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Background:Systemic lupus erythematosus (SLE) is a chronic, progressive autoimmune disease characterized by the loss of immune tolerance and the persistent production of autoantibodies. Type I interferon (IFN-I) plays a significant role in the pathogenesis of SLE, with its production being linked to the activation of the Stimulator of Interferon Genes (STING) pathway in monocytic cells. The significance of IFN-I in the maintenance therapy of SLE has been recently acknowledged, as exemplified by the regulatory approval of anifrolumab, a therapeutic agent targeting IFN-I. In Japan and other parts of Asia, apheresis treatment has been employed since the 1970s, and its efficacy in inducing remission therapy is well-documented. Despite the availability of new drugs that have expanded treatment options for SLE, regular double filtration plasmapheresis (DFPP) remains a staple in maintenance therapy in Japan. However, the specific therapeutic mechanisms within the body have not been fully elucidated, even though DFPP is designed to remove antibody-containing fractions from plasma.Objectives:Our study aimed to elucidate the therapeutic mechanisms of DFPP in the context of maintaining SLE therapy, with a particular focus on investigating changes in IFN-I using patient plasma.Methods:We collected plasma samples from patients with SLE (n=11) who regularly underwent DFPP at Juntendo University Hospital in Tokyo, Japan. These samples were then analyzed using a cell-based reporter system that allows the detection of IFN-I bioavailability and inducing activity. Additionally, we examined the Stimulator of STING pathway through reporter cells in which STING had been knocked out. We also measured the concentration of plasma double-stranded DNA (dsDNA) using the Pico Green method. Western blot analysis was employed to assess the phosphorylation of STING and Interferon Regulatory Factor (IRF) 3.Results:Patients with SLE exhibited higher IFN-I bioavailability in their plasma compared to that of healthy controls (HCs). This heightened bioavailability decreased after undergoing DFPP. Similarly, IFN-I-inducing activity was more pronounced in patients compared to HCs and decreased after undergoing DFPP. The reduction in IFN-I-inducing activity was particularly prominent in patients with higher disease activity. Notably, this reduction was not observed in STING-knockout reporter cells. Additionally, plasma dsDNA levels decreased after DFPP, suggesting that the inhibition of the STING pathway was responsible for the observed decrease in activity. To further support this, we conducted Western blot analysis, which revealed a suppression of STING and IRF3 phosphorylation following DFPP.Conclusion:Our findings provide evidence that DFPP effectively reduces IFN-I bioavailability and IFN-I-inducing activity in patients with SLE. This reduction in IFN-I-inducing activity is likely attributable to the inhibition of the STING pathway achieved through the elimination of dsDNA from the bloodstream. Importantly, our study represents the first report to acknowledge the reduction of IFN-I bioavailability and IFN-I-inducing activity as a therapeutic effect of DFPP.Figure 1.Plasma from patients with SLE had high IFN-I bioavailability and IFN-I-inducing activity, which decreased after DFPP treatment. IFN-I bioavailability(A) and inducing activity(B) in the plasma of patients with SLE were significantly higher than those in HCs, and DFPP reduced both IFN-I bioavailability and inducing activity in the plasma. A higher level of disease activity was associated with a greater pre–post ratio of the therapeutic effects of DFPP (D).Figure 2.Western blotting analysis revealed reduced STING and IRF3 phosphorylation following DFPP. To investigate the role of the STING pathway in the reduction of IFN-I-inducing activity by DFPP treatment, we analysed STING phosphorylation in stimulated human macrophages using western blotting. Reduction in STING phosphorylation following DFPP treatment (A, C). Similary, IRF3 phosphorylation was reduced (B, D). Those reduction indicating that DFPP reduced STING pathway activation.REFERENCES:NIL.Acknowledgements:The authors are deeply grateful to Moeko Inoue for her invaluable contributions as a research assistant, which significantly enriched the quality and success of this study. The authors also thank the members of the Laboratory of Cell Biology and Laboratory of Molecular and Biochemical Research, Biomedical Research Core Facilities, Juntendo University Graduate School of Medicine for their technical assistance.Disclosure of Interests:Takumi Saito This work was supported by Asahi Kasei Medical Company Limited as a joint research course., Goh Murayama This work was supported by Asahi Kasei Medical Company Limited as a joint research course., Makio Kusaoi This work was supported by Asahi Kasei Medical Company Limited as a joint research course., Ken Yamaji This work was supported by Asahi Kasei Medical Company Limited as a joint research course., Naoto Tamura AbbVie/Abbott, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, GlaxoSmithKlein(GSK), janssen, Mitsubisi Tanabe Pharma Corporation, Novartis.

Although the phylogenetic relationships between monocot orders are sufficiently understood, a timescale of their evolution is needed. Several studies on molecular clock dating are available, but their results have been biased by their calibration schemes. Recently, the fossilized birth-death model, a type of Bayesian dating method, was proposed, and it does not require prior calibration and allows the use all available fossils. Using this model, we conducted divergence-time estimations of monocots to explore their evolutionary timeline without calibration bias. This is the first application of this model to seed plants. The dataset contained the matK and rbcL chloroplast genes of 118 monocot genera covering all extant orders. We employed information from 247 monocot fossils, which exceeded previous dating analyses that used a maximum of 12 monocot fossils. The crown group of monocots was dated to approximately the Late Jurassic–Early Cretaceous periods, and most extant monocot orders were estimated to diverge throughout the Early Cretaceous. Our results overlapped with the divergence time of insect lineages, such as beetles and flies, suggesting an association with pollinators in early monocot evolution. In addition, we proposed three new orders based on divergence time: Orchidales separated from Asparagales and Tofieldiales and Arales separated from Aslimatales.

In state-of-the-art stellarators, turbulence is a major cause of the degradation of plasma confinement. To maximize confinement, which eventually determines the amount of nuclear fusion reactions, turbulent transport needs to be reduced. Here we report the observation of a confinement regime in a stellarator plasma that is characterized by increased confinement and reduced turbulent fluctuations. The transition to this regime is driven by the injection of submillimetric boron powder grains into the plasma. With the line-averaged electron density being kept constant, we observe a substantial increase of stored energy and electron and ion temperatures. At the same time, the amplitude of the plasma turbulent fluctuations is halved. While lower frequency fluctuations are damped, higher frequency modes in the range between 100 and 200 kHz are excited. We have observed this regime for different heating schemes, namely with both electron and ion cyclotron resonant radio frequencies and neutral beams, for both directions of the magnetic field and both hydrogen and deuterium plasmas. In stellarators, turbulence is detrimental for the confinement of the plasma. In the Large Helical Device, a confinement regime with reduced turbulence and improved confinement is observed.

Defying the requirements of translational periodicity in 3D, rotation of the lattice orientation within an otherwise single crystal provides a new form of solid. Such rotating lattice single (RLS) crystals are found, but only as spherulitic grains too small for systematic characterization or practical application. Here we report a novel approach to fabricate RLS crystal lines and 2D layers of unlimited dimensions via a recently discovered solid-to-solid conversion process using a laser to heat a glass to its crystallization temperature but keeping it below the melting temperature. The proof-of-concept including key characteristics of RLS crystals is demonstrated using the example of Sb 2 S 3 crystals within the Sb-S-I model glass system for which the rotation rate depends on the direction of laser scanning relative to the orientation of initially formed seed. Lattice rotation in this new mode of crystal growth occurs upon crystallization through a well-organized dislocation/disclination structure introduced at the glass/crystal interface. Implications of RLS growth on biomineralization and spherulitic crystal growth are noted.

Synchrotron x-ray microdiffraction ( μ XRD ) allows characterization of a crystalline material in small, localized volumes. Phase composition, crystal orientation and strain can all be probed in few-second time scales. Crystalline changes over a large areas can be also probed in a reasonable amount of time with submicron spatial resolution. However, despite all the listed capabilities, μ XRD is mostly used to study pure materials but its application in actual device characterization is rather limited. This article will explore the recent developments of the μ XRD technique illustrated with its advanced applications in microelectronic devices and solar photovoltaic systems. Application of μ XRD in microelectronics will be illustrated by studying stress and microstructure evolution in Cu TSV (through silicon via) during and after annealing. The approach allowing study of the microstructural evolution in the solder joint of crystalline Si solar cells due to thermal cycling will be also demonstrated.

Background:A typical common symptom of rheumatic diseases is arthralgia, a factor that reduces quality of life and the leading unresolved PRO of rheumatic diseases. The main causes of arthralgia are inflammatory pain due to synovial inflammation and non-inflammatory pain due to neuropathic pain (NeP), and elucidating the causes of arthralgia in rheumatic diseases is an important issue for improving PROs.Objectives:To investigate the involvement of synovial inflammation and NeP in arthralgia, which rheumatologists have difficulty determining.Methods:This study enrolled 195 patients with rheumatic diseases who had arthralgia that was difficult for their physicians to determine. Systematic ultrasound examination was used to assess synovial inflammation, and the Pain DETECT Questionnaire (PDQ) was used to further assess non-inflammatory pain, NeP. Multivariate logistic analysis was used to determine contributing factors to arthralgia. Spearman’s rank correlation coefficient, single regression, and receiver operating characteristic (ROC) curve analysis were performed to examine associations among arthralgia, synovial inflammation, and NeP.Results:We studied 187 patients including 70 RA, 8 PMR, 8 SjS, 5 PsA, 4 MCTD, 3 SLE, 2 RS3PE, 2 UC, 1 FMF, 1 dermatomyositis, 1 gout, 1 APS, 1 GCA, 80 patients with undetermined arthritis and 8 patients excluded from this study due to NeP with carpal tunnel syndrome, spinal canal stenosis or cervical disc hernia. In both overall and RA patients, numerical rating scale (NRS) was significantly associated with NeP (p<0.001), while synovial inflammation showed no association with NRS and NeP. In the analysis grouped by the intensity of synovial inflammation, patients with moderate to severe synovial inflammation (Mod/High group) had significantly more burning pain in pain quality of PDQ than those with no or mild synovial inflammation (Non/Low group). Only in the Non/Low group of RA, NRS was not associated with NeP.Conclusion:Unexplained arthralgia in rheumatic diseases is predominantly noninflammatory pain similar to NeP. Synovial inflammation in RA may cause burning pain, which may alter pain quality and affect the value of PDQ score and thus require careful interpretation when used PDQ in RA.REFERENCES:[1] Rutter-Locher, Zoe et al. “A systematic review and meta-analysis of questionnaires to screen for pain sensitisation and neuropathic like pain in inflammatory arthritis.” Seminars in arthritis and rheumatism vol. 61 (2023): 152207. doi:10.1016/j.semarthrit.2023.152207.Figure 1.Study flow chartPatients with arthralgia who were examined by US at our department and interviewed with the PDQ to evaluate the presence of NeP were enrolled in this study from August 2020 to June 2021, excluding patients with diagnosed neuropathy. NeP, neuropathic pain.Figure 2.The optimal NRS cut-off score for diagnosing NePReceiver operating characteristic (ROC) curve analysis was performed to determine the NRS cut-off for diagnosing NeP in the N/L and M/H groups.(a) N/L group. Cut-off: 5, 82.6% sensitivity and 61.8% specificity, area under the curve (AUC)=0.737, 95% CI 0.623–0.851.(b) M/H group. Cut-off: 7, 55.6% sensitivity and 77.1% specificity, AUC=0.695, 95% CI 0.562–0.828.Acknowledgements:NIL.Disclosure of Interests:None declared.

BackgroundDespite of recent developments in therapeutic agents for rheumatoid arthritis (RA) patients[1], it is reported that half of the patients are unable to achieve remission even with existing drugs[2]. Therefore, there is an urgent need to gain mechanistic insight into treatment resistance. Nowadays, single-cell RNA sequencing (scRNA-seq) technology have dramatically improved our understanding of the heterogeneity in synovial cells. However, it has not been fully elucidated how the cell clusters are related to treatment response, especially in Asian races[3].ObjectivesWe intend to analyze the RA synovium from Japanese patients based on single-cell transcriptomics to explore the pathological key players related to treatment resistance.MethodsSynovial specimens were collected from 31 RA patients using an ultrasound-guided needle biopsy. The proportion of 5 immune cell subsets (CD4+ T cells, CD8+ T cells, B cells, NK cells, monocytes) and mesenchymal cells (synovial fibroblasts (SF), endothelial cells, mural cells) were analyzed by flow cytometry. CD45+ and CD45- live cells were isolated, and scRNA-seq libraries were prepared using the 10x chromium system.ResultsWe classified the patients into the following three groups based on treatment status at the time of biopsy; treatment-naïve, inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs-IR), or biological DMARDs (bDMARDs-IR). The proportion of CD8+ T cells, especially GZMB+ GZMK+ CD8+ T cells, was significantly lower in csDMARDs-IR patients compared to treatment-naïve patients. This population was characterized by enhanced expression of IFNG and GZMK, the cooperative inducers of IL-6 production from SF. Meanwhile, an increased proportion of SF, especially THY1low sublining and CD34+ sublining, was observed in csDMARDs-IR and bDMARDs-IR patients. Intriguingly, by integrating gene set variation analysis (GSVA) with transcriptomic data of cytokine-stimulated SF in vitro4, THY1low sublining was indicated to be activated independently of the effects of inflammatory cytokines (e.g., TNF-α, IL-1β, IFNs) (Figure 1). Collectively, this SF subpopulation was inferred to be less susceptible to cytokine-blocking agents such as IL-6 receptor or TNF-α inhibitors.ConclusionThe synovial analysis has the potential to be useful in parsing the mechanism of treatment resistance in Japanese RA patients, and gaining insights into novel therapeutic targets.References[1] Tan Y, Buch MH. ‘Difficult to treat’ rheumatoid arthritis: current position and considerations for next steps. RMD Open. 2022 Jul;8(2):e002387.[2] Burmester GR, Bijlsma JWJ, Cutolo M, et al. Managing rheumatic and musculoskeletal diseases - past, present and future. Nat Rev Rheumatol. 2017 Jul;13(7):443-448.[3] Chang F, Wei K, Slowikowski K, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20(7):928-42.[4] Tsuchiya H, Ota M, Sumitomo S, et al. Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis. Ann Rheum Dis. 2021 Apr;80(4):440-450.Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

BackgroundSystemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are often complicated by heart disease. In severe cases, heart surgery is required, but little is known about clinical background and immunohistological pathology of diseases.ObjectivesThe differences in clinical and immunohistological backgrounds of each disease were examined by comparing cases of heart disease associated with SLE and RA.MethodsFrom 2012 to 2021, we observed 45 patients with SLE (32 patients underwent surgery), 67 patients with RA (33 patients underwent surgery), and 8 patients with overlapping SLE/RA (3 patients underwent surgery), all complicated with heart disease. The heart disease cases were divided into the aortic valve disease (Av), mitral valve disease (Mv), ischemic heart disease (I), and aortic aneurysm disease (Aa) groups, all from patients who had visited our hospital. The SLE (S) group consisted of Av, Mv, I, and Aa in 5, 6, 11, and 13 respective cases (10 duplicate cases), and in the RA (R) group there were 24, 12, 15, and 10 respective cases (6 duplicate cases). Immunohistological analysis of patients with left atrial appendage tissue (seven SLE, six RA, and two overlapping SLE/RA patients) was performed on left atrial cardiomyocytes for anti-human IgG, IgM, and C3 antibodies. Left atrial cardiomyocytes of eight cases of heart disease with non-connective tissue disease were used as the control.ResultsThe age (in years) at diagnosis of heart disease in the S and R groups was S/R: 57.6/71.5 (p=0.057), and the duration (in years) from onset of the connective tissue disease to onset of the heart disease was S/R: 22.6/10.1 (p<0.001). Anti-SS-A antibody (P=0.041), anti-U1RNP antibody (p=0.0044), and anti-CLβ2GP1 antibody (p=0.022) showed a high positivity rate in the S group. In disease I, the age at the time of diagnosis of heart disease was S/R: 51.6/70.9 years (p = 0.0083); and in disease Aa, the age and duration of disease were S/R: 63.5/74.8 years (p = 0.0088) and 29.6/7.0 years (p = 0.0013), respectively. There was no significant difference in S/R in patients suffering from diabetes, hypertension, and hyperlipidemia. Immunohistological analysis revealed IgG deposition in the cardiomyocytes in six of the seven patients in the S-alone group, while no IgG deposition was observed in six patients in the R-alone group. In two patients with overlapping S-R, IgG deposition was observed in both. In the S group, two or more antibodies of antiphospholipid antibodies, anti-Ro/SSA or anti-U1RNP antibodies, were positive in five out of the seven patients, and preoperative anti-DNA antibody elevation or complement reduction was seen in only two patients. Two of the seven patients in the S group were negative for either antibody, and a patient showed no IgG deposition uniquely in the S group. Both patients with overlapping S-R were positive for anti-CL antibody and anti-Ro/SSA antibody. In the R group, all antibodies were negative within the measured range.ConclusionA comparison of SLE and RA patients complicated with heart disease revealed that the SLE patients tend to be younger at diagnosis than RA patients and had a longer morbidity period. It is possible that various autoantibodies, such as antiphospholipid antibodies, anti-Ro/SSA antibodies, and anti-U1RNP antibodies were involved and had immunological effects on the myocardial tissue. In contrast, in RA patients complicated with heart disease, the autoantibodies observed in SLE were negative, and immunoglobulins were not deposited in the myocardial tissue of the RA patients who underwent surgery, suggesting that immunological involvement was poor and older diagnostic age was involved.References[1]Ju Zhang, Jie Gao, Ruina Kong, et al. Clinical Rheumatology 2022; 41(2):377-386[2]Sara R, Schoenfeld, Shanthini Kasturi, et al. Seminars in Arthritis and Rheumatism 2013; 43: 77-95Acknowledgements:NIL.Disclosure of InterestsNone Declared.

BackgroundThe utility of vascular ultrasonography (v-US) was proved recently in European countries, due to which the technology, diagnosis, and classification methods have been spreading. However, the use of v-US is not prevalent in Japan. Therefore, giant cell arteritis (GCA) is usually diagnosed by combining v-US with other imaging methods scrupulously. Furthermore, progressive Computed Tomography Angiography (CTA) technologies, increased use of Positron Emission Tomography (PET-CT), and a high population with Takayasu disease are found in Japan.ObjectivesGiant cell arteritis of cranial type (c-GCA) can quickly lead to blindness and stroke. Therefore, a rapid and appropriate diagnostic method is required to differentiate between c-GCA cases and those mimicking c-GCA. Thus, we aimed to construct a diagnostic method for c-GCA by optimizing the available imaging methods in Japan and using v-US as a diagnosing method from Europe.MethodsWe targeted 56 patients with suspected GCA, who visited our hospital from 2019 to 2022. v-US had been performed previously in all patients and 23 patients were diagnosed with GCA. These GCA patients were classified as c-GCA vs c-GCA + Large vessel (LV)-GCA vs LV-GCA in the ratio 11: 6: 6. In this study, we established 17 cases as c-GCA, and the other 39 as mimic cases using clinical and imaging methods. Furthermore, we analyzed and compared 31 patients evaluated with v-US from 2021 to 2022 using a vascular map, which was originally made by us and we were making maps for blood flow and writing down clinical symptoms evaluated at three stages.ResultsThe sensitivity of the imaging methods to c-GCA patients was high for v-US (82.3%), Temporal artery biopsy (TAB) (78.6%), and CTA (71.4%) and low for PET-CT (50.0%) and Magnetic resonance imaging angiography (MRI/A) (38.5%). However, we did not use a contrast agent for MRI/A because our main objective to perform MRI/A was to distinguish cerebral infarction. The match rate of the imaging methods between v-US and PET-CT was 87.5% (CTA: 71.4%, TAB and v-US: 64.3%, and CTA: 63.6%). Among the 39 mimic cases, 15 cases were found to be Polymyalgia Rheumatica (PMR), 6 cases were LV-GCA, 5 cases were chronic headache, and others were collagen diseases, including 2 cases of Takayasu diseases. In 31 cases (10 cases of c-GCA and 21 mimic cases) from 2021 to 2022, halo sign of v-US (p-value: 0.01), jaw claudication (p-value: 0.02), and temporal headache on both sides (p-value: 0.01) were significant statistically.ConclusionIn this study, we constructed a flowchart to diagnose c-GCA in Japan using v-US and other complementary imaging methods. First, we distinguished GCA cases from mimic cases with high precision. Thereafter, we combined imaging methods, which contributed highly to diagnosis in our results. Lastly, we considered the accommodation of TAB. We have started using this flowchart, and this contribute to be higher rate of diagnosing GCA and decreasing blindness and stroke.References[1]Ponte C, Grayson PC, Robson JC, et al.. 2022 American College of Rheumatology/EULAR classification criteria for giant cell arteritis. Ann. Rheum. Dis. 2022;81(12):1647–1653.[2]Ponte C, Martins-Martinho J, Luqmani RA. Diagnosis of giant cell arteritis. Rheumatol. (Oxf. Engl.). 2020;59(Suppl 3);Suppl 3:iii5–iii16.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:The importance of the role of ACPA in the pathogenesis of rheumatoid arthritis has been reported. ABT is a biologic DMARD that inhibits T-cell activation, and its efficacy is higher in ACPA-positive patients. However, it remains unclear which patients with positive autoantibodies to specific citrullinated proteins are particularly likely to benefit from ABT.Objectives:We designed a prospective 2-year observational follow-up study (ORIJIN study) of bDMARDs-naïve Japanese rheumatoid arthritis patients newly started subcutaneous ABT injections. This study was planned to analyze the association between clinical information and antigen-specific ACPA expression profiles in patients who responded to ABT.Methods:Patients with active rheumatoid arthritis inadequately respond to at least one csDMARD and decided to start subcutaneous ABA as a first bDMARD were eligible for observation. A total of 92 patients from six hospitals were enrolled in this observational study in the period of December 2016 to November 2020. The Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Disease Activity Score with 28-joint count C-reactive protein (DAS28-CRP), and DAS28 erythrocyte sedimentation rate (DAS28-ESR). Responders were defined as achieving low disease activity or remission measured by SDAI at 12 or 24 months Human leukocyte antigen (HLA) genotype was examined with written informed consent. Antigen-specific ACPA was investigated for 13 citrullinated peptides (Apolipoprotein E, Biglycan, 2 kinds of Clusterin, Enolase, 4 kinds of Fibrinogen A, Filaggrin, 2 kinds of Histone(H2A/a 1-20, H2B/a 62-81), and Vimentin) using a custom multiplex bead array (MagPlexTM). The fluorescence intensity was measured using the Luminex® System.Results:The SDAI remission rates after ABT in 92 patients were 22.8% and 29.3% at 12 and 24 months, respectively, and the rates of achieving low disease activity (SDAI≦11) were 64.1% and 74.7% at 12 and 24 months, respectively. The continuation rates of ABT at 12 and 24 months were 84.8% and 65.2%, respectively.Antibody titers against citrullinated fibrinogen (FibrinogenA_211_230) at 12 and 24 months in the group achieving low disease activity or below (364.7±585.2, 249.6±308.1) compared with the non-remission group (961.1±1330.7, 1074±1423.1), It was significantly lower than before treatment (p<0.05, Wilcoxon signed rank test).Conclusion:The antibody titer against citrullinated fibrinogen may be related to the therapeutic effect of ABT. Further investigation is required in the future.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Makio Kusaoi Asahi Kasei Medical Co.,Ltd, Asahi Kasei pharma Co.,Ltd, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Goh Murayama: None declared, Takanori Azuma: None declared, Shintaro Hirata AbbVie/Abbott, Asahi-Kasei Pharma, Astellas, Ayumi, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, Gilead, GlaxoSmithKlein(GSK), janssen, kyorin, Novartis, Pfizer, Sanofi, Tanabe-Misubishi, UCB, AbbVie/Abbott, Asahi-Kasei Pharma, Ayumi, Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, Otsuka, Pfizer, Sanofi, Shionogi, Tanabe-Misubishi, UCB, Nobunori Takahashi AbbVie/Abbott, Astellas Pharma Inc, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, janssen Pharmaceutical KK., Pfizer Japan, Tanabe-Misubishi, UCB, Akiko Mitsuo: None declared, Yoshiyuki Abe: None declared, Kentaro Minowa: None declared, Toshio Kawamoto: None declared, Akira Katagiri: None declared, Masakazu Matsushita: None declared, Kurisu Tada: None declared, Michihiro Ogasawara: None declared, Hirofumi Amano: None declared, Shinji Morimoto: None declared, Ken Yamaji Asahi Kasei Medical Co.,Ltd, Asahi Kasei pharma Co.,Ltd, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Naoto Tamura AbbVie/Abbott, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, GlaxoSmithKlein(GSK), janssen, Mitsubisi Tanabe Pharma Corporation, Novartis.