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Background The lymphatic system has been suggested to play an important role in cardiovascular diseases including heart failure (HF). Vascular endothelial growth factor C (VEGF-C) and D (VEGF-D) are key regulators of lymphangiogenesis, and we recently reported the association of low VEGF-C with the risk of all-cause death and high VEGF-D with the risk of HF hospitalization in patients with HF. Purpose To investigate the association of VEGF-C and VEGF-D with prognosis in patients with HF with preserved ejection fraction (EF) (HFpEF: EF≥50%), mildly reduced EF (HFmrEF: EF, 40–49%), and reduced EF (HFrEF: EF Methods The PREHOSP-CHF study is a multicenter prospective cohort study to determine the predictive value of angiogenesis-related biomarkers in HF. A total of 1,024 patients (mean age 75.5±12.6 years; 58.7% male) admitted to acute decompensated HF were included in the analyses. Serum levels of VEGF-C and VEGF-D, as well as N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin-I (hs-cTnI), high sensitivity C reactive protein, were measured at the time of discharge. Patients were followed-up over two years. Results The numbers of HFpEF, HFmrEF, and HFrEF were 429 (41.9%), 186 (18.2%), and 409 (39.9%), respectively. HFpEF patients were older, more likely to be female, and had more hypertension, atrial fibrillation, and anemia, but less coronary artery disease. NT-proBNP and hs-cTnI levels increased with decreasing EF. VEGF-C levels decreased with increasing EF (median [interquartile range]: HFpEF, 4508 [3318–5919] pg/ml; HFmrEF, 4719 [3663–6203] pg/ml; HFrEF, 5023 [3804–6382] pg/ml), whereas VEGF-D levels were comparable among the three EF groups (HFpEF, 404.6 [293.1–560.3] pg/ml; HFmrEF, 386.0 [298.5–556.3] pg/ml; HFrEF, 414.2 [296.1–557.3] pg/ml). In multivariate stepwise logistic regression analyses, anemia and high NT-proBNP were independently associated with low VEGF-C levels, and high NT-proBNP was independently associated with high VEGF-D levels, across all the EF groups. During the follow-up, incidences of all-cause death and HF hospitalizations were similar among the three EF groups (log-rank P=0.6 for all-cause death, and log-rank P=0.3 for HF hospitalization). On multivariate Cox proportional hazard analyses including established risk factors and cardiovascular biomarkers, VEGF-C levels tended to be inversely associated with the incidence of all-cause death in patients with HFpEF and HFrEF (Figure). On the contrary, VEGF-D levels were significantly and positively associated with the incidence of HF hospitalization in patients with HFpEF, and tended to be positively associated with it in patients with HFmrEF and HFrEF (Figure). Conclusions Low VEGF-C was associated with the risk of all-cause death in patients with HFpEF and HFrEF, while high VEGF-D was associated with the risk of HF hospitalization especially in HFpEF. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Grant-in-Aid for Clinical Research from the National Hospital Organization

Background Stroke is a significant cause of mortality and a leading cause of disability in elderly patients. Atrial fibrillation (Af) is the most common cardiac disease with assumed embolic stroke. Therefore, patients with Af need anti-coagulant therapy with a Warfarin (vitamin K antagonist) or a DOAC (Direct Oral Anti-Coagulant), also considering the risk and benefit net balance. It has been suggested that significant mitral regurgitation (MR) and its vortex jet in the left atrium might reduce embolic stroke source in patients with Af. However, the effect of MR on the risk of stroke in patients with Af is still controversial. Therefore, we hypothesized whether MR might be associated with a lower risk of thromboembolic events in patients with Af. Purpose This study aims to investigate whether MR was associated with a decreased risk of stroke in patients with Af, especially in the elderly population. Methods We studied 1,714,955 patients in the LIFE Study database, comprising Japanese claims data for public insurance policyholders between 2014 and 2020. We identified 51,939 patients with new-onset Af. Among them, patients with pre-existing stroke patients (N=28,519) were excluded, and new-onset Af patients without stroke (N=23,420) were obtained. Based on the baseline information, the Af patients were stratified into the MR group (N=3,439) and Without-MR group (N=19,981). Propensity score matching (the nearest neighbor method with a caliper of 0.2) was performed to balance baseline features and stroke risk factors between the MR group (N=3439) and the Without-MR group (N=3439). Propensity scores were estimated using logistic regression with age, sex, and all factors in Elixhauser's comorbidity system. The incidence rate of the stroke (events per person-year) was calculated by the event numbers divided by the overall period for the observations months × 12. Kaplan-Meier curves of stroke-free survival were generated, and the two groups' comparisons were performed using the log-rank test. Results As expected, patients' characteristics were comparable between the two groups. The observation period was 3 years for both groups. In the MR group, 136 patients with stroke were detected. On the other hand, 122 patients with stroke were detected in the Without-MR group. The incidence rate of the stroke per person-year was 0.027 and 0.025 events per person-year in patients with the MR and Without-MR groups. In addition, the Kaplan-Meier analysis showed that the incidence rate of stroke was comparable between the two groups (P=0.43). Conclusions The frequency of stroke in patients with atrial fibrillation was similar, despite mitral regurgitation. Therefore, patients with atrial fibrillation should have anti-coagulation therapy, regardless of the presence or absence of mitral regurgitation. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by grants provided by the Japan Science and Technology Agency (JST) Fusion Oriented Research for disruptive Science and Technology (FOREST) Program (Grant Number: JPMJFR205J) and the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) Program (Grant Numbers: JP20H00563 and JP19K21590).

In this study, cardiac current source localization was simulated using the spatial filter method. We estimated current sources using data from two measurement surfaces, i.e., the front and back of the subject, to reduce the large spatial extension in the depth direction. Three methods for creating spatial filters were developed using the exact low-resolution brain electromagnetic tomography method based on different creation procedures. The first method is a general method that has been conventionally used to create a spatial filter (64ch spatial filter) using a 64ch sensor on the front side. The second method is to create a spatial filter (128ch spatial filter) using two 64ch sensors on the front and back sides as a 128ch sensor. The third method is to create two spatial filters separately and use them as one spatial filter (2 × 64ch spatial filter). In this case, different Tikhonov regularization parameters can be determined on the front and back sides, and optimum noise immunity can be given to each. The accuracy of the estimated current sources using the three types of spatial filters was examined using simulation and MCG data. The results show that the 2 × 64 spatial filter has the highest estimation accuracy and suppresses the large spatial extension of the estimated current sources.

PUMA, antiProton Unstable Matter Annihilation, is a nuclear-physics experiment at CERN aiming at probing the surface properties of stable and rare isotopes by use of low-energy antiprotons. Low-energy antiprotons offer a very unique sensitivity to the neutron and proton densities at the annihilation site, i.e. in the tail of the nuclear density. Today, no facility provides a collider of low-energy radioactive ions and low-energy antiprotons: while not being a collider experiment, PUMA aims at transporting one billion antiprotons from ELENA, the Extra-Low-ENergy Antiproton ring, to ISOLDE, the rare-isotope beam facility of CERN. PUMA will enable the capture of low-energy antiprotons by short-lived nuclei and the measurement of the emitted radiations. In this way, PUMA will give access to the so-far largely unexplored isospin composition of the nuclear-radial-density tail of radioactive nuclei. The motivations, concept and current status of the PUMA experiment are presented.

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

A high position resolution neutron detector for time-of-flight measurements is being developed to measure the ( p , p n ) reaction in inverse kinematics with an excitation energy resolution of 1 MeV at the RIKEN RI Beam Factory. In this study, a new method based on the segmentation of the neutron detector part is employed to achieve a position resolution on the order of mm with a prototype neutron detector. The prototype detector consists of 8 × 8 scintillating fibers, two multi-anode photomultiplier tubes (PMTs) and two light guides. The scintillating fibers have a cross sectional area of 3 . 75 × 3 . 75 mm 2 . The prototype’s performance is studied using the neutron and proton beams provided at the Cyclotron and Radioisotope Center (CYRIC), Tohoku University and the Research Center for Nuclear Physics (RCNP), Osaka University. It is confirmed that the hit pattern analysis correctly recognizes the neutron detection position within the fiber size of 3.75 mm. The obtained TOF resolution of 350 ps (FWHM), lateral position resolution of 2.5 mm (FWHM), and longitudinal position resolution of 50–60 mm (FWHM) satisfy the requirements to achieve an excitation energy resolution of 1 MeV. The typical detection efficiency is ∼ 2.0% for a neutron with a kinetic energy of 50–200 MeV. The detailed investigation of the detection efficiency in conjunction with the neutron hit position reveals the existence of the non-uniformity of the efficiency. It is shown that the non-uniformity can be mitigated by reducing the threshold level, and by increasing the detector size. For a larger neutron detector, based on the design of the prototype detector, the non-uniformity will thus be negligible.

BackgroundAlthough biological drugs have dramatically changed and improved the outcome of patients with rheumatoid arthritis (RA), a lot of unresolved problems still exist. Although comorbidity by which enough treatment drugs cannot be prescribed or RA patients refractory to biological agents are representatives, financial difficulty is another representative. There are RA patients who hesitate biological treatment or treatment with Janus-kinase inhibitor due to financial difficulty. Although biosimilar disease-modifying anti-rheumatic drugs (DMARDs) are promising treatment options for such patients, real-world clinical experiences are still lacking in respect to exchanging from biological originator DMARDs to biosimilar DMARDs.ObjectivesThis retrospective study investigated the effects of switching from etanercept originator (ETN-OR) to ETN biosimilar (ETN-BS: LBEC0101 developed by LG Chem) on disease activity, physical function, and patient reported outcome (PRO) regarding a self-injection device in patients with well-controlled RA.MethodsData from the Toyohashi RA Database (TRAD) was used, which is a collection of single-center retrospective data. We retrospectively investigated disease activity, modified health assessment questionnaire (mHAQ), and patient characteristics in 42 RA patients that switched from ETN-OR to ETN-BS at least 6 months prior. Patients were also requested to answer the Toyohashi Self-Injection Assessment Questionnaire (T-SAQ), originally designed to assess PRO. T-SAQ consisted of 18 questions about self-injection device such as burden, learning, pain, convenience, handling and so on. Best was 0 and worst was 4 in each question and mean score of 18 questions was called total T-SAQ score. ResultsAll the patients were female. The mean age, RA duration, and ETN-OR treatment duration were 63.1 years, 18.3 years, and 3107 days, respectively. Mean disease activity and mean mHAQ after switching were as follows (baseline-3 months-6): DAS28-CRP (1.86-2.00-2.03), SDAI (4.3-5.0-5.3), and mHAQ (0.43-0.44-0.46). SDAI after 6 months was significantly elevated compare to baseline. Among each parameter, tender joints count at 3 months and patients’ global assessment at 6 months after switching are significantly increased compared to baseline (Table 1). Other parameters such as swollen joint counts, physician global assessment and CRP were not significantly changed. Total T-SAQ scores before and after switching were 1.3 and 1.1 (p < 0.01), respectively. Ease of use, mental tension, and pain were especially improved after switching to ETN-BS.ConclusionSwitching from ETN-OR to ETN-BS worsened disease activity in well-controlled RA patients in our real-world clinical practice due to not objective findings, but subjective complaints by RA patient. We thought that nocebo effect was one of the reasons to explain the results. On the other hand, the PRO regarding the injection device was improved. This improvement may be due to Finer needle of ETN-BS (ETN-OR: 27G, ETN-OR: 29G).Disclosure of InterestsNone declared

BackgroundTocilizumab (TCZ) is a humanized anti-IL-6 receptor monoclonal antibody that improves the signs and symptoms of rheumatoid arthritis (RA). In previous clinical trials, long-term outcomes have been increasingly evaluated in daily clinical practice. We report the five-year outcomes of TCZ treatment at our institute.ObjectivesThis retrospective study determined the long-term trends in TCZ use in clinical practice.MethodsData from the Toyohashi RA database (TRAD) were used. The TRAD is single-center retrospective data. Last observation carried forward was used as a complementary method for missing data. Participants were 59 RA patients in whom TCZ therapy was started at our institute from September 2009 to May 2016. Subsequent items, baseline patient characteristics, disease activity, treatment continuation rates of TCZ using the Kaplan-Meier method, reasons for stopping TCZ, concomitant use of methotrexate (MTX) and prednisolone (PSL) were investigated.ResultsBaseline characteristics at the start of TCZ treatment were 17 men and 42 women with a mean age of 58.6 years (30–81). The mean RA duration was 8.7 years (0–31). The mean SDAI score was 27.9 ± 11.6; the mean DAS28-CRP was 5.0 ± 1.0. CRP was 4.1 ± 3.0 mg/dl and MMP-3 388.3 ± 311.5 ng/ml. Methotrexate (MTX) was administered in 37 patients (62.7%, mean 6.0 mg, mean MTX dose administered in cases, 9.6 mg/week). Prednisolone (PSL) was administered in 37 patients (62.7%, mean 3.6 mg; the mean PSL dose administered in cases 5.7 mg/day).Regarding disease activity, the mean SDAI was 27.9 at baseline; 12.3 at three months; 8.1 at one year; 7.3 at two years; 6.5 at three years; 46.7 at four years; 5.6 at five years, and 5.2 at final observation. The SDAI significantly improved after two years compared to baseline. Remission and low disease activity also significantly improved at one year and gradually improved after one year (Figure 1). The remission rate at the final observation was 55.2%, with an SDAI ≦3.3.TCZ continuation rates were 86.9% at one year, 78.7％ at three years, and 68.9% at five years (Figure 2). TCZ was discontinued due to adverse events in 11 cases (18%), and inadequate efficacy occurred in 9 (14.8%). The adverse events were respiratory infection (5), purulent arthritis (1), infectious endocarditis (1), subarachnoid hemorrhage (1), breast cancer (1), pruritis (1), and skin ulcer (1). Other reasons for discontinuation were dialysis (2), suspension of hospital visits (2), kidney transplant (1), and financial difficulties (1). Concomitant use from baseline to final observation declined from 62.7% to 15.3% for MTX and from 62.7% to 23.7% for PSL.ConclusionLong-term treatment with TCZ was acceptable. We found that with TCZ therapy, the remission and low disease activity rates significantly improved at one year and continued to improve after one year. Treatment persistence was high, but careful monitoring for infection is necessary.Disclosure of InterestsNone declared

BackgroundRomosozumab (ROMO) is an antisclerostin antibody that is used in the treatment of severe osteoporosis (OP). In March 2019, ROMO was approved for use in Japan for treating severe OP in clinical practice, causing an increase in its prescription in our institute. Although efficacy data for ROMO have been presented in clinical trials, there is a lack of real-world data. In our experience, ROMO treatment results in significant bone mineral density (BMD) gain in some patients, but not all. Therefore, understanding the predictors that enhance the efficacy of ROMO treatments to achieve BMD gain is essential.ObjectivesThis study investigated the efficacy of a 12-month ROMO treatment in patients with OP and explored the efficacy predictors of increased BMD.MethodsOur study included 52 patients with OP, who were started on ROMO treatment between June 2019 and August 2020. The following information was collected: 1) baseline characteristics, 2) time-course of BMD (lumbar spine [LS] and total hip [TH]) and bone turnover markers (BTM; bone-specific alkaline phosphatase [BAP], type I procollagen-N-propeptide [P1NP], type I procollagen-N-propeptide[NTX], and tartrate-resistant acid phosphatase-5b [TRACP-5b]), 3) multiple regression analysis results following Spearman’s correlation analysis of increased BMD values (%) at 12 months and BL characteristics, including BTM change (%) at one month, to investigate the efficacy predictors of ROMO.Results1) The mean age of the participants was 72.9 years (48 female and four male). Of the 52 understudied patients, 78.8% had past insufficiency fractures, whereas 21.2% had been treated with concomitant prednisolone. Furthermore, 21 patients had primary OP, 20 had rheumatoid arthritis, nine had glucocorticoid-induced OP, and two had other conditions. Pretreatments for OP were bisphosphonate (33 patients), vitamin D (6), none (5), selective estrogen receptor modulator (4), and denosumab (3).2) Both mean LS- and TH-BMD significantly increased in the patients for whom ROMO administration was continued for 12 months. The average percentage changes of LS- and TH-BMD were 7.1% and 1.6% at six months and 11.7% and 3.0% at 12 months, respectively (Figure 1). However, BAP and P1NP increased steeply at one month, followed by a gradual decrease. As observed, the average percentage changes of BAP and P1NP were +70.1% and +166.8% at one month, +50.3% and +91.7% at six months, and +24.4% and +41.5% at 12 months, respectively. The results also showed that TRACP-5b decreased from one to 12 months, with the average percentage changes being −22.9% at one month, −13.8% at six months, and −17.7% at 12 months. Moreover, NTX, a bone-resorptive marker, was slightly increased during ROMO treatment.3) Multiple regression analysis results revealed that the baseline BAP and percentage calcium changes at 12 months were significant factors positively correlated with the percentage change of LS-BMD at 12 months. As observed, the baseline T-score of LS-BMD was a significant factor negatively correlated with the percentage change of LS-BMD at 12 months. The standardized partial regression coefficient values were +0.68, +0.26, and −0.40, respectively. Moreover, the multiple regression analysis results revealed no significant factor that was correlated with the percentage changes of TH-BMD at 12 months.Figure 1.ConclusionROMO treatments rapidly increased BMD, especially LS-BMD, and changed BTM after one month. Baseline BAP were correlated with increased LS-BMD but not with TH-BMD. The factors correlated with increased BMD may differ between LS-BMD and TH-BMD.Disclosure of InterestsNone declared

BackgroundOsteoporosis (OP) is a frequent complication identified in patients with rheumatoid arthritis (RA). Effective treatment must be provided to treat OP in RA (RAOP). Denosumab (DMB) is a promising drug, currently being used for the treatment of RAOP. Although DMB was determined to be effective in a long-term FREEDOM extension trial [1] for treating postmenopausal OP, its efficacy in the treatment of RAOP in real-world is not be fully evaluated.ObjectivesThis retrospective study assessed the five-year treatment outcome of DMB in Japanese patients with RAOP.MethodsData from the Toyohashi RA Database (TRAD) was used, which is a collection of single-center retrospective data. Our study included 65 female patients with RAOP for whom DMB treatment was initiated between October 2013 and May 2016. The following information was collected: 1) baseline characteristics, 2) DMB continuation rates using the Kaplan–Meier method and reasons for stopping DMB, 3) fracture occurrence during DMB treatment, and 4) time-course of bone mineral density (BMD) [lumbar spine (LS) and total hip (TH)] and bone turnover markers (BTM) [bone-specific alkaline phosphatase (BAP), type I procollagen-N-propeptide (P1NP), type I procollagen-N-propeptide (NTX), and tartrate-resistant acid phosphatase-5b (TRACP-5b)] in 38 patients who underwent DMB treatment over a period of five years.Results1) The mean age and RA duration were 69.4 years (46–86) and 17.2 years (1–49), respectively. Prednisolone and biologics were administered in 21 (32.3%) and 20 (30.8%) patients, respectively. Twenty-seven patients (41.5%) had a history of fragility fractures, and 24 patients (36.9%) had a history of vertebral fractures. Pretreatment drugs for OP were as follows: bisphosphonate in 22 patients; teriparatide, 17; none, 16; activated vitamin D, 7; and selective estrogen receptor modulator, 3.2) Continuation rates of DMB were 96.9% at one year, 95.4% at two years, 85.8% at three years, 79.4% at four years, and 71.1% at five years. DMB treatment was terminated in 24 patients due to lack of efficacy in nine patients, death in seven patients (unknown reason in four, pneumonia in two, and senile decay in one), adverse events except death in five patients (worsening of dementia in two, brain hemorrhage in one, necrosis of jaw in one, and pneumonia in one), and other reasons in three patients.3) Nine patients (13.8%) experienced fractures during DMB treatment; vertebral and non-vertebral fractures occurred in three and four patients, respectively. Two cases of fractures remained undefined.4) Both mean LS-BMD and TH-BMD significantly increased in 38 patients for whom DMB administration was continued for five years. Average percent changes of LS-BMD and TH-BMD were 3.9% and 3.0% at six months, 5.5% and 3.8% at one year, 7.6% and 4.1% at two years, 9.8% and 5.7% at three years, 10.8% and 6.5% at four years, and 12.9% and 6.8% at five years (Figure 1). Four BTMs, BAP, P1NP, NTX, and TRACP-5b, significantly decreased from six months to five years when compared to baseline values, with average changes at 5 years equaling −38.4%, −37.8%, −23.8%, and −24.6%, respectively.ConclusionDMB treatment of RAOP proved effective and reasonably safe, and it increased BMD by a percentage similar to that observed in the FREEDOM extension trial. However, DMB administration was ceased in 13.8% of cases due to fractures and lack of efficacy. Although DMB is recommended for the treatment of RAOP, future evaluations should be conducted to predict its efficacy and determine alternative treatment strategies.References[1]Bone HG et al. Lancet Diabetes Endocrinol. 2017.Disclosure of InterestsNone declared

The tensile properties of XM-19 austenitic stainless steels with thick plates (30 mm thickness), extra-thick plates (100 mm thickness), and rectangular bars (square of 14.3 mm) were examined at cryogenic temperatures. Influence of thermomechanical treatments on the steels was demonstrated. Even though their 0.2 % proof stresses were over 1200 MPa at 4.2 K, there were variations in strength depending on location. Namely, the 1/2t specimen (the position of the half in the thickness) of extra-thick plate showed lower 0.2% proof stress, elongation, and reduction of area at 4.2 K than the 1/4t (the position of the quarter in the thickness) and the thick plates. The effect of grain size on the 0.2% proof stress was clearly described by the Hall-Petch relationship for the materials.

State-of-the-art variable speed drive inverter systems are typically employing 1200 V Si IGBTs with antiparallel freewheeling diodes, resulting in a large overall semiconductor chip area, relatively high switching losses and/or low switching frequencies, and causing a substantial on-state voltage drop in both current directions, which inherently limits the peak and part-load efficiency. SiC MOSFETs are seen as natural future replacement of Si IGBTs, since they benefit from high switching speeds and low on-state resistances, which drastically reduces switching and conduction losses. However, the high switching speed of SiC devices results in a dv/dt-stress on the motor windings of up to 60...80 V/ns, which must be limited to 3...6 V/ns in order to prevent partial discharge phenomena and/or progressive insulation aging. Full sinewave filtering could solve this issue, but would also reduce the achievable performance improvement, as a higher switching frequency and/or a bulky filter would be required. Therefore, this paper comparatively evaluates different dv/dt-limitation approaches proposed in literature, i.e. active, hybrid and passive filter concepts, for a next generation 10kW SiC PWM inverter supplied from an 800V DC-bus. First, the different filter concepts are described and analyzed, and in a second step their design procedure is explained based on the design space approach. Afterwards, a Pareto optimization is conducted and Pareto optimal designs are selected, evaluated and compared regarding efficiency and power density. All considered filter designs outperform a state-of-the-art typically 98.3% efficient IGBT inverter drive. The hybrid filter enables a part-load (at 8 kW) efficiency of 99.0% for a dv/dt limited to 6 V/ns. If higher dv/dt -values can be tolerated, e.g. 12 V/ns, 99.3% part-load efficiency with a power density above 80 kW/L can be achieved by the active concept.

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Beneficial effects of sesame lignans, especially antioxidative effects, have been widely reported; however, its potential effects on autonomic nerves have not yet been investigated. Therefore, the current study aimed to investigate the effect of sesame lignans on the autonomic nervous system. The sympathetic nerve activity in rat skeletal muscle was measured using electrophysiological approaches, with blood flow determined using the laser Doppler method. Sesame lignans were administered intragastrically at 2 and 20 mg/kg, and after 60 min, the sympathetic nerve activity was observed to increase by 45.2 % and 66.1 %, respectively. A significant increase in blood flow (39.6 %) was also observed for the 20-mg/kg dose when measured at 55 min after administration. These sympathomimetic effects were completely prevented by subdiaphragmatic vagotomy, and the increase in blood flow was eliminated in the presence of the β2-adrenergic receptor inhibitor butoxamine. Thus, it is proposed that sesame lignans can increase the blood flow of skeletal muscle, possibly by exciting sympathetic nerve activity through the afferent vagal nerve.

Low-density lipoprotein (LDL) oxidative susceptibility is recognized as a risk factor for atherosclerosis. We previously reported that the ingestion of a supplement containing sesame lignans (sesamin/episesamin) for 4 weeks reduced LDL oxidative susceptibility in humans.To elucidate the mechanisms underlying this observation, 12-week-old New Zealand White rabbits were fed a fat/cholesterol-enriched diet (100 g/day) for 6 weeks followed by oral administration of vehicle (control) or sesame lignans (50 mg/kg) for 4 weeks with the fat/cholesterol-enriched diet.The results showed that the ingestion of sesame lignans prolonged LDL oxidation lag time, regardless of the existence of the anti-oxidative catechol metabolite of sesamin/episesamin in LDL. Plasma platelet-activating factor acetylhydrolase (PAF-AH) activity was significantly reduced by sesame lignans. The prolongation of LDL oxidation lag time was abolished by the addition of a PAF-AH inhibitor. The expression level of pro-inflammatory cytokines and macrophage infiltration observed in the liver following the feeding of the fat/cholesterol-enriched diet were also significantly reduced by sesame lignans.These results indicate that sesame lignans reduce LDL oxidative susceptibility by downregulating plasma PAF-AH activity via the reduction of inflammation in the liver induced by fat/cholesterol-enriched diets.

Type 2 red-fleshed apples are attractive to consumers due to their sweet taste, which is not present in type 1 apples, in addition to their vivid colour and the accumulation of health-promoting pol...

Purpose/Objective(s) Radiotherapy (RT) is performed not only to reduce pain but also to prevent pathological fractures due to bone metastases of the spine. However, it is unclear to what extent radiotherapy increases bone strength. Bone density is sometimes used as a marker for assessment of local response to RT in spinal bone metastases. The purpose of this study was to evaluate the changes of bone strength using CT-based finite element (FE) methods in radiotherapy for metastases at the lumber vertebra in comparison with bone density. Materials/Methods Five patients with metastases to the lumber vertebra who could be followed for more than 6 months were included. Primary lesions were lung cancer in all patients. All patients had osteolytic changes of the bone cortex in the vertebral body. Median radiation dose was 37.8 Gy in 14 fractions. CT images were taken before and at 1, 3, 6, 9 and 12 months after irradiation. Bone density was measured in Hounsfield units (HU) in each CT scan. The regions of interest were set to include the whole vertebral body of the metastatic spine and that of a non-irradiated unaffected neighboring spine used for reference. The 3-dimensional FE models of the same vertebrae were constructed from each CT image. The models consisted of 1- or 2-mm linear tetrahedral elements and the cortical shell with a thickness of 0.1 mm. A uniaxial compressive load with uniform distribution was applied on the upper surface of the vertebral body with the lower surface completely restrained. The predicted fracture load was defined to be present when at least one element or cortical shell failed. The ratios of the values on the follow-up CT to the values on the pre-irradiation CT were calculated, and single regression equations were determined for these ratios. Results At one month after irradiation, the bone density decreased in all except one case of the affected vertebral bodies, and the predicted fracture load decreased in all except one case of the unaffected vertebral bodies. In the affected vertebral bodies, the slopes of the single regression equations of bone density were positive in 4 out of 5 cases. The slopes of those of predicted fracture loads were negative in 3 out of that 4 cases. In the unaffected vertebral bodies, the slopes of the single regression equations of bone density were positive in 3 out of 5 cases. The slopes of predicted fracture loads were positive in those 3 cases. Conclusion The bone strength might not improve in one month after irradiation. The predicted fracture load did not necessarily increase even if the bone density increased in the irradiated affected vertebral bodies. Bone density alone might not be sufficient as an indicator of bone strength. The FE method could evaluate the changes in bone strength in radiotherapy for bone metastases based on predicted fracture loads.

We present the first measurement of the Michel parameters η ‾ and ξκ in the radiative leptonic decay of the τ lepton using 703 fb-1 of data collected with the Belle detector at the KEKB e + e − collider. The Michel parameters are measured by an unbinned maximum likelihood fit to the kinematic information of e + e − → τ + τ − → ( π + π 0 ν ‾ ) ( l − ν ν ‾ γ ) ( l = e or μ ) . The preliminary values of the measured Michel parameters are η ‾ = − 2.0 ± 1.5 ± 0.8 and ξ κ = 0.6 ± 0.4 ± 0.2 , where the first error is statistical and the second is systematic.

This paper introduces a novel integrated series power pulsation buffer (iSPPB) concept for a single-phase AC-to-DC two-switch buck+boost PFC rectifier to compensate the fluctuating power mismatch between the AC input and the DC output. Accordingly the DC-link capacitance can be drastically reduced and an electrolytic-capacitor-Iess PFC rectifier system featuring a higher power density and an increased lifetime is obtained. The proposed iSPPB concept consists of a simple full-bridge circuit with a buffer capacitor and is placed in series with the buck-boost inductor thus no additional inductive component is required for the iSPPB realization. The basic operating principle of the buck+boost PFC rectifier with iSPPB is investigated and the characteristic waveforms are presented. As shown in the analysis due to the employment of the iSPPB also the maximum buck+boost inductor current is reduced which compared to the conventional rectifier system without iSPPB allows to further downsize the inductive component. Consequently the major drawbacks of conventional single-phase PFC rectifiers are eliminated. Furthermore the control structure is presented and the proper operation is verified based on a closed-loop circuit simulation. Finally the proposed buck+boost PFC rectifier with iSPPB and a conventional two-switch implementation employing electrolytic capacitors are quantitatively compared by means of simple performance indices.

Sesamin is a major lignan constituent of sesame and possesses various health-promoting effects. Previous studies have demonstrated that sesamin extends the lifespan of Drosophila and Caenorhabditis elegans and corrects oxidative damage-related tissue dysfunction in mammals. To understand its anti-aging effects, we aimed to determine whether sesamin restores tissue function hampered by oxidative damage and suppresses several aging-related phenotypes using Drosophila senescence-accelerated models.We elucidated the anti-aging effects of sesamin on several aging-related phenotypes in the muscle, brain and midgut using the senescence-accelerated models (Sod1n1 mutant and Sod1-depleted flies) by immunostaining experiments. We determined the expression levels of several anti-oxidative and DNA repair genes using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). We also identified the metabolite of sesamin in Drosophila by LC-MS/MS.We confirmed that sesamin (0.35 and 2 mg/ml) extended the lifespan of the fly models. As observed in mammals, it can be absorbed and metabolized by Drosophila adults. The sesamin feeding suppressed the age-dependent impairment of locomotor activity and inhibited the accumulation of reactive oxygen species (ROS) in their bodies. Sesamin delayed the age-dependent accumulation of damaged proteins in the muscle, partially suppressed the loss of dopaminergic neurons in adult brains displaying ROS accumulation, and suppressed the accumulation of DNA damage and hyperproliferation of intestinal stem cells. Four antioxidative genes and two DNA repair genes were simultaneously upregulated in sesamin-fed adults. CONCLUSIONS: These observations represent the first direct evidence of the anti-aging effects of sesamin at the individual level. We propose that sesamin exerts anti-aging effects in the muscles, brain and midgut by inducing antioxidative and DNA repair genes, resulting in extended lifespan in flies.

A $3208\times 2184$ global shutter image sensor with back-illuminated architecture is implemented in a 90 nm/65 nm imaging process. The sensor, having $2.74\ \mu \mathrm{m}$ -pitch-pixels, achieves 10000 electrons full-well capacity and −80 dB parasitic light sensitivity. Furthermore, 13.8 e-/s dark current at 60°C and 1.85 erms random noise are obtained. In this paper, the structure of a pixel with memory along with saturation enhancement technology is described.

Transmutation using intense negative muon beams is useful to mitigate long-lived fission products from nuclear plants. To produce high intensity negative muon beams, the MERIT (multiplex energy recovery internal target) scheme was suggested. To prove the MERIT scheme, a proof-of-principle experiment was performed at KURNS (Institute of Radiation and Nuclear Science at Kyoto University). This paper presents the results of the experiment.