) and 42 patients as non-COPD. The COPD group were older and had fewer never-smokers than the non-COPD group. The objective response rate did not differ between groups (p=0.14). There was no significant difference in overall survival between COPD and non-COPD groups (15.0 and 17.0 months, log-rank test p=0.57). In the multivariate Cox’s proportional hazard model, the adjusted hazard ratio (HRadj) was statistically significant for male sex (HRadj =5.382, 95% CI: 1.496–19.359; p=0.010), pathological diagnosis of adenocarcinoma (HRadj =0.460, 95% CI: 0.223–0.948; p=0.035), and epithelial growth factor receptor negative mutation (HRadj =6.040, 95% CI: 1.158–31.497; p=0.033), but not for the presence of COPD (HRadj =0.661, 95% CI: 0.330–1.325; p=0.24). Toxicity profile in COPD group was favorable, as in the non-COPD group.Conclusion: Mild to moderate COPD did not have a significant deleterious impact on toxicity and prognosis in NSCLC patients. Keywords: toxicity, survival, prognostic factors&nbsp

Kazuo Sakamoto,Masatsugu Nozoe,Yoshitomo Tsutsui,Nobuhiro Suematsu,Toru Kubota,Masanori Okabe,Yusuke Yamamoto Division of Cardiology, Cardiovascular and Aortic Center, Saiseikai Fukuoka General Hospital, Fukuoka, Japan Abstract: Cardiac magnetic resonance imaging (MRI) is a useful tool for detecting the arrhythmogenic substrate in cardiac sarcoidosis. We herein present a case of bipolar radiofrequency catheter ablation for ventricular tachycardia (VT) complicated with cardiac sarcoidosis, guided by pre-procedural cardiac MRI. Neither echocardiography nor endocardial voltage mapping suggested a septal VT substrate. However, MRI alone detected intramural lesions in the septum. Although application of endocardial energy failed to treat the VT, bipolar ablation targeting the potential substrate identified by MRI successfully eliminated the VT. Even when no abnormalities are depicted on echocardiography and endocardial voltage mapping, intramural scar tissue identified by cardiac MRI could be critical for VT. Keywords: cardiac sarcoidosis, VT, MRI, bipolar ablation&nbsp

Koji Ishikawa,1 Takashi Nagai,1 Keizo Sakamoto,1 Kenji Ohara,2 Takeshi Eguro,1,2 Hiroshi Ito,1 Yoichi Toyoshima,1 Akatsuki Kokaze,3 Tomoaki Toyone,1 Katsunori Inagaki1 1Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo, 2Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi, 3Department of Public Health, Showa University School of Medicine, Tokyo, Japan Abstract: Hypocalcemia is the most common major adverse event in patients with osteoporosis receiving the bone resorption inhibitor denosumab; however, limited information is available regarding risk factors of hypocalcemia. Therefore, this study aimed to identify the risk factors of hypocalcemia induced by denosumab treatment for osteoporosis. We retrospectively reviewed the records of patients who had received initial denosumab supplemented with activated vitamin D for osteoporosis. Serum levels of the following bone turnover markers (BTMs) were measured at baseline: bone-specific alkaline phosphatase (BAP), total N-terminal propeptide of type 1 procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and urinary cross-linked N-telopeptide of type 1 collagen (NTX). Of the 85 denosumab-treated patients with osteoporosis studied, 22 (25.9%) developed hypocalcemia. Baseline serum total P1NP, TRACP-5b, and urinary NTX were significantly higher in patients with hypocalcemia than in those with normocalcemia following denosumab administration (all P76.5µg/L, TRACP-5b>474mU/dL, or urinary NTX >49.5nmol bone collagen equivalent/mmol creatinine had a higher risk of hypocalcemia (P

We investigate neutralization processes (especially thermal surface neutralization), which are required for the magneto-optical trapping of radioactive atoms. A variety of neutralization methods are first summarized: neutral beam injection for fusion reactors, neutral atom implantation in semiconductor processing, and the production of radioactive neutral atoms in accelerators. We focus on thermal surface neutralization, which produces neutral atoms in the thermal energy range for laser cooling. The experiments were carried out with yttrium, gadolinium, and zirconium foils to neutralize francium and rubidium ions for magneto-optical trapping. The results reconfirm that yttrium foil is a good neutralizer (i.e., it has a neutral release efficiency $>65\%$). In addition, the release fraction when using yttrium foil exceeds 75\% at 1350 K, which is greater than the release fraction for the other foils. This reconfirmation is important because few previous studies have focused on thermal surface neutralization. Moreover, the results show that the neutralization efficiency is strongly influenced by the experimental process itself.

Occasionally, cells must adapt to an inimical growth conditions like amino acid starvation (AAS) by downregulating protein synthesis. A class of transcripts containing 5’terminal oligopyrimidine (5’TOP) motif encodes translation-related proteins such as ribosomal proteins (RPs) and elongation factors, and therefore, their translation is severely repressed during AAS to conserve energy1. The RNA-binding protein LARP1 transduces amino acid signaling to TOP gene expression by controlling translation and stability of TOP mRNAs2-6. When released from AAS, translation machineries in turn have to be restored, however, the underlying mechanism of such re-adaptation is largely unknown. Here we show that LARP1 preserves TOP mRNAs in a long polyadenylated state during long-term AAS. We found that TOP mRNAs become highly polyadenylated when cells are in AAS or treated with the mTOR (mechanistic target of rapamycin) inhibitor Torin1. Importantly, depletion of LARP1 completely abrogated the polyadenylation of TOP mRNAs. Comprehensive analysis of poly(A) tail length using the Nanopore direct RNA sequencing revealed that TOP mRNAs are selectively polyadenylated under mTOR inhibition. Since a long poly(A) tail confers increased stability and polysome formation of TOP mRNAs, we predict that LARP1-dependent preservation of TOP mRNAs enables rapid translational resumption after the release from AAS.

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The layered van der Waals antiferromagnet MnBi2Te4 has been predicted to combine the band ordering of archetypical topological insulators such as Bi2Te3 with the magnetism of Mn, making this material a viable candidate for the realization of various magnetic topological states. We have systematically investigated the surface electronic structure of MnBi2Te4(0001) single crystals by use of spin- and angle-resolved photoelectron spectroscopy experiments. In line with theoretical predictions, the results reveal a surface state in the bulk band gap and they provide evidence for the influence of exchange interaction and spin-orbit coupling on the surface electronic structure., We acknowledge financial support from the DFG through SFB1170 ’Tocotronics’, SFB1143 ’Correlated Magnetism’, SPP 1666 ’Topological insulators’, ERA-Chemistry Programm (RU-776/15-1), and the Wurzburg-Dresden Cluster of ¨Excellence on Complexity and Topology in Quantum Matter – ct.qmat (EXC 2147, project-id 39085490). We also acknowledge the support by Spanish Ministerio de Economia y Competitividad (MINECO Grant No. FIS2016-75862-P), Academic D.I. Mendeleev Fund Program of Tomsk State University (Project No. 8.1.01.2018), the Saint Petersburg State University grant for scientic investigations (Grant No. 15.61.202.2015), and Russian Foundation for Basic Research (Grant No. 18-52-06009). S.M. acknowledges support by the Swiss National Science Foundation (Grant No. P300P2-171221). This research used resources of the Advanced Light Source, which is a DOE Office of Science User Facility under contract no. DE-AC02-05CH11231. We acknowledge Diamond Light Source for access to beamline I05 (proposals No. SI19278 and No. SI22468) that contributed to the results presented here. Parts of this research were carried out at PETRA III (DESY, Hamburg, Germany) under Proposal No. I-20180510. This work has been partly performed in the framework of the Nanoscience Foundry and Fine Analysis (NFFA-MIUR, Italy) facility. M.M.O. acknowledges support by the Diputacion Foral de Gipuzkoa ((SAREA 2018 - RED ´2018, project no. 2018-CIEN-000025-01).

Physical review / B covering condensed matter and materials physics 100(12), 121104-1-121104-6 (2019). doi:10.1103/PhysRevB.100.121104, The layered van der Waals antiferromagnet $MnBi_{2}Te_{4}$ (0001) has been predicted to combine the band ordering of archetypical topological insulators such as Bi2Te3 with the magnetism of Mn, making this material a viable candidate for the realization of various magnetic topological states. We have systematically investigated the surface electronic structure of $MnBi_{2}Te_{4}$ (0001)single crystals by use of spin- and angle-resolved photoelectron spectroscopy experiments. In line with theoretical predictions, the results reveal a surface state in the bulk band gap and they provide evidence for the influence of exchange interaction and spin-orbit coupling on the surface electronic structure., Published by Inst., Woodbury, NY

AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis, acting as a sensor of energy and nutrient status. As such, AMPK is considered a promising drug target for treatment of medical conditions particularly associated with metabolic dysfunctions. To better understand the downstream effectors and physiological consequences of AMPK activation, we have employed a chemical genetic screen in mouse primary hepatocytes in an attempt to identify novel AMPK targets. Treatment of hepatocytes with a potent and specific AMPK activator 991 resulted in identification of 65 proteins phosphorylated upon AMPK activation, which are involved in a variety of cellular processes such as lipid/glycogen metabolism, vesicle trafficking, and cytoskeleton organisation. Further characterisation and validation using mass spectrometry followed by immunoblotting analysis with phosphorylation site-specific antibodies identified AMPK-dependent phosphorylation of Gapex-5 (also known as GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1)) on Ser902 in hepatocytes and starch-binding domain 1 (STBD1) on Ser175 in multiple cells/tissues. As new promising roles of AMPK as a key metabolic regulator continue to emerge, the substrates we identified could provide new mechanistic and therapeutic insights into AMPK-activating drugs in the liver.

Hiroko Sugawara,1,2 Kaoru Sakamoto,1 Tsuyoto Harada,3 Satoru Shimizu,4 Jun Ishigooka1 1Department of Psychiatry, Tokyo Women’s Medical University, 2Support Center for Women Health Care Professionals and Researchers, Tokyo Women’s Medical University, Shinjuku-ku, 3Department of Psychiatry, Tokyo Women’s Medical University Medical Center East, Arakawa-ku, 4Department of Research, Medical Research Institute, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan Background: Several studies have evaluated the efficacy and tolerability of aripiprazole for augmentation of antidepressant therapy for treatment-resistant depression (TRD). Here, we investigated the efficacy of aripiprazole augmentation for TRD including both major depressive disorder and bipolar disorder and the clinical predictors of treatment efficacy in a Japanese population. Methods: Eighty-five depressed Japanese patients who underwent aripiprazole augmentation therapy after failing to respond satisfactorily to antidepressant monotherapy were included in the study. Treatment responses were evaluated based on Clinical Global Impression Improvement scores assessed 8 weeks after initiation of aripiprazole administration. We compared demographic and diagnostic variables, psychiatric medication variables, and clinical variables between remission and nonremission groups. Results: The aripiprazole augmentation remission rate was 36.5%. Multiple logistic regression analysis indicated that aripiprazole augmentation was significantly more effective for bipolar depression than for major depressive disorder, and both absence of comorbid anxiety disorders and current episode duration >3 months were significantly associated with the efficacy of aripiprazole augmentation. Conclusion: Polarity of depression, comorbidity of anxiety disorders, and current episode duration may predict the efficacy of aripiprazole augmentation for TRD including both major depressive disorder and bipolar disorder. Among them, comorbidity of anxiety disorders was significantly related to the efficacy for TRD including only major depressive disorder. Additional studies are needed to examine the association between the efficacy of aripiprazole augmentation and bipolarity, and these findings should be validated further in a prospective study. Keywords: TRD, aripiprazole, predictor, bipolar depression, anxiety disorder&nbsp

The necessity of a neutron source for fusion materials research was identified already in the 70s. Though neutrons induced degradation present similarities on a mechanistic approach, thresholds energies for cru- cial transmutations are typically above fission neutrons spectrum. The generation of He via 56 Fe (n, α) 53 Cr in future fusion reactors with around 12 appm/dpa will lead to swelling and structural materials embrittlement. Existing neutron sources, namely fission reactors or spallation sources lead to different degradation, attempts for extrapolation are unsuccessful given the absence of experimental observations in the operational ranges of a fusion reactor. Neutrons with a broad peak at 14 MeV can be generated with Li(d,xn) reactions; the technological effort s that started with FMIT in the early 80s have finally ma- tured with the success of IFMIF/EVEDA under the Broader Approach Agreement. The status today of five technological challenges, perceived in the past as most critical, are addressed. These are: 1. the feasibil- ity of IFMIF accelerators, 2. the long term stability of lithium flow at IFMIF nominal conditions, 3. the potential instabilities in the lithium screen induced by the 2 ×5 MW impacting deuteron beam, 4. the uniformity of temperature in the specimens during irradiation, and 5. the validity of data provided with small specimens. Other ideas for fusion material testing have been considered, but they possibly are ei- ther not technologically feasible if fixed targets are considered or would require the results of a Li(d,xn) facility to be reliably designed. In addition, today we know beyond reasonable doubt that the cost of IFMIF, consistently estimated throughout decades, is marginal compared with the cost of a fusion reactor. The less ambitious DEMO reactor performance being considered correlates with a lower need of fusion neutrons flux; thus IFMIF with its two accelerators is possibly not needed since with only one acceler- ator as the European DONES or the Japanese A-FNS propose, the present needs > 10 dpa/fpy would be fulfilled. World fusion roadmaps stipulate a fusion relevant neutron source by the middle of next decade, the success of IFMIF/EVEDA phase is materializing this four decades old dream.

Last year the number of people who committed suicide in Japan was 21,681, with roughly 39% of that total made up of elderly people. In this rapidly aging country, the need to come up with a strategy for suicide prevention is of the utmost urgency. Taking notice of the fact that Town X in Japan, a small town with rare suicide incidence, has many alleys where cars aren’t allowed to pass through as well as a large number of benches, we have hypothesized that the space structures of communities can have a noticeable impact on the habitants’ behaviour and mental health. As a result of our analysis, we found a significant difference in that citizens of Town X, which has many such alleys, in comparison to towns without, have lower suicide incidence, the higher levels of self-efficacy and less opposed to help-seeking. In compact communities with complicatedly crossed alleyways, the elderly are able to move around more easily on foot, encouraging them to more naturally socialize with their neighbors and be a part of the circulation of news. This kind of space structure of communities possibly enforces the ability to detect problems early and intervene.

第8回極域科学シンポジウム/個別セッション：[OA] 南極隕石 / はやぶさ12月4日（月）国語研究所 2階講堂The Eighth Symposium on Polar Science/Ordinary sessions: [OA] Antarctic meteorites / HayabusaMon. 4 Dec./2F Auditorium, National Institute for Japanese Language and Linguistics

第8回極域科学シンポジウム/個別セッション：[OA] 南極隕石 / はやぶさ12月4日（月）国語研究所 2階講堂The Eighth Symposium on Polar Science/Ordinary sessions: [OA] Antarctic meteorites / HayabusaMon. 4 Dec./2F Auditorium, National Institute for Japanese Language and Linguistics

Masushi Kohta,1 Kazumi Sakamoto,2 Yasuhiro Kawachi,3 Tsunao Oh-i4 1Medical Engineering Laboratory, ALCARE Co, Ltd, Tokyo, 2Department of Nursing, 3Department of Dermatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, 4Department of Dermatology, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan Purpose: There have been previous clinical studies regarding the impact of dressings on the prevention of pressure ulcer development. However, it remains unclear whether one type of dressing is better than any other type for preventing ulcer development during surgery. Therefore, we compared the effects of ceramide 2-containing hydrocolloid dressing with film dressings in high-risk patients with regard to reducing the incidence of pressure ulcer development during surgery. Patients and methods: A prospective, randomized, open-label, clinical trial was conducted involving patients who were at a high risk of developing pressure ulcers at a Japanese hospital. The intervention group received ceramide 2-containing hydrocolloid dressings (n=66), and the control group received film dressings (n=64). The primary end point was the incidence rate of pressure ulcer development in both groups; skin damage, such as blanchable erythema, skin discoloration, contact dermatitis, and stripped skin, was recorded as the secondary end point. The relative risk (RR) and 95% confidence interval (CI) were assessed to compare the probability ratios of pressure ulcer development between the groups. Results: There were significantly fewer patients who developed pressure ulcers in the intervention group than in the control group (RR, 0.37; 95% CI, 0.05–0.99; P=0.04). In the post hoc subgroup analysis, the superiority of the intervention group was more marked when patients had a lower body mass index (P=0.02), lower albumin values (P=0.07), and operation time of 3 hours or more and less than 6 hours (P=0.03). There was no evidence of any statistically significant differences in the types of skin damage reported. Conclusion: Application of ceramide 2-containing hydrocolloid dressing reduced the risk of pressure ulcer development in patients who were at a high risk during surgery compared with film dressings. Keywords: operating room, wound dressing, friction, skin protection, shear

Masushi Kohta,1 Kazumi Sakamoto,2 Tsunao Oh-i31Medical Engineering Laboratory, ALCARE Co, Ltd, Sumida-ku, Tokyo, 2Department of Nursing, 3Department of Dermatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, JapanBackground: Numerous clinical challenges regarding adhesive dressings have shown that using an adhesive dressing could minimize or prevent superficial skin loss in patients at risk of developing pressure ulcers. However, evidence that polyurethane film dressings and ceramide 2-containing hydrocolloid dressing can reduce the risk of pressure ulcer development in high-risk patients undergoing surgery is limited. Therefore, we assessed the effects of application of these dressings for reducing the risk of pressure ulcer development in these patients and identified other risk factors.Methods: A matched case-control study was conducted involving 254 patients at high risk for pressure ulcer development at one acute care hospital in Japan. No patients in this study had a pressure ulcer at the start of the study. Thirty-one patients developed a pressure ulcer during surgery, and these patients were defined as cases. Controls were randomly matched for sex and age (±4 years), from which 62 patients were selected. Medical records were obtained for preoperative factors, including age, sex, body mass index, diabetes mellitus, albumin, total protein, C-reactive protein, white cell count, red cell count, and hemoglobin, and for intraoperative factors, including dressing application, operation time, body position, and surgery type. The odds ratio (OR) and 95% confidence interval (CI) were determined to identify risk factors for pressure ulcer development in patients undergoing surgery.Results: By multiple logistic regression analysis, there was a significantly reduced risk of pressure ulcer development for patients who had dressing applications as compared with those without dressing applications (OR 0.063; 95% CI 0.012–0.343; P=0.001). Prone position (OR 8.791; 95% CI 1.630–47.400; P=0.01), prolonged operation time (OR 1.684; 95% CI 1.189–2.385, P=0.003), and reduced body mass index (OR 0.774; 95% CI 0.584–0.948; P=0.02) were also significant predictive risk factors for development of a pressure ulcer.Conclusion: Application of film dressing and ceramide 2-containing hydrocolloid dressing reduced the risk of pressure ulcer development in high-risk patients undergoing surgery.Keywords: pressure ulcer prevention, operating room, wound dressing, friction

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High-resolution submillimeter line and continuum observations are important in probing the morphology, column density, and dynamics of the molecular gas and dust around obscured active galactic nuclei (AGNs). With high-resolution (0.? 06 × 0.? 05 (6 × 5 pc)) ALMA 690 GHz observations we have found bright (TB > 80 K) and compact (full width half maximum size (FWHM) size of 10 × 7 pc) CO 6-5 line emission in the nuclear region of the extremely radio-quiet galaxy NGC 1377. The CO 6-5 intensity is partially aligned with the previously discovered jet/outflow of NGC 1377 and is tracing dense (n > 104cm-3) hot molecular gas at the base of the outflow. The velocity structure is complex and shifts across the jet/outflow are discussed in terms of separate overlapping kinematical components or rotation. High-velocity gas (Δv ± 145km s-1) is detected inside r < 2-3 pc and we suggest that it is emerging from an inclined rotating disk or torus of position angle PA = 140° ± 20° with a dynamical mass of 3 × 106M⊙. This mass is consistent with that of a supermassive black hole (SMBH), as inferred from the M-σ relation. The gas mass of the proposed disk/torus constitutes

CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that has emerged as a key regulator of neurite outgrowth, vesicle trafficking and cancer cell proliferation. CDK16 is activated through binding to cyclin Y via a phosphorylation-dependent 14-3-3 interaction and has an unique consensus substrate phosphorylation motif compared to conventional CDKs. To elucidate the structure and inhibitor binding properties of this atypical CDK we screened the CDK16 kinase domain against different inhibitor libraries and determined the co-structures of identified hits. We discovered that the ATP-binding pocket of CDK16 can accommodate both type I and type II kinase inhibitors. The most potent CDK16 inhibitors revealed by cell-free and cell-based assays were the multi-targeted cancer drugs dabrafenib and rebastinib. An inactive DFG-out binding conformation was confirmed by the first crystal structures of CDK16 in separate complexes with the inhibitors indirubin E804 and rebastinib, respectively. The structures revealed considerable conformational plasticity suggesting that the isolated CDK16 kinase domain was relatively unstable in the absence of a cyclin partner. The unusual structural features and chemical scaffolds identified here hold promise for the development of more selective CDK16 inhibitors and provide opportunity to better characterise the role of CDK16 and its related CDK family members in various physiological and pathological contexts.

Tsuyoto Harada, Ken Inada, Kazuo Yamada, Kaoru Sakamoto, Jun Ishigooka Department of Psychiatry, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan Objective: Patients often develop neuropsychiatric symptoms such as anxiety and agitation after they have started taking an antidepressant, and this is thought to be associated with a potentially increased risk of suicide. However, the incidence of antidepressant-induced jitteriness/anxiety syndrome has not been fully investigated, and little has been reported on its predictors. The aim of this study was to survey the incidence of antidepressant-induced jitteriness/anxiety syndrome and clarify its predictors in a natural clinical setting.Materials and methods: Between January 2009 and July 2012, we prospectively surveyed 301 patients who had not taken any antidepressants for 1 month before presentation, and who were prescribed antidepressants for 1 month after their initial visit. Patients were classified as developing antidepressant-induced jitteriness/anxiety syndrome if they experienced any symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, or mania during the first month.Results: Among the 301 patients, 21 (7.0%) developed antidepressant-induced jitteriness/anxiety syndrome. Major depressive disorder and a diagnosis of mood disorder in first-degree relatives of patients were significantly associated with induction of antidepressant-induced jitteriness/anxiety syndrome (odds ratio 10.2, P=0.001; odds ratio 4.65, P=0.02; respectively). However, there was no such relationship for sex, age, class of antidepressant, combined use of benzodiazepines, or diagnosis of anxiety disorder.Conclusion: The findings of this study suggest that major depressive disorder and a diagnosis of mood disorder in first-degree relatives may be clinical predictors of antidepressant-induced jitteriness/anxiety syndrome.Keywords: side effects, antidepressants, selective serotonin-reuptake inhibitors, tricyclic antidepressive agents, suicide