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Muscle strength, balance, and flexibility has been associated with the development of type 2 diabetes and atherosclerosis, but little is known whether the physical score (PS) , which integrates these physical fitness indices, can predict future metabolic diseases. We investigated the longitudinal relationship between baseline and changes in PS and future prediabetes and MetS. Analyzed were 5620 men aged 30 to 69 y without MetS who underwent physical fitness tests. Principal component analysis was performed on the correlation matrix of the physical fitness test results according to age. PS was defined as the first principal component score. Associations between PS values at the start of observation (year 0) , change in the PS one year later (year 1) and the onset of prediabetes and MetS at the end of observation (years 4 or 5) were examined by Cox hazard regression analysis. The same analysis was performed for the 3812 men without prediabetes at baseline. No significant difference was found for the development of prediabetes, but a significant difference was found for development of MetS. The hazard ratio for the development of MetS was 1.30 (1.18,1.44) for every 1 decrease in the PS in year 0 and 1.35 (1.13,1.60) for every 1 decrease in the change in PS from year 0 to year 1. PS was a simple and non-invasive indicator to predict MetS. Disclosure T. Sato: None. K. Fujihara: None. M. Yamamoto: None. M. Kitazawa: None. H. Ishiguro: None. T. Osawa: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited.

This study aims to examine the impact of the association between metabolic syndrome (MetS) and metabolic dysfunction-associated fatty liver disease (MAFLD) , which both have insulin resistance and are pathophysiologically similar, on the development of new-onset cardiovascular disease, with and without type 2 diabetes mellitus (T2DM) A total of 570,426 participants without a history of cardiovascular disease who were enrolled in the nationwide claims database from 2008-2016 were included in this study. Participants were classified according to the presence or absence of MetS and/or MAFLD, and the risk of developing coronary artery disease (CAD) and/or cerebrovascular disease (CVD) in each category was analyzed using a multivariate Cox proportional hazard model. The same analysis was performed with stratification by the presence or absence of T2DM. During a median follow-up of 5.2 years, 2,252 CAD and 3,128 CVD events occurred. The hazard ratio (HR) (95% CI) for CAD, compared with the group with neither MAFLD nor MetS, was 1.46 (1.32-1.62) for MAFLD only (without MetS) , 2.02 (1.51-2.70) for MetS only (without MAFLD) , and 2.33 (2.10-2. 58) for MAFLD + MetS. For CVD, The HR was 1.41 (1.28-1.55) for MAFLD only, 1.67 (1.38-2.02) for MetS only, and 1.89 (1.72-2.08) for MAFLD + MetS. These results were similar for non-T2DM participants but different for T2DM participants, with no significant increased risk for CAD in MetS only and a significant increased risk for CVD only when both MAFLD and MetS coexisted. The predictive ability for cardiovascular disease development in patients with MetS and MAFLD differed depending on the presence or absence of T2DM. These results suggest that distinguishing between the diagnosis of MetS and MAFLD, taking into account the presence or absence of T2DM, may lead to more accurate identification of patients at high risk of developing cardiovascular disease. Disclosure K. Fujihara: None. M.H. Yamada: None. M. Yamamoto: None. H. Ishiguro: None. M. Kitazawa: None. M. Iwanaga: None. S. Kodama: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding The Japan Society for Promotion of Science (JSPS) KAKENHI Grant Number JP 20K19706)

Since advanced microangiopathy of diabetes severely impairs activities of daily living (ADL) and quality of life (QoL) and macroangiopathy is life-threatening regardless of severity, treatment of diabetes requires appropriate risk management to avoid all such complications. However, current studies have analyzed and reported diabetes complications separately, despite varying incident rates and impacts on ADL/QoL and severity of illness. It is difficult to determine which predictors should be prioritized when extrapolating the results of these studies to the comprehensive care of individual patients. We defined the combined severe diabetic complications as a new life-altering outcome and determined the association of established risk factors with combined severe diabetic complications. We analyzed data from a nationwide database involving 36,994 participants with diabetes mellitus without any prior life-altering complication of diabetes during 2008-19. Combined severe diabetic complications included severe diabetic eye disease, initiating dialysis, coronary artery disease (CAD) , cerebrovascular disease (CVD) , heart failure (HF) , or amputation which were determined according to ICD-codes, medication and medical procedures. During a median follow-up period of 5.0 years, the following events occurred: severe diabetic eye disease, 774; dialysis initiated, 134: CAD, 703; CVD, 535; HF, 161; and amputations, 31. Multivariate Cox regression model showed the HRs per 1SD for combined severe diabetic complications of HbA1c, SBP, current smoking, HDL-C, BMI and LDL- C were 1.54 (1.49-1.59) , 1.37 (1.31-1.42) , 1.35 (1.23-1.48) , 0.83 (0.79-0.88) , 0.85 (0.81-0.90) and 1. (1.06-1.16) , respectively. We found that HbA1c was the most strongly associated with combined severe diabetic complications among established risk factors. Also, our results implied the necessity of revisiting the value of BMI in risk management for combined severe diabetic complications. Disclosure Y.Yaguchi: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. K.Fujihara: None. M.H.Yamada: None. Y.Matsubayashi: None. T.Yamada: None. M.Iwanaga: None. M.Kitazawa: None. M.Yamamoto: None. S.Kodama: None.

The association between screen time (ST) , including that for smartphones, and overweight/obesity (OW/OB) in children was examined separately for boys and girls, considering the influence of lifestyle factors including diet, physical activity, and sleep time. A cross-sectional study was conducted in 2242 Japanese children (1278 girls) aged 10-14 years. OW/OB was defined by the International Obesity Task Force. Logistic regression analysis showed that only for girls, total ST (≥4h) , smartphone ST (≥3h) and non-smartphone ST (≥2h) were all independently and significantly associated with overweight/obesity compared to In Japanese girls, smartphone ST, non-smartphone ST, and total ST were all significantly associated with OW/OB. To avoid OW/OB, it is suggested to keep smartphone ST, non-smartphone ST, and total ST to Disclosure K. Fujihara: None. S.Y. Morikawa: None. H. Ishiguro: None. M.H. Yamada: None. C. Horikawa: None. Y. Ogawa: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited.

Although a linear relationship between SBP and risk of coronary artery disease or cerebrovascular disease was observed regardless of GTS, this association in HF is little known. We analyzed data from a nationwide claims database from 20to 20on 589,621 individuals. A Cox proportional hazards model identified risks of HF among 5 levels of SBP according to GTS [i.e. normal glucose tolerance (NGT) , prediabetes, diabetes (DM) ]. Incidence of HF per 1,000 person-years was 0.for NGT, 0.18 for prediabetes, and 0.80 for DM. Compared with SBP Disclosure K.Fujihara: None. M.H.Yamada: None. M.Yamamoto: None. M.Oe: None. T.Osawa: None. M.Iwanaga: None. T.Yamada: None. S.Kodama: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding JSPS (21K11569)

In adults, short sleep duration and late bedtime were associated with hyperglycemia and obesity, but these relationships in children are little known. We evaluated the association of bedtime and sleep duration with overweight/obesity or hyperglycemia in children by sex, considering the effects of diet, physical activity, and screen time. A cross-sectional study was conducted for 1139 Japanese children (553 boys) aged 10-y. Overweight was as defined by the International Obesity Task Force. Cutoff value for hyperglycemia was HbA1c ≥5.6%. Variables associated with hyperglycemia or overweight were based on logistic regression analysis. Multivariate logistic regression analysis showed that compared with an early bedtime (˜21:59) and long sleep duration (weekdays ≥8.67 h, weekends ≥9 h) , short sleep duration (weekdays Disclosure H. Shiozaki: None. K. Fujihara: None. M.H. Yamada: None. T. Osawa: None. M. Kitazawa: None. M. Yamamoto: None. T. Sato: None. T. Yamada: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Patient Centered Outcomes Research Institute

Insulin and its secretagogues are essential for some patients with type 2 diabetes (T2D) to maintain glycemic control (GC) . However, these drugs are inevitably accompanied by hypoglycemia. Avoiding severe hypoglycemia (SH) is essential considering its poor prognosis. This network meta-analysis aimed to find optimal hypoglycemic treatment regimens for T2D in terms of GC and SH. MEDLINE and EMBASE were used to identify trials comparing 2 or more treatments including insulins and/or SU/glinide and included both GC and SH in study outcomes. Treatment hierarchy was summarized as the surface under cumulative ranking probabilities (SUCRA) . There were 137 eligible trials from which 36 treatments were identified. Insulin plus (+) non-insulin drugs except for SU/glinide (others) had a higher SUCRA for changes in hemoglobin A1c (A1C) compared with only insulins (68.2±5.6% vs. 39.9±6.6%; P=0.01) although the difference in the SUCRA for SH was not significant (P=0.59) . Compared with only insulins, SU/glinide + others had a lower SUCRA for SH (42.4±5.8% vs. 58.5±3.4%, P=0.05) and comparable SUCRA for A1C change (P=1.00) . Cluster analysis indicated that premixed insulin + glucagon-like peptide-1 receptor agonist (Mix-ins+GLP1) consistently belonged to the high-efficacy group for A1C change and achievement of A1C Disclosure S.Kodama: None. K.Kato: None. K.Watanabe: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. T.Sato: None. M.H.Yamada: None. M.Yamamoto: None. Y.Matsubayashi: None. H.Ishiguro: None. M.Iwanaga: None. K.Fujihara: None. T.Yamada: None.

Breslow’s Health Practice Index (HPI) includes recommendations for a healthy lifestyle and is composed of 7 simple lifestyle factors (sleep, breakfast, snacks, body mass index (BMI) , physical activity, drinking alcohol, and smoking status) . Cardiovascular health metrics (CVHMs) defined according to the American Heart Association are composed of lifestyle factors and clinical laboratory values (smoking status, BMI, physical activity, diet, systolic blood pressure In summary, not only to follow a healthy lifestyle but to achieve laboratory treatment targets may be essential in people with diabetes. Disclosure T.Iijima: None. T.Yamada: None. S.Kodama: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. K.Fujihara: None. M.H.Yamada: None. M.Yamamoto: None. T.Osawa: None. Y.Matsubayashi: None. T.Sato: None. Y.Yaguchi: None. M.Iwanaga: None.

Cell-penetrating peptides (CPPs) are short peptides with the ability to translocate through the cell membrane to facilitate their cellular uptake. CPPs can be used as drug-delivery systems for molecules that are difficult to uptake. Ocular drug delivery is challenging due to the structural and physiological complexity of the eye. CPPs may be tailored to overcome this challenge, facilitating cellular uptake and delivery to the targeted area. Retinal diseases occur at the posterior pole of the eye; thus, intravitreal injections are needed to deliver drugs at an effective concentration in situ. However, frequent injections have risks of causing vision-threatening complications. Recent investigations have focused on developing long-acting drugs and drug delivery systems to reduce the frequency of injections. In fact, conjugation with CPP could deliver FDA-approved drugs to the back of the eye, as seen by topical application in animal models. This review summarizes recent advances in CPPs, protein/peptide-based drugs for eye diseases, and the use of CPPs for drug delivery based on systematic searches in PubMed and clinical trials. We highlight targeted therapies and explore the potential of CPPs and peptide-based drugs for eye diseases.

Aim To compare the long‐term efficacy of sodium‐glucose co‐transporter‐2 inhibitors and dipeptidyl peptidase‐4 inhibitors as second‐line drugs after metformin for patients not at high risk of atherosclerotic cardiovascular disease (ASCVD). Materials and methods In a 52‐week randomized open‐label trial, we compared ipragliflozin and sitagliptin in Japanese patients diagnosed with type 2 diabetes, without prior ASCVD and treated with metformin. The primary endpoint was a glycated haemoglobin (HbA1c) reduction of ≥0.5% (5.5 mmol/mol) without weight gain at 52 weeks. Results Of a total of 111 patients (mean age 59.2 years, mean body mass index [BMI] 26.6 kg/m2, 61.3% men), 54 patients received ipragliflozin and 57 received sitagliptin. After 52 weeks, achievement of the primary endpoint was not significantly different (37.0% and 40.3%; P = 0.72). HbA1c reduction rate at 24 weeks was greater for sitagliptin (56.1%) than for ipragliflozin (31.5%; P = 0.01). From 24 to 52 weeks, the HbA1c reduction with sitagliptin was attenuated, with no significant difference in HbA1c reduction after 52 weeks between sitagliptin (54.4%) and ipragliflozin (38.9%; P = 0.10). Improvements in BMI, C‐peptide and high‐density lipoprotein cholesterol were greater with ipragliflozin than with sitagliptin. Adverse events occurred in 17 patients with ipragliflozin and in 10 patients with sitagliptin (P = 0.11). Conclusion The HbA1c‐lowering effect at 24 weeks was greater with sitagliptin than with ipragliflozin, but with no difference in efficacy related to HbA1c and body weight at 52 weeks. However, some ASCVD risk factors improved with ipragliflozin.

Early division of the dorsal pancreatic artery (DPA) or its branches to the uncinate process during pancreaticoduodenectomy (PD) in addition to early division of the gastroduodenal artery and inferior pancreaticoduodenal artery should be performed to reduce blood loss by completely avoiding venous congestion. However, the significance of early division of DPA or its branches to the uncinate process has not been reported. The aim of this study was to investigate the anatomy of DPA and its branches to the uncinate process using the currently available high-resolution dynamic computed tomography (CT) as the first step to investigate the significance of DPA in the artery-first approach during PD. Preoperative dynamic thin-slice CT data of 160 consecutive patients who underwent hepato–pancreato–biliary surgery were examined focusing on the anatomy of DPA and its branches to the uncinate process. DPA was recognized in 103 patients (64%); it originated from the celiac axis or its branches in 70 patients and from the superior mesenteric artery or its branches in 34 patients. The branches to the uncinate process were visualized in 82 patients (80% of those with DPA), with diameters of 0.5–1.5 mm in approximately 80% of the 82 patients irrespective of DPA origin. DPA branches to the uncinate process were recognized using high-resolution CT in approximately half of the patients.

Funding Acknowledgements Type of funding sources: None. Background In patients with sludge or severe spontaneous echo contrast (SEC) in the left atrial appendage (LAA), isoproterenol loading transesophageal echocardiography (ISP-TEE) has been reported to check the presence of thrombus in the LAA, as the sludge or severe SEC disappears (Figure 1). Purpose The aim of this study was to assess the safety of ISP-TEE for the identification of LAA thrombus and the hemodynamic changes in the LAA caused by ISP loading. Methods We prospectively enrolled 25 patients with atrial fibrillation (AF) and sludge or SEC in the LAA who underwent ISP-TEE from April 2020 to July 2021. ISP was administered intravenously to achieve the target heart rate (HR) defined as follows: Max HR [beats per minutes: bpm] = 220 – age (years), Target HR [bpm] = Max HR × 0.8. Patients with tachycardia exceeding Max HR before ISP administration, hemodynamic instability, and other contraindications to ISP were excluded from the study. To assess the safety of ISP-TEE, we evaluated patients’ condition, changes in systolic blood pressure (sBP) and HR before and after ISP loading. We also assessed the presence or absence of worsening heart failure, new arrhythmias other than atrial fibrillation, and cerebral infarction or transient ischemic attack during the examination, and after 24 hours. Hemodynamic evaluation was performed using LAA blood flow velocity, LAA tissue Doppler imaging (TDI) velocity, and LAA volume fraction (LAAVF) defined as follows: LAAVF (%) = (Max LAA volume – Min LAA volume) / Max LAA volume × 100. Quantification of LAA volume was performed using the stacked-contour method of a 3-dimensional TEE full-volume acquisition. Results Among 25 patients, 13 patients had sludge or grade3 SEC, 7 patients had grade2 SEC, 5 patients had grade1 SEC. HR after ISP loading was significantly higher than before loading, but sBP did not change significantly before and after ISP loading. No complications due to ISP loading were observed during examination and after 24 hours. After ISP loading, there were 18 patients with grade 1 SEC or no SEC (classified as Group1), 7 patients had residual sludge or grade 2 to 3 SEC (classified as Group2). The differences in LAA blood flow velocity between before and after ISP loading was faster in Group1 than in Group2: 13.0 ± 10.5 vs 2.6 ± 4.2. p = 0.019. The differences in TDI velocity was also faster in Group1 than in Group2: 1.46 ± 1.14 vs 0.19 ± 0.50, p = 0.010. The differences in LAAVF was higher in Group1 than in Group2: 13.7 ± 10.3 vs 2.2 ± 2.0, p = 0.009. Conclusions In our study, no complications were observed in ISP-TEE for the identification of LAA thrombus. Patients with grade 1 SEC or no SEC, the LAA function was increased by ISP loading. These results may provide insights into the mechanisms of ISP loading on SEC in the LAA. Abstract Figure.

Nature 606(7915), 678 - 682 (2022). doi:10.1038/s41586-022-04827-6, Published by Nature Publ. Group, London [u.a.]

The study of moral judgements often centres on moral dilemmas in which options consistent with deontological perspectives (that is, emphasizing rules, individual rights and duties) are in conflict with options consistent with utilitarian judgements (that is, following the greater good based on consequences). Greene et al. (2009) showed that psychological and situational factors (for example, the intent of the agent or the presence of physical contact between the agent and the victim) can play an important role in moral dilemma judgements (for example, the trolley problem). Our knowledge is limited concerning both the universality of these effects outside the United States and the impact of culture on the situational and psychological factors affecting moral judgements. Thus, we empirically tested the universality of the effects of intent and personal force on moral dilemma judgements by replicating the experiments of Greene et al. in 45 countries from all inhabited continents. We found that personal force and its interaction with intention exert influence on moral judgements in the US and Western cultural clusters, replicating and expanding the original findings. Moreover, the personal force effect was present in all cultural clusters, suggesting it is culturally universal. The evidence for the cultural universality of the interaction effect was inconclusive in the Eastern and Southern cultural clusters (depending on exclusion criteria). We found no strong association between collectivism/individualism and moral dilemma judgements. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Calpains are calcium-regulated cysteine proteases that have been implicated in the regulation of cell death pathways. Here, we used our calpain-1 null mouse model to evaluate the function of calpain-1 in neural degeneration following a rodent model of traumatic brain injury. In vivo, calpain-1 null mice show significantly less neural degeneration and apoptosis and a smaller contusion 3 days post-injury than wild type littermates. Protection from traumatic brain injury corroborated with the resistance of calpain-1 neurons to apoptosis induced by oxidative stress. Biochemical analysis revealed that caspase-3 activation, extracellular calcium entry, mitochondrial membrane permeability, and release of apoptosis-inducing factor from mitochondria are partially blocked in the calpain-1 null neurons. These findings suggest that the calpain-1 knock-out mice may serve as a useful model system for neuronal protection and apoptosis in traumatic brain injury and other neurodegenerative disorders in which oxidative stress plays a role.

The cancer cells secrete VEGF, which induces vascular leakage and metastasis. Inhibition of VEGFR2 trafficking to the cell surface prevents receiving VEGF, vascular leakage, and cancer metastasis., VEGF-A induces vascular leakage and angiogenesis via activating the cell surface localized receptor VEGF receptor 2 (VEGFR2). The amount of available VEGFR2 at the cell surface is however tightly regulated by trafficking of VEGFR2 by kinesin family 13 B (KIF13B), a plus-end kinesin motor, to the plasma membrane of endothelial cells (ECs). Competitive inhibition of interaction between VEGFR2 and KIF13B by a peptide kinesin-derived angiogenesis inhibitor (KAI) prevented pathological angiogenesis in models of cancer and eye disease associated with defective angiogenesis. Here, we show the protective effects of KAI in VEGF-A-induced vascular leakage and cancer metastasis. Using an EC-specific KIF13B knockout (Kif13biECKO) mouse model, we demonstrated the function of EC expressed KIF13B in mediating VEGF-A-induced vascular leakage, angiogenesis, tumor growth, and cancer metastasis. Thus, KIF13B-mediated trafficking of VEGFR2 to the endothelial surface has an essential role in pathological angiogenesis induced by VEGF-A, and is therefore a potential therapeutic target.

Phosphatidylinositol 3,4,5-triphosphate (PIP3) plays a key role in neuronal polarization and axon formation. PIP3-containing vesicles are transported to axon tips by the kinesin KIF13B via an adaptor protein, centaurin α1 (CENTA1). KIF13B interacts with CENTA1 through its forkhead-associated (FHA) domain. We solved the crystal structures of CENTA1 in ligand-free, KIF13B-FHA domain-bound, and PIP3 head group (IP4)-bound conformations, and the CENTA1/KIF13B-FHA/IP4 ternary complex. The first pleckstrin homology (PH) domain of CENTA1 specifically binds to PIP3, while the second binds to both PIP3 and phosphatidylinositol 3,4-biphosphate (PI(3,4)P 2 ). The FHA domain of KIF13B interacts with the PH1 domain of one CENTA1 molecule and the ArfGAP domain of a second CENTA1 molecule in a threonine phosphorylation-independent fashion. We propose that full-length KIF13B and CENTA1 form heterotetramers that can bind four phosphoinositide molecules in the vesicle and transport it along the microtubule.

Purpose Vascular endothelial growth factor (VEGF) and its receptor VEGFR2 are promising therapeutic targets for wet age-related macular degeneration (AMD). As a topically applicable option, we developed the peptide KAI to selectively interfere with VEGFR2 trafficking to the cell surface where it receives VEGF. This study sought to determine the efficacy of KAI in the mouse model of choroidal neovascularization (CNV). Methods The specificity of KAI was tested by surface plasmon resonance. The drug delivery was analyzed by cryosection and the ELISA after treatment of KAI eyedrop to the mouse eyes. For the laser-induced CNV model, mice with laser-induced ruptures in Bruch's membrane received daily treatment of KAI eyedrop or control peptide. The other groups of mice received intravitreal injection of anti-VEGF or IgG control. After two weeks, CNV was quantified and compared. Results First, we showed the specificity and high affinity of KAI to VEGFR2. Next, biodistribution revealed successful delivery of KAI eyedrop to the back of the mouse eyes. KAI significantly reduced the disease progression in laser-induced CNV. The comparison with current therapy suggests that KAI eyedrop is as effective as current therapy to prevent CNV in wet AMD. Moreover, the genetic deletion of a kinesin KIF13B, which mediates VEGFR2 trafficking to the cell surface, confirmed the pivotal role of KIF13B in disease progression of wet AMD and neovascularization from choroidal vessels. Conclusions Taken together, pharmacologic inhibition and genetic deletion complementarily suggest the therapeutic possibility of targeting VEGFR2 trafficking to inhibit pathological angiogenesis in wet AMD.

We present recent highlights from the most recent operation phases of Wendelstein 7-X, the most advanced stellarator in the world. Stable detachment with good particle exhaust, low impurity content, and energy confinement times exceeding 100 ms, have been maintained for tens of seconds. Pellet fueling allows for plasma phases with reduced ion-temperature-gradient turbulence, and during such phases, the overall confinement is so good (energy confinement times often exceeding 200 ms) that the attained density and temperature profiles would not have been possible in less optimized devices, since they would have had neoclassical transport losses exceeding the heating applied in W7-X. This provides proof that the reduction of neoclassical transport through magnetic field optimization is successful. W7-X plasmas generally show good impurity screening and high plasma purity, but there is evidence of longer impurity confinement times during turbulence-suppressed phases. This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014-2018 and 2019-2020 under Grant Agreement No. 633053. Peer Reviewed Article signat per 497 autors/es: Thomas Sunn Pedersen1,2,∗ , I. Abramovic3, P. Agostinetti4, M. Agredano Torres1, S. Äkäslompolo1, J. Alcuson Belloso1, P. Aleynikov1, K. Aleynikova1, M. Alhashimi1, A. Ali1, N. Allen5, A. Alonso6, G. Anda7, T. Andreeva1, C. Angioni8, A. Arkhipov8, A. Arnold1, W. Asad8, E. Ascasibar6, M.-H. Aumeunier9, K. Avramidis10, E. Aymerich11, S.-G. Baek3, J. Bähner1, A. Baillod12, M. Balden1, M. Balden8, J. Baldzuhn1, S. Ballinger3, M. Banduch1, S. Bannmann1, A. Banon Navarro8, A. Bañon Navarro ´ 1, T. Barbui13, C. Beidler1, C. Belafdil9, A. Bencze7, A. Benndorf1, M. Beurskens1, C. Biedermann1, O. Biletskyi14, B. Blackwell15, M. Blatzheim1, T. Bluhm1, D. Böckenhoff1, G. Bongiovi16, M. Borchardt1, D. Borodin17, J. Boscary8, H. Bosch1,18, T. Bosmann19, B. Böswirth8, L. Böttger1, A. Bottino8, S. Bozhenkov1, R. Brakel1, C. Brandt1, T. Bräuer1, H. Braune1, S. Brezinsek17, K. Brunner1, S. Buller1, R. Burhenn1, R. Bussiahn1, B. Buttenschön1, A. Buzás7, V. Bykov1, I. Calvo6, K. Camacho Mata1, I. Caminal20, B. Cannas11, A. Cappa6, A. Carls1, F. Carovani1, M. Carr21, D. Carralero6, B. Carvalho22, J. Casas20, D. Castano-Bardawil17, F. Castejon6, N. Chaudhary1, I. Chelis23, A. Chomiczewska24, J.W. Coenen13,17, M. Cole1, F. Cordella25, Y. Corre9, K. Crombe26, G. Cseh7, B. Csillag7, H. Damm1, C. Day10, M. de Baar27, E. De la Cal6, S. Degenkolbe1, A. Demby13, S. Denk3, C. Dhard1, A. Di Siena8,28, A. Dinklage12, T. Dittmar17, M. Dreval14, M. Drevlak1, P. Drewelow1, P. Drews17, D. Dunai7, E. Edlund3, F. Effenberg29, G. Ehrke1, M. Endler1, D.A. Ennis5, F.J. Escoto6, T. Estrada6, E. Fable8, N. Fahrenkamp1, A. Fanni11, J. Faustin1, J. Fellinger1, Y. Feng1, W. Figacz4, E. Flom13, O. Ford1, T. Fornal24, H. Frerichs13, S. Freundt1, G. Fuchert1, M. Fukuyama30, F. Füllenbach1, G. Gantenbein10, Y. Gao1, K. Garcia13, J.M. García Regaña6, I. García-Cortés6, J. Gaspar31, D.A. Gates29, J. Geiger1, B. Geiger13, L. Giudicotti32, A. González6, A. Goriaev26,33, D. Gradic1, M. Grahl1, J.P. Graves12, J. Green13, E. Grelier9, H. Greuner8, S. Groß1, H. Grote1, M. Groth34, M. Gruca24, O. Grulke1,35, M. Grün1, J. Guerrero Arnaiz1, S. Günter8, V. Haak1, M. Haas1, P. Hacker1, A. Hakola36, A. Hallenbert1, K. Hammond29, X. Han17,37, S.K. Hansen3, J.H. Harris38, H. Hartfuß1, D. Hartmann1, D. Hathiramani1, R. Hatzky8, J. Hawke39, S. Hegedus7, B. Hein8, B. Heinemann8, P. Helander12, S. Henneberg1, U. Hergenhahn8,40, C. Hidalgo6, F. Hindenlang8, M. Hirsch1, U. Höfel1, K.P. Hollfeld17, A. Holtz1, D. Hopf8, D. Höschen17, M. Houry9, J. Howard19, X. Huang41, M. Hubeny17, S. Hudson29, K. Ida9, Y. Igitkhanov10, V. Igochine8, S. Illy10, C. Ionita-Schrittwieser42, M. Isobe39, M. Jabłczynska ´ 24, S. Jablonski24, B. Jagielski1, M. Jakubowski1, A. Jansen van Vuuren1, J. Jelonnek10, F. Jenko8, F. Jenko8, T. Jensen35, H. Jenzsch1, P. Junghanns8, J. Kaczmarczyk24, J. Kallmeyer1, U. Kamionka1, M. Kandler8, S. Kasilov43, Y. Kazakov26, D. Kennedy1, A. Kharwandikar1, M. Khokhlov1, C. Kiefer8, C. Killer1, A. Kirschner17, R. Kleiber1, T. Klinger12, S. Klose1, J. Knauer1, A. Knieps17, F. Köchl44, G. Kocsis7, Ya.I. Kolesnichenko45, A. Könies1, R. König1, J. Kontula34, P. Kornejew1, J. Koschinsky, M.M. Kozulia14, A. Krämer-Flecken17, R. Krampitz1, M. Krause1, N. Krawczyk24, T. Kremeyer1, L. Krier10, D.M. Kriete5, M. Krychowiak1, I. Ksiazek46, M. Kubkowska24, M. Kuczynski1, G. Kühner1, A. Kumar15, T. Kurki-Suonio34, S. Kwak1, M. Landreman47, P.T. Lang8, A. Langenberg1, H.P. Laqua12, H. Laqua1, R. Laube1, S. Lazerson1, M. Lewerentz1, C. Li17, Y. Liang17, Ch. Linsmeier17, J. Lion1, A. Litnovsky17,48, S. Liu37, J. Lobsien1, J. Loizu12, J. Lore38, A. Lorenz1, U. Losada6, F. Louche26, R. Lunsford29, V. Lutsenko45, M. Machielsen12, F. Mackel8, J. Maisano-Brown3, O. Maj8, D. Makowski49, G. Manduchi50, E. Maragkoudakis6, O. Marchuk17, S. Marsen1, E. Martines4, J. Martinez-Fernandez6, M. Marushchenko1, S. Masuzaki41, D. Maurer5, M. Mayer8, K.J. McCarthy6, O. Mccormack4, P. McNeely1, H. Meister8, B. Mendelevitch8, S. Mendes1, A. Merlo1, A. Messian26, A. Mielczarek49, O. Mishchenko1, B. Missal1, R. Mitteau9, V.E. Moiseenko14, A. Mollen1, V. Moncada9, T. Mönnich1, T. Morisaki41, D. Moseev1, G. Motojima41, S. Mulas6, M. Mulsow1, M. Nagel1, D. Naujoks1, V. Naulin35, T. Neelis19, H. Neilson29, R. Neu8, O. Neubauer17, U. Neuner1, D. Nicolai17, S.K. Nielsen35, H. Niemann1, T. Nishiza1, T. Nishizawa1, T. Nishizawa8, C. Nührenberg1, R. Ochoukov8, J. Oelmann17, G. Offermanns17 K. Ogawa41, S. Okamura41, J. Ölmanns17, J. Ongena26, J. Oosterbeek1, M. Otte1, N. Pablant29, N. Panadero Alvarez6, N. Panadero Alvarez6, A. Pandey1, E. Pasch1, R. Pavlichenko14, A. Pavone1, E. Pawelec46, G. Pechstein1, G. Pelka24, V. Perseo1, B. Peterson41, D. Pilopp1, S. Pingel1, F. Pisano11, B. Plöckl8, G. Plunk1, P. Pölöskei1, B. Pompe2, A. Popov51, M. Porkolab3, J. Proll19, M.J. Pueschel19,27, M.-E. Puiatti52, A. Puig Sitjes1, F. Purps1, K. Rahbarnia1, M. Rasinski ´ 17, J. Rasmussen35, A. Reiman29, F. Reimold1, M. Reisner8, D. Reiter17, M. Richou9, R. Riedl8, J. Riemann1, K. Riße1, G. Roberg-Clark1, V. Rohde8, J. Romazanov17, D. Rondeshagen1, P. Rong1, L. Rudischhauser1, T. Rummel1, K. Rummel1, A. Runov1, N. Rust1, L. Ryc24, P. Salembier20, M. Salewski35, E. Sanchez6, S. Satake41, G. Satheeswaran17, J. Schacht1, E. Scharff1, F. Schauer8, J. Schilling1, G. Schlisio1, K. Schmid8, J. Schmitt5, O. Schmitz13, W. Schneider1, M. Schneider1, P. Schneider8, R. Schrittwieser42, T. Schröder1, M. Schröder1, R. Schroeder1, B. Schweer26, D. Schwörer1, E. Scott1, E. Scott8, B. Shanahan1, G. Sias11, P. Sichta29, M. Singer1, P. Sinha29, S. Sipliä34, C. Slaby1, M. Sleczka53, H. Smith1, J. Smoniewski54, E. Sonnendrücker8, M. Spolaore4, A. Spring1, R. Stadler8, D. Stanczak24, T. Stange1, I. Stepanov26, L. Stephey13, J. Stober8, U. Stroth8,55, E. Strumberger8, C. Suzuki41, Y. Suzuki41, J. Svensson1, T. Szabolics7, T. Szepesi7, M. Szücs7, F.L. Tabares6, N. Tamura41, A. Tancetti35, C. Tantos10, J. Terry3, H. Thienpondt6, H. Thomsen1, M. Thumm10, J.M. Travere9, P. Traverso5, J. Tretter8, E. Trier8, H. Trimino Mora1, T. Tsujimura41, Y. Turkin1, A. Tykhyi45, B. Unterberg17, P. van Eeten1, B.Ph. van Milligen6, M. van Schoor26, L. Vano1, S. Varoutis10, M. Vecsei7, L. Vela56, J.L. Velasco6, M. Vervier17, N. Vianello50, H. Viebke1, R. Vilbrandt1, G. Vogel8, N. Vogt1, C. Volkhausen1, A. von Stechow1, F. Wagner1, E. Wang17, H. Wang57, F. Warmer1, T. Wauters26, L. Wegener1, T. Wegner1, G. Weir1, U. Wenzel1, A. White3, F. Wilde1, F. Wilms1, T. Windisch1, M. Winkler1, A. Winter1, V. Winters1, R. Wolf118, A.M. Wright29, G.A. Wurden39, P. Xanthopoulos1, S. Xu17, H. Yamada58, H. Yamaguchi41, M. Yokoyama41, M. Yoshinuma41, Q. Yu8, M. Zamanov14, M. Zanini1, M. Zarnstorff29, D. Zhang1, S. Zhou17, J. Zhu1, C. Zhu29, M. Zilker8, A. Zocco1, H. Zohm8, S. Zoletnik7 and L. Zsuga7 // 1 Max Planck Institute for Plasma Physics, Garching and Greifswald, Germany: 2 University of Greifswald, Greifswald, Germany; 3 Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA 02139, United States of America; 4 Consorzio RFX, Corso Stati Uniti, 4-35127 Padova, Italy; 5 Auburn University, Auburn, AL 36849, United States of America; 6 CIEMAT, Avenida Complutense, 40, 28040 Madrid, Spain; 7 Center for Energy Research, Konkoly-Thegeut 29-33, 1121 Budapest, Hungary; 8 Max-Planck-Institute for Plasma Physics, Boltzmannstraße 2, 85748 Garching bei München, Germany; 9 CEA Cadarache, 13115 Saint-Paul-lez-Durance, France; 10 Karlsruhe Institute of Technology, Kaiserstr. 12, 76131 Karlsruhe, Germany; 11 University of Cagliari, Via Universita, 40, 09124 Cagliari, Italy; 12 École Polytechnique Fédérale de Lausanne, Swiss Plasma Center, CH-1015 Lausanne, Switzerland; 13 University of Wisconsin–Madison, Engineering Drive, Madison, WI 53706, United States of America; 14 Institute of Plasma Physics, National Science Center ‘Kharkiv Institute of Physics and Technology’, Kharkiv, Ukraine; 15 The Australian National University, Acton ACT 2601, Canberra, Australia; 16 Department of Engineering, University of Palermo, Viale delle Scienze, Edificio 6, Palermo, 90128, Italy; 17 Forschungszentrum Jülich GmbH, Institut für Energie-und Klimaforschung—Plasmaphysik, 52425 Jülich, Germany; 18 Technical University of Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany; 19 Eindhoven University of Technology, 5600 MB Eindhoven, Netherlands; 20 Universitat Politècnica de Catalunya. BarcelonaTech, C. Jordi Girona, 31, 08034 Barcelona, Spain; 21 Culham Center for Fusion Energy, Abingdon OX14 3EB, United Kingdom; 22 Instituto de Plasmas e Fusao Nuclear, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; 23 Department of Physics, National and Kapodistrian University of Athens, 15784 Athens, Greece; 24 Institute of Plasma Physics and Laser Microfusion, 23 Hery Str., 01-497 Warsaw, Poland; 25 ENEA—Centro Ricerche Frascati, Via Enrico Fermi, 45, 00044 Frascati RM, Italy; 26 Laboratory for Plasma Physics, LPP-ERM/KMS, TEC Partner, B-1000 Brussels, Belgium; 27 Dutch Institute for Fundamental Energy Research, PO Box 6336, 5600 HH Eindhoven, Netherlands; 28 University of Texas, Austin, TX, United States of America; 29 Princeton Plasma Physics Laboratory, Princeton, NJ 08543, United States of America; 30 Kyushu University, 744 Motooka Nishi-ku, Fukuoka 819-0395, Japan; 31 Aix-Marseille University, Jardin du Pharo, 58 Boulevard Charles Livon, 13007, Marseille, France; 32 Department of Physics and Astronomy, Padova University, Via Marzolo 8, 35131 Padova, Italy; 33 Department of Applied Physics, Ghent University, Sint-Pietersnieuwstraat 41 B4, 9000 Ghent, Belgium; 34 Aalto University, 02150 Espoo, Finland; 35 Department of Physics, Technical University of Denmark, Anker Engelunds Vej, 2800 Kgs Lyngby, Denmark; 36 VTT Technical Research Center of Finland Ltd., PO Box 1000, FI-02044 VTT, Finland; 37 Institute of Plasma Physics, Chinese Academy of Sciences, 230031 Hefei, Anhui, China; 38 Oak Ridge National Laboratory, 1 Bethel Valley Rd, Oak Ridge, TN 37830, United States of America; 39 Los Alamos National Laboratory, NM 87545, United States of America; 40 Fritz-Haber-Institut der Max-Planck-Gesellschaft, 14195 Berlin, Germany; 41 National Institute for Fusion Science, National Institutes of Natural Sciences, 322-6 Oroshi-cho, Toki, Gifu Prefecture 509-5292, Japan; 42 Institute for Ion Physics and Applied Physics, University of Innsbruck, Innsbruck, Austria; 43 Graz University of Technology, Rechbauerstraße 12, 8010 GRAZ, Austria; 44 Austrian Academy of Science, Doktor-Ignaz-Seipel-Platz 2, 1010 Wien, Austria; 45 Institute for Nuclear Research, prospekt Nauky 47, Kyiv 03028, Ukraine; 46 University of Opole, plac Kopernika 11a, 45-001 Opole, Poland; 47 University of Maryland, Paint Branch Drive, College Park, MA 20742, United States of America; 48 National Research Nuclear University MEPhI, 115409 Moscow, Russian Federation; 49 Department of Microelectronics and Computer Science, Lodz University of Technology, Wolczanska 221/223, 90-924 Lodz, Poland; 50 Consiglio Nazionale delle Ricerche, Piazzale Aldo Moro, 7, 00185 Roma, Italy; 51 Ioffe Physical-Technical Institute of the Russian Academy of Sciences, 26 Politekhnicheskaya, St Petersburg 194021, Russian Federation; 52 Istituto di Fisica del Plasma Piero Caldirola, Via Roberto Cozzi, 53, 20125 Milano, Italy; 53 University of Szczecin, 70-453, aleja Papieza Jana Pawła II 22A, Szczecin, Poland; 54 Lawrence University, 711 E Boldt Way, Appleton, WI 54911, United States of America; 55 Physik-Department E28, Technische Universität München, 85747 Garching, Germany; 56 Universidad Carlos III de Madrid, Av. de la Universidad, 30 Madrid, Spain; 57 Yale University, New Haven, CT 06520, United States of America; 58 University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chhiab 277-0882, Japan Objectius de Desenvolupament Sostenible::7 - Energia Assequible i No Contaminant Objectius de Desenvolupament Sostenible::7 - Energia Assequible i No Contaminant::7.a - Per a 2030, augmentar la cooperació internacional per tal de facilitar l’accés a la investigació i a les tecnolo­gies energètiques no contaminants, incloses les fonts d’energia renovables, l’eficiència energètica i les tecnologies de combustibles fòssils avançades i menys contaminants, i promoure la inversió en infraestructures energètiques i tecnologies d’energia no contaminant

In this study, Sc concentration dependence of Sc x Al1−x N/AlN/poly-crystalline diamond/Si surface acoustic wave (SAW) characteristics at high Sc from 23.8% to 44.3% was investigated by fabricating one-port SAW resonator at high frequency. 3.8 GHz one-port resonator fabricated on Sc0.43Al0.57N showed an excellent performance of electro-mechanical coupling coefficient (K 2) as high as 6.34% for 2nd mode Sezawa wave, which enables a wide bandwidth in high frequency applications. The temperature coefficient of frequency was approximately −40 to −50 ppm deg−1 for the device fabricated with Sc concentration of 42.9%. This is a smaller value compared to conventional high K2 bulk materials such as LiNbO3. As the result, a high K2 6.34% material system at a higher Sc concentration of ScAlN/AlN/PCD was found to be possible at a high phase velocity of 7000 m s−1. Combined with the extremely high-power durability of diamond based device, high-power durable wideband SAW device at high frequency can be expected.

The present study is the first report of Spiroxys larvae parasitizing stomach and intestine of three fish species in stream of Caatinga domain, Northeast, Brazil. A total of 120 fish specimens, 40 of Astyanax bimaculatus, 40 of Hoplias malabaricus, and 40 of Hoplosternum littorale were examined for nematodes. A total of 633 specimens of Spiroxys larvae were recovered for the three fish species: 227 in A. bimaculatus (prevalence (%) = 48; mean abundance = 5.78 ± 1.78 (range = 0–70); and mean intensity = 11.95 ± 2.7 (range = 2–70)), 176 in H. malabaricus (prevalence (%) = 42.5; mean abundance = 4.40 ± 1.55 (range = 0–53); and mean intensity = 10.35 ± 2.38 (range = 2–53)) and 230 in H. littorale (prevalence (%) = 42.5; mean abundance = 5.75 ± 1.98 (range = 0–52); and mean intensity = 13.53 ± 3.04 (range = 1–52)). This study expands the range of the geographic distribution of nematodes of the genus Spiroxys and increase the list of hosts, as well as contributing to the knowledge of fish parasites biodiversity in Caatinga domain.

Made available in DSpace on 2022-04-29T08:40:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 This study compared the plasma progesterone concentrations from pregnant and non-pregnant buffaloes to identify non-pregnant females and submit cows earlier to oestrous resynchronization. Forty-four multiparous mix-breed Murrah buffaloes were selected for the study. The cows were subjected to hormonal oestrous synchronization and separated into 4 groups, P12 (pregnant, n = 8) and P18 (n = 8) at 12 and 18 days post-insemination; NP12 (non-pregnant, n = 7) and NP18 (n = 7) at 23 and 29 days after the onset of synchronization, respectively. The embryos and blood were collected, and the plasma was separated for centrifugation and used to determine progesterone concentration. Progesterone concentration was higher in P18 than P12 (p =.02) and NP18 groups (p

GaN-on-Diamond high electron mobility transistors were successfully fabricated by surface-activated room-temperature bonding technique. Various diamond substrates were finely polished and bonded to GaN-HEMTs by surface-activated room-temperature bonding. Fabricated devices showed superior characteristics in thermal dissipation compared to the device with conventional structure.

Although UP is a very important feature of diabetic nephropathy, decreased eGFR without UP has become phenotypic of renal complications of DM in the new definition of DKD. Although both UP and reduced eGFR are strong predictors of kidney disease, only a few studies have examined the association between these two variables and risk of dialysis in the same cohort that included people with and without DM. We analyzed data from a nationwide claims database involving 335,778 participants (DM 20,223, non-DM 315,555) during 2008-16. Multivariate Cox regression model identified risks of starting dialysis. HRs were compared among 8 groups of combinations of DM+/-, UP (-, ≥+) and eGFR ( In summary, both eGFR Disclosure T. Osawa: None. K. Fujihara: None. M. H. Yamada: None. Y. Yaguchi: None. T. Sato: None. M. Kitazawa: None. Y. Matsubayashi: None. T. Yamada: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Funding Japan Society for the Promotion of Science (18K17897)

Although a history of both CVD and glucose abnormality are risk factors for CVD, few large studies have examined the association between prior CVD and glucose abnormality on subsequent CVD in the same cohort. Thus, we compared the impact of prior CVD, glucose abnormality status and their combinations on subsequent CVD using real-world data. Men aged 18-72 years and followed for ≥3 years between 2008 and 2016 were classified as normoglycemia (n = 210,434), borderline glycemia (n = 119,933) or diabetes (DM) (n = 33,260) defined by fasting plasma glucose, HbA1c, and antidiabetic drug prescription. Prior and subsequent CVD were identified according to claims using ICD-10 codes, medical procedures and questionnaires. Cox regression showed that CVD+ conferred a 5- to 8-fold excess risk for CVD regardless of glucose abnormality status (Table). Borderline glycemia did not influence risk of CVD in both prior CVD+ and CVD- status, whereas DM affected subsequent CVD in CVD-. In CVD-/DM, age, current smoking, SBP, HDL-C and HbA1c were associated with risk of CVD, but only SBP was related to CVD risk in CVD+/DM. Impacts of glucose tolerance and glycemic control on risk of CVD were much less than prior CVD. SBP was more strongly associated with CVD risk than glycemia in DM with prior CVD. Individualized treatment strategies should consider glucose tolerance status and prior CVD. Disclosure M. Oe: Employee; Self; Kowa Company, Ltd. T. Yamada: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. K. Fujihara: None. M. H. Yamada: None. T. Osawa: None. M. Kitazawa: None. Y. Matsubayashi: None. T. Sato: None. Y. Yaguchi: None. M. Iwanaga: None.

We investigated the impact of medication adherence for a one-year period and subsequent glycemic control and their combinations on the risk of micro/macrovascular diseases among Japanese using nationwide claims data. Analyzed were 19,565 patients with diabetes whose medication records for oral hypoglycemic agents (OHAs) were available for at least 1 year without prior treatment-requiring diabetic eye disease (TRDED), initiation of dialysis (dialysis), coronary artery disease (CAD), or cerebrovascular disease (CVD), respectively (mean age 53y, HbA1c 7.2%). Medication adherence was evaluated by the proportion of days covered (PDC), and PDC Disclosure Y. Yaguchi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. K. Fujihara: None. M. H. Yamada: None. Y. Matsubayashi: None. T. Yamada: None. M. Iwanaga: None. M. Kitazawa: None. M. Yamamoto: None. S. Kodama: None.

Heavy total alcohol consumption was reported to increase the risk of development and progression of diabetic retinopathy. However, differing from total alcohol consumption, whether the quantity of alcohol intake per occasion had harmful or beneficial effects related to severe eye diseases caused by diabetes remains unknown. To clarify this, we utilized ICD-10 and medical treatment codes from a nationwide claims database that finally included 21,392 men with type 2 diabetes (mean age 53 y, HbA1c 7.0%, mean follow-up period 4.3 y). During the study period, 425 patients developed vision-threatening treatment-required diabetic eye diseases (TRDED) (4.6/1000 person-years). Multivariate Cox analysis demonstrated that a large quantity of alcohol per occasion defined as ≥3 drinks per occasion was positively associated with future occurrence of TRDED. One drink was defined as a standard Japanese drink with a volume equivalent to 23 g ethanol. Hazard ratio in patients drinking large amounts of alcohol per occasion for incident TRDED was 4.49 (95% confidence interval, 1.98-10.19) compared with the reference group (≤1 drink per occasion) after adjusting for covariates including total alcohol consumption. This finding demonstrated that a large quantity of alcohol per occasion had a significant association with future vision-threatening retinopathy in men with type 2 diabetes. The mechanism of this finding with regard to severe retinopathy awaits further research. Disclosure M. Yamamoto: None. T. Yamada: None. S. Kodama: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. K. Fujihara: None. Y. Yaguchi: None. T. Osawa: None. M. Kaneko: None. M. Kitazawa: None. T. Sato: None. M. H. Yamada: None. Y. Matsubayashi: None.

An important method to improve the sensitivity of a nuclear magnetic resonance (NMR) system is to increase the quality factor ( Q ) of the pickup coils. In this paper, we focus on the following three items: 1) effect of the surface resistance ( R s) of the YBa2Cu3O7-δ (YBCO) films on the Q of the NMR pickup coil; 2) relationship between coil line width and current flowing through coil; and 3) effect of Si-ion irradiation to YBCO films on the Q of the NMR pickup coils. In the study of 1), we examined the Q of the NMR pickup coils made by YBCO films with different R s and found that reduction of R s is useful in increasing the Q of the NMR pickup coils. In the study of 2), we simulated the current flowing in the NMR coils by an electromagnetic simulator, and found that wider microstrip lines of the NMR pickup coil increase the current. In the study of 3), we examined Si-ion irradiation effect to reduce R s of YBCO films, and found low irradiation energy and low irradiation density of Si-ion is useful to decrease R s and useful to obtain the high Q NMR pickup coils.

We investigate magnetic properties of mixed crystals of spinel oxides Zn(Cr1−xFex)2O4 and Cd(Cr1−xFex)2O4 to study Cr-site substitution effects on the geometrically-frustrated magnetism of chromite spinels ZnCr2O4 and CdCr2O4. Zn(Cr1−xFex)2O4 and Cd(Cr1−xFex)2O4 with above x ∼ 0.1 exhibit spin-glass-like behavior below ∼10 K which is suppressed by magnetic field H > 1 kOe. Moreover, the Fe concentration x dependence of Weiss temperature ΘW in Zn(Cr1−xFex)2O4 (Cd(Cr1−xFex)2O4) exhibits the sign change of ΘW from negative below x ∼ 0.4 (x ∼ 0.1) to positive above x ∼ 0.4 (x ∼ 0.1). This suggests that, in Zn(Cr1−xFex)2O4 and Cd(Cr1−xFex)2O4, the competition of antiferromagnetic and ferromagnetic interactions (bond frustration) becomes stronger with increasing the Fe concentration x, while the geometrical frustration becomes weaker with increasing x.

Background: Docetaxel, trastuzumab, and pertuzumab (DTP) therapy is established first-line therapy for patients with HER2-positive metastatic breast cancer (HER2 + MBC). However, the poor tolerability of docetaxel impedes its long-term administration. The safety of eribulin, trastuzumab, and pertuzumab (ETP) therapy for HER2 + MBC has been confirmed in Japan. We examined the primary endpoint—overall response rate, the secondary endpoints—time to treatment failure, progression-free survival, and overall survival, as well as adverse events (AEs) of ETP therapy. (University Hospital Medical Information Network identifier:000021585) Methods: Eribulin 1.4 mg/m2/day iv (days 1 and 8), trastuzumab 8 mg/kg iv over 90 min (initial dose) and 6 mg/kg iv over 30 min (second and subsequent doses), and pertuzumab 840 mg/body over 60 min (initial dose) and 420 mg/body over 30 min (second and subsequent doses) were administered. Cycles consisting of 2 doses of eribulin and 1-week drug holiday were repeated. Patients were treated with trastuzumab and pertuzumab when AEs developed that did not allow medication continuation by reducing the dose of eribulin. Antitumor effect was assessed according to RECIST version 1.1. and toxicities to CTCAE Japanese version 4.0. All patients provided written informed consent before enrollment. The study protocol was approved by the Institutional or Central Ethics Committee, and the study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and local ethical and legal regulations. Results: 25 female patients (median age: 57 years [41-75]) were enrolled from April 18, 2016, through November 22, 2017. Twenty-four had performance status (PS) 0, 1 PS 1, 8 stage 4 breast cancer, and 17 metastatic breast cancer. Anthracycline, taxane, and trastuzumab were administered as neoadjuvant and adjuvant pharmacotherapies to 13, 15, and 14 patients, respectively. Primary tumor was positive for estrogen and progesterone receptors in 12 and 6 patients, respectively. Lung, liver, and bone metastases occurred in 9, 9, and 6 patients, respectively. Three (12%), 17 (68%), 1 (4%), 1 (4%), and 2 (8%) patients showed complete response (CR), partial response (PR), long-term stable disease (LSD; stable disease ≥24 weeks), stable disease (SD; stable disease Conclusions: Similar to DTP, ETP showed high response rates and good safety as first-line therapy for HER2 + MBC. Citation Format: Inoue K, Ninomiya J, Okubo K, Nakakuma T, Yamada H, Kimizuka K, Higuchi T, Saito T. Eribulin, trastuzumab, and pertuzumab as first-line therapy for patients with HER2-positive metastatic breast cancer: A multicenter, collaborative, open-label, phase II clinical trial for the SBCCSG-36 investigators [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-14.

The tetraneutron has attracted the attention of nuclear physicists during the past decades, but there is still no unambiguous confirmation of its existence or non-existence. A new experiment based on $$^{8}$$ He(p, 2p) $$^{7}$$ H{t+ $$^{4}n$$ } reaction, with direct detection of the four neutrons, has been carried out at RIBF, which can hopefully help to draw a definite conclusion on the tetraneutron system.

In the present study, ~2.0-μm microspheres of blended poly(lactide-co-glycolide) (PLGA) and poly lactide (PLA), both are biodegradable and biocompatible, were prepared either through a preparation technique for particles using a microhomogenizer or membrane emulsification technique. To understand the potential of the drug delivery system (DDS) formulation, fundamental physical properties, degradation and drug release studies on microspheres prepared using two particle preparation techniques were analysed. The PLGA/PLA particles prepared using the microhomogenizer were polydisperse or irregular-shaped, but the particles prepared using the membrane emulsification technique were very monodisperse and spherical. Increasing the PLA fraction in PLGA/PLA microspheres allowed control over the degradation of the prepared particles. Furthermore, such microspheres could also be used for the controlled drug release behaviour of particles. The particles prepared using the membrane emulsification technique exhibited better controlled drug releasing behaviour than those prepared using the microhomogenizer. From the above, this study revealed that PLGA/PLA microspheres prepared using the membrane emulsification method were advantageous for the study of DDS formulations.

BackgroundMyeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells with suppressive functions (1). It is known that MDSCs are expanded in inflammatory sites after migrating from bone marrow (BM) or spleen. Rheumatoid arthritis (RA) is an autoimmune disease characterized as polyarthritis. Although previous reports indicate that MDSCs are increased in BM and spleen of arthritis model mice, detailed analysis of MDSCs in inflammatory joints is limited.ObjectivesThe purpose of this study is to characterize the MDSCs in the joints of autoimmune arthritis.MethodsWe isolated CD11b+Gr1+ cells as MDSCs from joints (Jo-MDSCs), bone marrow (BM-MDSCs) and spleen (Sp-MDSCs) of arthritis-induced SKG mice, and investigated differential expressed genes (DEGs) among MDSCs from three tissues by microarray expression analysis. Furthermore, we analyzed the suppressive function of each MDSCs by investigating the effect of them on T cell -proliferation and the osteoclast differentiation of each MDSCs stimulated by M-CSF and RANKL.ResultsMicroarray analysis revealed that Jo-MDSCs highly expressed immunosuppressive DEGs (Pdl1, Arg1, Egr2 and Egr3) compared to BM MDSCs or Sp MDSCs. In addition, Jo-MDCSs highly expressed NF-κB non-canonical pathway DEGs (Nfkb2 and Relb), which are related to osteoclast differentiation. BM-MDSCs differentiated into osteoclasts but didn’t suppress T cell-proliferation and Sp-MDSCs suppressed T cell-proliferation but didn’t differentiate into osteoclasts. On the other hand, Jo-MDSCs was found to have both functions: T cell suppression and osteoclast differentiation potential.ConclusionJo-MDSCs have a strong inhibitory effect on T cell proliferation and have the ability osteoclast differentiation potential.References[1]Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19(2):108–19.Disclosure of InterestsNone declared.

BackgroundButyric acid is known to improve chronic inflammation such as inflammatory bowel disease and arthritis [1, 2]. Dendritic cells activate in inflammatory condition, migrate to regional lymph nodes, and activate naive T cells.ObjectivesIn this study, we investigated the effect of butyric acid on the migration ability of monocyte-derived dendritic cells (moDC).MethodsHuman CD14+ Monocytes were purified by positive selection from PBMC using CD14 magnetic beads. Cells were cultured in the presence of GM-CSF (50 ng/ml) and IL-4 (20 ng/ml) for 5 days. After culturing for 5 days, cells were matured with LPS (1ug/ml) for 24 hours. Butyric acid was administered at different dose or period. Surface antigen on moDC was analyzed by flow cytometry (BD FACS VERSE). Migration assay was performed on Boyden chamber CytoSelect 24-Well Cell Migration Assay (5um). Actin was stained with Alexa Fluor 488 Phalloidin before and after migration assay. After administration with butyric acid assigned to each period and concentration, moDC were lysed for western blot analysis for evaluating signaling. Chemiluminescent signals were detected and calculated by Amersham Imager.ResultsWe demonstrated that butyric acid decreased the CCR7 expression of moDC, which has a key role in DC homing to the lymph nodes and intestinal Peyer’s patches. We also showed that butyric acid decreased the migration ability of moDC. Furthermore, moDCs cultured with butyric acid showed a round shape and poor formation of dendrites and pseudopodia. Then we studied the effect of butyric acid on cytoskeleton, which plays an important role in migration and pseudopodia formation of DCs. Polymerized Actin (F-Actin) staining revealed that butyrate suppressed actin polymerization of moDC in a dose dependent manner. CDC42 works important role of lamellipodia and membrane protrusions. RhoA is upstream of mDia1, and mDia1 was reported to accelerate actin nucleation and elongation. We revealed that butyrate decreased the protein expression of mDia1, RhoA, and CDC42, while beta actin was not downregulated, by Western blot analysis. Our results suggested that butyric acid suppresses migration of moDCs by inhibiting mDia1-medicated actin polymerization.ConclusionButyric acid suppresses migration of moDCs by inhibiting mDia1-medicated actin polymerization.References[1]Mafalda R Couto 1, Pedro Gonçalves 2, Fernando Magro 3, Fátima Martel, et al. Microbiota-derived butyrate regulates intestinal inflammation: Focus on inflammatory bowel disease Pharmacol Res. 2020 Sep;159:104947.[2]Wenpeng Hui, Dapeng Yu, Zhong Cao, Xiwu Zhao, et al. Butyrate inhibit collagen-induced arthritis via Treg/IL-10/Th17 axis Int Immunopharmacol. 2019 Mar;68:226-233.Disclosure of InterestsNone declared

Amorphous bulk metallic glasses with the composition Fe48Cr15Mo14C15B6Y2 have been of interest due to their special mechanical and electronic properties, including corrosion resistance, high yield-strength, large elasticity, catalytic performance, and soft ferromagnetism. Here, we apply a reverse Monte Carlo technique to unravel the atomic structure of these glasses. The pair-distribution functions for various atomic pairs are computed based on the high-energy x-ray diffraction data we have taken from an amorphous sample. Monte Carlo cycles are used to move the atomic positions until the model reproduces the experimental pair-distribution function. The resulting fitted model is consistent with our ab initio simulations of the metallic glass. Our study contributes to the understanding of functional properties of Fe-based bulk metallic glasses driven by disorder effects.

SmS, a prototypical intermediate valence compound, has been studied by performing high-pressure nuclear magnetic resonance measurements on a $^{33}\mathrm{S}$-enriched sample. The observation of an additional signal below 15--20 K above a nonmagnetic-magnetic transition pressure ${P}_{\mathrm{c}2}\ensuremath{\approx}2$ GPa gives evidence of a magnetic transition. The absence of a Curie term in the Knight shift near ${P}_{\mathrm{c}2}$ indicates that the localized character of $4f$ electrons is entirely screened and the mechanism of the magnetic ordering is not described within a simple localized model. Simultaneously, the line shape in the magnetically ordered state is incompatible with a spin density wave order. These suggest that the magnetic order in SmS may require an understanding beyond the conventional framework for heavy fermions. The fact that hyperfine fields from the ordered moments cancel out at the S site leads us to a conclusion that the ordered phase has a type II antiferromagnetic structure.

Millimeter wave radar becomes very popular recently. Application of the radar is not only automotive radar but also human detection and man-machine interface, so forth. The radar often has superior resolution in range. However angular resolution improvement is often required. In this report, we propose virtual array technique by using so-called Khatri-Rao matrix product transform for the MIMO radar. Experimental results of indoor human detection is provided to show the validity of the technique.

Habitats characterized by geographic isolation such as islands have been studied using different organisms as models for understanding the dynamic and insular patterns of biodiversity. Determinants of parasite richness in insular host populations have been conducted mainly with mammals and birds, showing that parasite richness decreases in insular areas. In the present study, we predicted that the type of environment (insular or continental) can influence the richness, diversity and abundance of parasites associated with the endemic frog Haddadus binotatus (Spix, 1824). We sampled frogs in two insular and two mainland fragments to survey their helminth parasites. The total richness was composed of 15 taxa of Nematoda and two of Acanthocephala, and the community composition of the two islands had more similarities between them than the two mainland localities. The insular effect was positive for richness and abundance of helminths, and no significant effect was observed on helminth diversity - even the mean diversity presented high numbers for the islands. We presumed that insular hosts could have lost some parasites in the colonization process when these continental islands were separated from the mainland, approximately 11,000 years ago. However, the high richness and abundance on islands can be explained by an epidemiological argument, which considers high population density due to insularity and other features of the host as factors that increase parasite transmission success among individuals.

Although both hyperglycemia and HT are highly predictive of kidney disease, only a few studies have investigated the associations between the severity of HT and risk of end-stage renal disease especially the initiation of renal replacement therapy in DM+ or DM- in the same cohort at the same time. Thus, we analyzed data from a nationwide claim database involving 258,874 participants during 2008-16. Multivariate Cox regression model was used to identify risks of starting dialysis. HT as a covariate was determined according to systolic blood pressure (SBP)(mmHg) diagnosed by seven different cut-offs (≥110, ≥115, ≥120, ≥125, ≥130, ≥140, ≥150). Hazard ratios (HRs) were compared among 10 groups divided according to combinations of DM+ or DM- and five levels of SBP (mmHg) (≤119, 120-129, 130-139, 140-149, ≥150). Among DM-, baseline age, percent of men, BMI, smoking rate, SBP, and percent of medication for HT were higher in those who started dialysis. In those with DM+, baseline percent of men, SBP, and percent of medication for DM and HT were higher in those who started dialysis. HT was significantly associated with the initiation of dialysis regardless of the presence or absence of DM. The incidence of starting dialysis in those with SBP ≤119 mmHg and DM+ was almost the same as in those with SBP ≥150 mmHg and DM-. In comparison with SBP ≤119 mmHg, SBP ≥150 mmHg significantly increased the risk of the initiation of dialysis about 2.5 times regardless of DM+ or DM-. Compared with DM- and SBP ≤119mmHg, the HR for DM+ and SBP ≥150 mmHg was 6.88 (95% CI 3.66-12.9). Although the risks of HT differed only slightly regardless of the presence or absence of DM, risks for the initiation of dialysis with DM+ and SBP ≤119 mmHg were equivalent to DM- and SBP ≥150 mmHg, indicating stricter blood pressure interventions in DM+ are needed to avoid dialysis. Future studies are needed to clarify the cut-off SBP level to avoid initiation of dialysis considering the risks of strict control of blood pressure. Disclosure T. Osawa: None. K. Fujihara: None. M.H. Yamada: None. T. Sato: None. M. Kitazawa: None. Y. Yaguchi: None. Y. Matsubayashi: None. M. Iwanaga: None. N. Yamanaka: None. H. Seida: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Funding Japan Society for the Promotion of Science

DPP-4i do not increase weight and SGLT2i are expected to reduce weight; thus, are widely used in daily practice. SGLT2i are recommended as second-line drugs after metformin (Met) in those at high risk of atherosclerotic cardiovascular disease (ASCVD), but suitable second-line drugs for the majority of patients not at high risk are not yet determined. Furthermore, reports of appropriate second-line drugs in East Asians who have a lower risk of ASCVD than Europeans are scarce. We compared the effects of ipraglifrozin (Ipra) and sitagliptin (Sita) after Japanese patients with type 2 diabetes had been taking Met and were without prior ASCVD in a 52-week randomized open-label trial (jRCTs031180205). The primary endpoint (PE) was a HbA1c reduction of ≥0.5% with no weight gain at 52 weeks. Among 111 patients (mean age 59.2 y, mean BMI 26.6 kg/m2, and male 61.3%), 54 and 57 patients received Ipra and Sita, respectively. After 52 weeks, achievement of the PE was statistically the same (37.0% and 40.3%, p=0.72), as was the HbA1c reduction ≥0.5% (38.9% and 54.4%, p=0.13). Lack of weight gain was higher for Ipra than Sita (94.4% and 54.4%, p Disclosure M. Kitazawa: None. T. Katagiri: None. H. Suzuki: None. S. Matsunaga: None. M.H. Yamada: None. T. Ikarashi: None. M. Yamamoto: None. K. Furukawa: None. M. Iwanaga: None. M. Hatta: None. K. Fujihara: None. T. Yamada: None. S. Tanaka: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Funding Astellas Pharma Inc.

We examined whether the machine learning approach could be used as support for decision-making by general physicians as to whether to use insulin as an initial therapy for patients with type 2 diabetes. Prescription data on different antidiabetic agents from December 2009 to March 2015 from diabetes specialists’ patient registries were used to compare the machine learning decision of initial insulin use to that of general physicians. Gold standard was defined as consensus, that is, 80% agreement among nine diabetes specialists based on patients’ information. Twenty-two general physicians chose the most suitable medication according to the patients’ information. Analyzed were data on 4,860 patients who received initial monotherapy with either insulin (293 patients) or non-insulin (4,567 patients) and had laboratory data. Accuracy was calculated by 5-fold cross validation in machine learning. The average predictive values of initial insulin use by machine learning were 0.40, 0.50 and 0.82, respectively, for under-sampling ratios of 1:2, 1:4 and 1:8. General physicians achieved a mean accuracy for initial insulin use of 51%. The overall accuracy was 43%, 57% and 86% for under-sampling ratios of 1:2, 1:4 and 1:8. The difference in the accuracy between general physicians and machine learning in the under-sampling ratio of 1:8 was significant (P In conclusion, accuracy of machine learning with the sampling ratio of 1:8 was higher compared with that of general physicians in initial insulin use defined by diabetes specialists’ choice as the gold standard. Assistance by machine learning may be beneficial to any general physician in deciding upon initial insulin usage. Disclosure K. Fujihara: None. M.H. Yamada: None. Y. Matsubayashi: None. M. Yamamoto: None. T. Iizuka: None. K. Miyamura: None. Y. Hasegawa: None. T. Yamazaki: None. S. Kodama: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Funding Japan Society for the Promotion of Science (18K17897)