Search

OBJECTIVES: This study aimed to clarify the impact of the coronavirus disease 2019 outbreak on the levels of activity among older patients with frailty or underlying diseases. A total of 175 patients (79.0±7.0 years) undergoing outpatient or home-based rehabilitation, stratified into groups, based on frailty status. The percentage of patients who went out at least once a week decreased after the outbreak from 91% to 87%, from 65% to 46%, and from 47% to 36% in the non-frail, frail, and nursing care requirement groups, respectively. The proportion of older patients participating in exercise during the outbreak was 75%, 51%, and 41% in the non-frail, frail, and nursing care requirement groups, respectively. The proportion of older patients participating in voluntary exercise after instruction was lowest in the frail group (35%). Older patients with frailty are susceptible to the negative effects of refraining from physical activity and require careful management.

Background: northern Chile has the highest levels of lithium in surface waters in the world which is reflected in very high lithium levels in the plants and animals that depend on these water systems and consequently in the indigenous population.Methods: the lithium tissue burdens in populations from two valleys in the extreme north of Chile have been studied. The bulk of this report is based on analyses of lithium levels in urine, hair, and breast milk in the population of several villages. Data on serum levels, some of which had been previously published, are included for the sake of completeness. Since this paper reports studies by several groups of workers samples were analysed by a variety of methods. These include atomic emission, atomic absorption, other photospectroscopic techniques and mass spectroscopy.Results: in all samples studied the average lithium level (5.3 ppm) was found to be significantly elevated compared to levels reported in the literature and measured in this study for people not exposed to high levels in water and food (0.009-0.228 ppm).Conclusions: the people studied represent a unique longitudinal cohort. The work should provide important insights into the potential neuroprotective effects of lithium also help us set guidelines to assess the risks from high dose environmental exposure.

Background Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. Methods Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. Results Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. Conclusions This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. Trial Registry UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691

BackgroundThrombosis is a unique complication in coronavirus disease 2019 (COVID-19). We have reported that elevated ferritin and D-dimer on admission were the risk factors of thromboses by analyzing the patients sequentially admitted to our hospital due to COVID-19 (1). However, we have not analyzed thrombotic complications in the view of the antiphospholipid antibodies (aPLs), which are frequently detected in the COVID-19 patients.ObjectivesTo elucidate the thrombogenic effects of aPLs in COVID-19, we analyzed the development of thrombosis in three lupus models after SARS-CoV-2 infection. Additionally, we evaluated the association of thrombotic events and the serum profile of aPLs in Japanese patients with COVID-19.MethodsThree animal models of lupus (MRL-lpr/lpr, NZBxNZW F1 and NZW×BXSB F1) were evaluated in this study. NZW×BXSB F1 was also considered as a model of antiphospholipid syndrome (APS) since aPLs were detected with a high titer (2). Experimental SARS-CoV-2 infection was induced using mouse-passaged virus strain (3). The incidence of thromboses in the lungs and kidneys were identified by evaluating H&E staining and PTAH staining of paraffin-embedded sections. We have experienced 44 thrombotic events in 34 out of 594 patients admitted to our institute. As a non-thrombotic COVID-19, 68 patients were selected to make a 1 to 2 matched-pair based on the propensity score. In total 102 patients, seven types of aPLs (anti-cardiolipin (CL) IgG/IgM, anti-β2GP1 IgG/IgA/IgM, and anti-phosphatidyl serine/prothrombin complex (PS/PT) IgG/IgM) were measured using specific ELISA kits. The patients’ clinical characteristics and serological profile of aPLs were further evaluated.ResultsWe identified the development of thromboses in the lungs or kidneys in 6 out of 12 (50%) NZW×BXSB F1 mice after the SARS-CoV-2 infection, whereas no thrombosis was observed in non-infected mice. Further, there was no thrombosis in the other lupus models (0%) after the infection. These findings might suggest the pathogenic role of aPLs under the SARS-CoV-2 infection.Among our COVID-19 patients, 39 out of 102 (38%) were tested positive for one or more aPLs. The positive ratios of any aPLs were statistically indifferent between the patients with or without thrombosis; anti-CL IgG (8.8% vs 5.9%)/IgM (0% vs 5.9%), anti-β2GP1 IgG (21% vs 12%)/IgA (8.8% vs 15%)/IgM (0% vs 1.5%), and anti-PS/PT IgG (0% vs 2.9%)/IgM (12% vs 13%), respectively. In addition, their titers were relatively lower than those observed in APS patients. The patients’ characteristics and the prognosis of COVID-19 were comparable regardless of the detection of any aPLs. These findings suggested that COVID-19 associated aPLs were irrelevant to thrombotic complications.ConclusionThromboses were induced after the infection of SARS-CoV-2 only in the APS model. However, aPLs detected in COVID-19 patients have little impact on the development of thrombosis. SARS-CoV-2 infection might have a high risk of thrombosis, especially in APS patients, as shown in the case report (4). The discrepancy of its thrombogenic effects of aPLs might be explained by the low titer of the antibody or the diversity of antibody epitope. Further analyses are required to clarify the mechanisms of aPLs production and the development of thrombosis in COVID-19.References[1]Oba S, et al. Arterial and Venous Thrombosis Complicated in COVID-19: A Retrospective Single-Center Analysis in Japan. Front Cardiovasc Med. 2021 Nov 19;8:767074.[2]Hashimoto Y, et al. Anticardiolipin antibodies in NZW x BXSB F1 mice. A model of antiphospholipid syndrome. J Immunol. 1992 Aug 1;149(3):1063-8.[3]Iwata-Yoshikawa N, et al. A lethal mouse model for evaluating vaccine-associated enhanced respiratory disease during SARS-CoV-2 infection. Sci Adv. 2022 Jan 7;8(1):eabh3827.[4]Chidharla A, et al. A Case Report of COVID-Associated Catastrophic Antiphospholipid Syndrome Successfully Treated with Eculizumab. J Blood Med. 2021 Oct 30;12:929-933.Disclosure of InterestsSeiya Oba: None declared, Tadashi Hosoya Speakers bureau: Janssen Pharmaceutical K.K.Daiichi Sankyo Company, limitedAsahi Kasei CorporationOno pharmaceuticalsEisaiEli Lilly, Daisuke Kawata: None declared, Wenshi Lee: None declared, Mari Kamiya: None declared, Yoji Komiya: None declared, Hideyuki Iwai: None declared, Yuko Nukui: None declared, Shuji Tohda: None declared, Shinsuke Yasuda Speakers bureau: Abbvie,Asahi Kasei Pharma,Chugai Pharmaceutical,Eisai, Eli Lilly,GlaxoSmithKline,Mitsubishi Tanabe Pharma,Ono pharmaceutical,Pfizer., Consultant of: ImmunoForge, Grant/research support from: Abbvie,Asahi Kasei Pharma,Chugai Pharmaceutical,CSL Behring,Eisai,ImmunoForge,Mitsubishi Tanabe Pharma,Ono pharmaceutical

BackgroundAchievement of normal physical function is an important outcome for older patients. Previous studies of younger cohorts showed that aging, comorbidities, and joint damage influenced the physical function of patients with RA who achieved clinical remission or low disease activity (LDA). We previously demonstrated that a treat-to-target (T2T) strategy for methotrexate (MTX)-naïve elderly-onset RA (EORA) was effective with an acceptable safety profile. It showed that 60.9% of 197 patients achieved HAQ Disability Index (HAQ-DI) ≤0.5 at three years by following the T2T strategy targeting LDA (1).ObjectivesWe aimed to evaluate associated factors with HAQ-DI in the T2T strategy targeting LDA for patients with EORA during three-year observational period.MethodsTreatment was adjusted to target LDA with conventional synthetic disease-modifying antirheumatic drugs (DMARDs), followed by biological DMARDs (bDMARDs) in 197 MTX-naïve EORA patients (mean age 74.9 years) with moderate-to-high disease activity. HAQ-DI was evaluated at week 0, 24, 52, 76, 104, 128, and 156. To evaluate associated factors with SDAI and HAQ-DI over the 36-month follow-up, Bayesian hierarchical logistic regression modeling was applied for 1067 periods from the 197 patients.ResultsAt baseline, the enrolled 197 patients with EORA who had normal physical function (HAQ-DI ≤0.5) in 29.4%, HAQ-DI >0.5 and In the multilevel logistic model, the association of MTX, bDMARDs, and GC use with changes in SDAI in each period was evaluated. Age, sex, and comorbidities (chronic lung disease, cardiovascular disease, history of malignancy, osteoporosis, history of serious infections, and osteoarthritis) were included as inter-individual factors. The model indicated that the use of bDMARDs was associated with a reduction of the SDAI (ΔSDAI: -9.75, SD 0.75, pThe association of age, sex, the comorbidities, and MTX, bDMARDs, and GC use with physical function in each period was evaluated by the multilevel logistic model. The model indicated that older age (ΔHAQ-DI: 0.03, SD 0.01, p ConclusionThese data indicate that bDMARDs had a central role in reducing disease activity in the T2T strategy targeting LDA in EORA patients. Chronic lung diseases and osteoporosis at baseline were associated with increase in disease activity and worsening of physical function. However, disease activity had a greater impact on physical function than the comorbidities at baseline.References[1]Sugihara T, et al. Rheumatology (Oxford). 2021;60(9):4252-4261Disclosure of Intereststakahiko sugihara Speakers bureau: TS has received honoraria from Abbvie Japan Co., Ltd., AsahiKASEI Co., Ltd., Astellas Pharma Inc., Ayumi Pharmaceutical, Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Mitsubishi-Tanabe Pharma Co., Ono Pharmaceutical, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., and UCB Japan Co. Ltd., Grant/research support from: TS has received research grants from AsahiKASEI Co., Ltd., Daiichi Sankyo., Chugai Pharmaceutical Co., Ltd., and Ono Pharmaceutical., Tatsuro Ishizaki: None declared, Hiroyuki Baba: None declared, Takumi Matsumoto: None declared, Kanae Kubo Speakers bureau: KK has received honoraria from Asahi KASEI, Astellas Pharma, Bristol Myers Squibb, Eisai, AbbVie GK, Boehringer Ingelheim, Daiichi-Sankyo, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma and Nippon Shinyaku., Grant/research support from: KK has received research grants from Asahi KASEI, Mari Kamiya: None declared, Fumio Hirano: None declared, Tadashi Hosoya: None declared, Masayo Kojima Speakers bureau: MK has received speakers bureau from AbbVie, Astellas, Ayumi Pharma, Chugai, Eisai, Eli Lilly, Janssen, Ono Pharmaceutical, Pfizer, Tanabe-Mitsubishi, and Takeda Pharmaceutical Co., Ltd., Nobuyuki Miyasaka: None declared, Masayoshi Harigai Speakers bureau: MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Consultant of: MH is a consultant for AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd. and Teijin Pharma., Grant/research support from: MH has received research grants from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekiui Medical, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd.

BackgroundJanus kinase inhibitors (JAKi) are effective in the treatment of patients with difficult-to-treat rheumatoid arthritis (D2T RA), regardless of previous use of biological disease-modifying antirheumatic drugs (bDMARDs), and receive equal billing with biological therapies in the latest version of the EULAR recommendations for treatment of RA1. However, as with bDMARDs, cases of discontinuation due to intolerance or inadequate response have been observed in patients treated with the so-called first-generation JAKi, leading to the development of a new generation of JAKi that aims to maximize efficacy and improve safety by enhancing kinase selectivity. The results of randomized controlled trials and meta-analyses suggest that the efficacy and safety of Upadacitinib (UPA) treatment are favorable. Although there have been no head-to-head trials between JAKi, a matched-adjusted indirect comparative study has shown a difference in efficacy between JAKi2, suggesting that the new generation of JAKi may be effective in rheumatoid arthritis patients with intolerance or inadequate response to first-generation JAKi. It is already apparent that a clear need exists for a JAK-IR trial to give guidance in those difficult patients who are JAKi non-responders3.ObjectivesTo evaluate real world efficacy of a second-generation JAK1-selective JAKi UPA in single-center cohort of RA patients who had discontinued first-generation JAKi.MethodsPatients with RA who had discontinued tofacitinib and/or baricitinib due to inadequate response or intolerance, regardless of whether they had used bDMARDs or not, were eligible for the study if they had received UPA by October 2021 and had been followed up for at least 12 weeks. Endpoints were Kaplan-Meier survival rate with inadequate response or intolerance as reasons for discontinuation, various disease activity assessments (DAS28-ESR, SDAI, CDAI, etc.), and patient reported outcomes (visual analogue scales (VASs) such as pain and stiffness, HAQ-DI, FACIT-Fatigue Scale, etc.) at 12 weeks. In addition, the reasons for discontinuation were investigated.ResultsFifty-one patients were included in the study, all of whom had D2T RA and had used at least one bDMARD as well as JAKi. The mean (median) age was 72.7 (77) years, disease duration 18.0 (17) years, number of bDMARDs used 3.34 (3), number of JAKi used 1.3(1), 5 patients with methotrexate, 6 patients with prednisolone, and DAS28-ESR 3.83 (3.9). At 12 weeks, the overall survival rate was 94% (94.6% in 37 cases used as 2nd JAKi and 92.9% in 14 cases used as 3rd JAKi). For reference, there was no significant difference from the 100% of the 15 cases used as the 1st JAKi (P=0.49). DAS28-ESR ConclusionUPA is more selective for JAK1 than first generation JAKi, and is expected to reduce adverse reactions caused by inhibition of JAK family members other than JAK1. The present study suggests that UPA is effective and well tolerated, regardless of the number and type of first-generation JAKi used in the past, albeit for a short period of time. Limitations include the small number of cases and the short time frame for discussing adverse reactions.References[1]Smolen JS, Landewé BM, Bijlsma WJ et al., EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020;79:685–699.[2]Christopher JE, Ruta S, Vishvas G et al. A Matching-Adjusted Indirect Comparison of Upadacitinib Versus Tofacitinib in Adults with Moderate-to-Severe Rheumatoid Arthritis. Rheumatol Ther 2021; 8:167–181.[3]Peter Nash, Clinical use of Jak 1 inhibitors for rheumatoid arthritis. Rheumatology, Volume 60, Issue Supplement_2, May 2021, Pages ii31–ii38Disclosure of InterestsNone declared

BackgroundWhile glucocorticoids (GC) are the cornerstone of the treatment for polymyositis (PM), GC-induced myopathy is inevitable, which further deteriorates muscle weakness. Therefore, novel therapeutic strategy that not only suppresses muscle inflammation but also improves muscle strength is awaited. We recently found that injured muscle fibers in PM undergo FASLG-mediated necroptosis1, a form of regulated cell death accompanied with release of pro-inflammatory mediators such as HMGB1, which contributes to accelerate muscle inflammation and muscle weakness. We also showed that inhibition of necroptosis or HMGB1 ameliorated the muscle weakness and muscle inflammation1 in C protein-induced myositis (CIM), a murine model of PM. Glucagon-like peptide-1 receptor (GLP-1R) agonists, which have been developed as an anti-diabetic therapy, have pleiotropic actions including anti-inflammatory effects2, suppression of muscle wasting3, and inhibition of cell death4. Accordingly, we hypothesized that GLP-1R agonists have beneficial effects on PM to recover muscle strength and to suppress muscle inflammation.ObjectivesThe aims of this study are to examine the role of GLP-1R in PM and the effect of a GLP-1R agonist on in vivo and in vitro models of PM.MethodsMuscle specimens of PM patients and CIM were examined with immunofluorescence staining for the expression of GLP-1R. The effect of PF1801, a GLP-1R agonist, on CIM was examined in monotherapy or in combination with prednisolone (PSL). As an in vitro model of PM, C2C12-derived myotubes were treated with FAS ligand (FASLG) to induce necroptosis. The levels of HMGB1, TNF-α, and IL-6 in the serum of CIM and in the culture supernatant of the in vitro model were measured by ELISA. The effect of PF1801 on the myotube necroptosis was examined using time lapse imaging 5 and its effect on the activation of AMP-activated protein kinase (AMPK), the expression of PGAM5, and ubiquitination of PGAM5 was assessed with immunoblotting. The levels of reactive oxygen species (ROS) in the myotubes were analyzed with CellROX assay. The effect of PF1801 on the expression of antioxidant molecules in the myotubes was analyzed with quantitative real-time PCR.ResultsGLP-1R was expressed on the inflamed muscle fibers of PM and CIM. The treatment with PF1801 in monotherapy or in combination with PSL suppressed CIM-induced muscle weakness and the muscle weight loss as well as the severity of histological myositis while the monotherapy with PSL did not suppress muscle weakness and muscle weight loss. PF1801 decreased the levels of inflammatory mediators such as HMGB1, TNF-α, and IL-6 in the serum of CIM. In vitro, PF1801 inhibited FASLG-induced myotube necroptosis and decreased the levels of HMGB1, TNF-α, and IL-6 in the supernatant. PF1801 activated AMPK and decreased the levels of PGAM5, which was crucial for FASLG-induced necroptosis of the myotubes. The inhibitory effect of PF1801 on myotube necroptosis was cancelled by compound C, an AMPK-kinase inhibitor, or MG132, a proteasome inhibitor, suggesting that PF1801 promoted ubiquitin-proteasome-mediated PGAM5 degradation through the activation of AMPK. Furthermore, PF1801 suppressed FASLG-induced reactive oxygen species (ROS) accumulation in myotubes, which was also crucial for the execution of necroptosis, thorough up-regulating the antioxidant molecules such as Nfe2l2, Hmox1, Gclm, and Nqo1.ConclusionGLP-1R agonist could be a novel therapy for PM that restores muscle strength as well as suppresses muscle inflammation through inhibiting muscle fiber necroptosis.References[1]Kamiya M, et al. Nat Commun. 2022;13:166[2]Du X, et al. Int Immunopharmacol. 2019;75:105732.[3]Hong Y, et al. J Cachexia Sarcopenia Muscle. 2019;10:903–918.[4]Younce CW, et al. Am J Physiol - Cell Physiol. 2013;304:508–518.[5]Kamiya M, et al. Rheumatology (Oxford). 2020; 59:224-232AcknowledgementsWe thank Katsuko Yamasaki for the histological analysis.Disclosure of InterestsMari Kamiya Speakers bureau: Pfizer and Ono Pharmaceutical, Grant/research support from: GlaxoSmithKline, Fumitaka Mizoguchi Speakers bureau: AbbVie, Asahi Kasei Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eizai, Eli Lilly and Company, Glaxo Smith Kline, Ono Pharmaceutical, and Pfizer., Consultant of: Asahi Kasei Pharma and ImmunoForge., Grant/research support from: AbbVie, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Company, Eisai, Eli Lilly and Company, ImmunoForge, Japan Blood Products Organization, Mitsubishi Tanabe Pharma, Novartis Pharma Japan, Ono Pharmaceutical, Otsuka Pharmaceutical Factory, Pfizer, Sanofi, Takeda Pharmaceutical Company and Teijin, Hirokazu Sasaki: None declared, Natsuka Umezawa: None declared, Shinsuke Yasuda Speakers bureau: Abbvie, Asahi Kasei Pharma, Chugai Pharmaceutical, Eisai, Eli Lilly, GlaxoSmithKline, Mitsubishi Tanabe Pharma, Ono pharmaceutical, and Pfizer., Consultant of: ImmunoForge, Grant/research support from: Abbvie, Asahi Kasei Pharma, Chugai Pharmaceutical, CSL Behring, Eisai, ImmunoForge, Mitsubishi Tanabe Pharma, and Ono pharmaceutical.

© 2017 Japanese Society of Phycology The discovery of a plethora of cryptic species in many algal groups has led to speculation as to the causes of this observation and has affected taxonomy, with reluctance to give names to species that look identical. While this is defensible for monophyletic cryptic species complexes, both our understanding of similar morphologies (crypsis) and nomenclature is challenged when we encounter non-monophyletic ‘cryptic’ species. Bostrychia simpliciuscula is a wide-ranging species in which multiple cryptic species are known. Our increased sampling shows that this species consists of four lineages that do not form a clade, but lineages are sister to species with different morphologies. Careful morphological examination shows that characters, especially branched monosiphonous laterals and rhizoid morphology in haptera, are able to distinguish these four lineages into two groups, that are still not monophyletic. The similar morphologies in these lineages could be due to convergence, but not developmental constraints or lack of time to diverge morphologically; or possibly maintenance of a generalized body plan. These lineages appear to have specific biogeographic patterns and these will be used to propose a new taxonomy. B. simpliciuscula is now confined to the tropics. Another of these lineages matches a previously described species, B. tenuissima, that was synonymized with B. simpliciuscula and is from cold temperate Australasia, and is resurrected. Another lineage is found in Japan in which a previous name is also available, B. hamana-tokidae; the last lineage is found in central New South Wales, morphologically it resembles B. tenuissima, with which it overlaps in distribution around Sydney, and is named as a new species, B. kingii sp. nov.

Background:In 20-30% of rheumatoid arthritis (RA) patients, the first biologic disease-modifying antirheumatic drugs (bDMARDs) (generally tumour necrosis factor inhibitors (TNFis)) is ineffective, and among the patients who do respond to therapy, 20% is faced with secondary ineffectiveness within the first 2 years of treatment [1]. In practice, when refractory RA is present, of which the definition implies previous use of at least two bDMARDs (generally TNFis), the next treatment choice often made is a bDMARD of another class (non-TNFis) [2]. On the other hand, patients who are inadequately responding to bDMARDs need new treatment options because subsequent bDMARD treatment reduces their response [3]. Janus Kinase inhibitors (JAKis) are the first targeted synthetic DMARDs (tsDMARD) licensed for the treatment of RA with comparable efficacy to bDMARDs. Unlike the single cytokine targeting approach of bDMARDs, JAKis are specifically designed to inhibit intracellular signalling molecules common to the receptors of multiple inflammatory cytokines implicated in RA pathogenesis.Objectives:Difficult-to-treat (D2T) RA is defined as refractory to two or more b/ts DMARDs with different mechanisms of action, with active and progressive disease, as published by Eular(4). We evaluated real world efficacy of approved JAKis and factors that may help to continue them in patients with D2T RA.Methods:Patients who had inadequate response to two or more bDMARDs (including both TNFis and non-TNFis) at our hospital by December 2019 were defined as D2T RA, and patients who switched to JAKis were retrospectively investigated. The drug retention rate was determined by Kaplan-Meier method, and the difference was tested by Logrank test. Multiple regression analysis was used as the statistical method to predict continuation of JAKis for more than 1 year, with patient background (age, gender, during the disease, number of bDMARDs used, with or without methotrexate and/or glucocorticoids, disease activity score assessing 28 joints using erythrocyte sedimentation rate’ presence of rheumatoid factor/anti-CCP antibody, matrix metalloproteinase 3 value, Health Assessment Questionnaire disability index) at the time of initiation as an explanatory variable.Results:A total of 915 bDMARDs had been administered to 394 RA patients. The retention rate of bDMARDs and the number of bDMARDs used were 89.3% and 1.48 bDMARDs at 1 year, 67.7% and 2.27 bDMARDs at 5 years, and 52.0% and 3.15 bDMARDs at 10 years, respectively. The retention rate of JAKis at 1 year was 60.2% in 65 patients with tofacitinib (TOF) and 67.2% in 70 patients with baricitinib (BAR) (P=0.38). Among them, the drug retention rate in D2T RA patients was 50.8% in 38 TOF patients and 66.3% in 35 BAR patients with no significant difference (P=0.30). There were no patient background factors that significantly predicted continuation at 1 year for any JAKis.Conclusion:Despite the limited number of patients and the retrospective nature of the study, TOF and BAR were shown to be effective options for D2T RA, regardless of patient background such as disease activity or number of bDMARDs used. Other JAKis and switches between JAKis need to be investigated in the future.References:[1]Schaeverbeke T, Truchetet ME, Kostine M et al. Immunogenicity of biologic agents in rheumatoid arthritis patients: lessons for clinical practice. Rheumatology 2016;55:210_20.[2]Smolen JS, Landewe R, Bijlsma J et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;76:960_77.[3]Rendas-Baum R, Wallenstein GV, Koncz T et al. Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors. Arthritis Res Ther 2011;13:R25.[4]Nagy G, et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2021;80:31–35. doi:10.1136/annrheumdis-2020-217344.Disclosure of Interests:None declared

Background:Polymyositis (PM) is a chronic inflammatory myopathy that impairs muscle functions. While the treatment with glucocorticoids (GC) has been the cornerstone of the treatment for PM to suppress immune-mediated muscle injury, some patients suffer from glucocorticoid-induced myopathy during the treatment, which further deteriorates the muscle weakness. It has been reported that significant disability and muscle weakness persist in a quarter of the patients even after successful treatment with the immunosuppressive therapy1. Ultimately, new therapeutic strategies to preserve and recover muscle strength as well as to suppress immune-mediated muscle injury are needed. Glucagon-like peptide-1 (GLP-1) is a peptide hormone with a variety of functions. Although GLP-1 receptor (GLP-1R) agonists have been developed as an anti-diabetic therapy to promote insulin secretion, emerging data suggest that they have pleiotropic actions including anti-inflammatory effects and suppression of muscle wasting2. We presumed that GLP-1R agonists have beneficial effect on PM to preserve and recover muscle strength.Objectives:To examine the effect of a GLP-1R agonist on C protein-induced myositis (CIM), a murine model of polymyositis3, in monotherapy or in combination with prednisolone (PSL).Methods:Muscle specimens of PM patients and CIM were examined with immunohistological staining for the expression of GLP-1R. The therapeutic effect of PF1801 (ImmunoForge), a GLP-1R agonist (5 mg/kg body weight (BW)/day), in monotherapy or in combination with PSL (20 mg/kg BW/day) on CIM was examined for grip strength, muscle weight and histological muscle inflammation.Results:GLP-1R was expressed on the plasma membrane of muscle cells of PM patients and CIM. The expression levels were high in the area where inflammatory infiltrates were observed. The treatment of CIM with PF1801 in monotherapy or in combination with PSL suppressed the CIM-induced decrease in grip strength on day 14. The combination therapy with PF1801 and PSL ameliorated the CIM-induced muscle weight loss in quadriceps, while the monotherapy with PF1801 or PSL did not. The histological analysis of muscle specimens on day 14 of CIM revealed that the muscle inflammation was suppressed by the treatments with PF1801, PSL, or the combination of PF1801 and PSL. None of the mice in the combination therapy group developed histologically evident myositis, while the myositis was observed in 90%, 40% and 40 % of the mice in vehicle treated group, PF1801 treated group, and PSL treated group, respectively. The necrotic area of the muscle in CIM was also reduced in the mice treated with PF1801, PSL, or the combination of PSL and PF1801. The CIM-induced increase in spleen weight was suppressed by PF1801, PSL, or the combination of PSL and PF1801. The additive effect of PSL and PF1801 on the suppression of CIM-induced increase in spleen weight was observed.Conclusion:PF1801 ameliorated CIM-induced muscle weakness and muscle inflammation in CIM. The combination therapy with PF1801 and PSL ameliorated CIM-induced muscle weight loss. PF1801 could be a novel therapy to recover muscle weakness and to suppress muscle inflammation in PM.References:[1]Bronner IM, et al.Ann Rheum Dis.2006;65:1456–61.[2]Hong Y, et al.J Cachexia Sarcopenia Muscle. 2019;10:903-18.[3]Sugihara T, et al.Arthritis Rheum. 2007;56:1304-14.Disclosure of Interests:Mari Kamiya: None declared, Seon Uk Kim: None declared, Jeong Yeon Kim: None declared, Yeong Wook Song: None declared, Eun Young Lee: None declared, Fumitaka Mizoguchi Grant/research support from: ImmunoForge, Consultant of: ImmunoForge

Background:In clinical practice, when refractory rheumatoid arthritis (RA) is present, of which the definition implies previous use of at least two biologic disease-modifying antirheumatic drugs (bDMARDs) (generally tumour necrosis factor inhibitors (TNFis)), the next treatment choice often made is a bDMARD of another class (non-TNFis) [1]. However, patients who are inadequately responding to bDMARDs need new treatment options because subsequent bDMARDs treatment reduces their response [2]. Janus Kinase inhibitors (JAKis) are the first targeted synthetic DMARDs (tsDMARD) licensed for the treatment of RA with comparable efficacy to bDMARDs. Unlike the single cytokine targeting approach of bDMARDs, JAKis are specifically designed to inhibit intracellular signalling molecules common to the receptors of multiple inflammatory cytokines implicated in RA pathogenesis. The choice of therapeutic agents for refractory RA is increasing, and its efficacy is expected. On the other hand, it is also true that some patients discontinued JAKis at a rate that cannot be overlooked because of insufficient efficacy. Difficult-to-treat (D2T) RA is defined as refractory to two or more b/ts DMARDs with different mechanisms of action, with active and progressive disease, as published by Eular(3)Objectives:To evaluate real world efficacy of approved JAKis switching in patients with D2T RA who were unable to control their disease activity due to insufficient efficacy despite the sequential use of multiple bDMARDs and JAKis, focusing on the drug retention rate.Methods:In our hospital, RA was diagnosed according to the 1987 or 2010 classification criteria, and when two or more bDMARDs (including both TNFis and non-TNFis) were inadequately effective, it was defined as D2T RA. We retrospectively investigated patients who switched to JAKis for D2T RA. The drug retention rate was investigated by the Kaplan-Meier method, and the difference was tested by the Logrank test.Results:The 1-year retention rate of JAKis for D2T RA was 50.8% in TOF 38 cases [28 women, age average 70.2 years, disease duration average 12.4 years, past bDMARDs use average 3.5 drugs, MTX combination 9 cases, DAS28 ESR average 4.11] and 66.3% in BAR 35 cases [26 cases, 73.0 years old, 14.8 years, 4.17 agents, 9 cases, 3.68], and there was no significant difference (P = 0.30). Among them, there were 17 cases [11 cases, 70.6 years old, 13.5 years, 4.18 drugs, 2 cases, 3.65] of switching between JAKis, all of which were switching from TOF to BAR. The 1-year retention rate was 45.8% [reason for discontinuation: insufficient effect in 3 cases, adverse events in 6 cases], which was not significantly different but tended to be lower than 72.7% [reason for discontinuation: insufficient effect in 1 case, adverse event in 2 cases, patient’s convenience in 1 case] in 16 patients [13 cases, 76.3 years old, 17.1 years, 3.19 drugs, 7 cases, 3.69] who received BAR as the first JAKi for D2T RA patients (P = 0.089).Conclusion:Although the number of cases is small in the retrospective survey, it is suggested that the retention rate of BAR switched to D2T RA may be slightly lower in patients with a history of TOF discontinuation due to insufficient efficacy than in JAKi naive patients. It is expected that the number of new JAKi usage cases will increase in the future, and it is necessary to consider switching between other JAKis in addition to switching from BAR to TOF.References:[1]Smolen JS, Landewe R, Bijlsma J et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;76:960_77.[2]Rendas-Baum R, Wallenstein GV, Koncz T et al. Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors. Arthritis Res Ther 2011;13:R25.[3]Nagy G, et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2021;80:31–35. doi:10.1136/annrheumdis-2020-217344.Disclosure of Interests:None declared

Background:Disease-modifying antirheumatic drugs (DMARDs) have been the main agents for treating rheumatoid arthritis (RA) unless there are serious clinical restrictions or contraindications such as comorbidities. With inefficacy of conventional synthetic DMARDs (e.g., methotrexate), biological DMARDs (bDMARDs) are now available to suppress progression of joint destruction. However, bDMARDs cannot control disease activity in some patients, so JAK inhibitors targeting different cytokines are expected to be beneficial.Objectives:This study investigated factors associated with the efficacy and continuation of JAK inhibitor therapy in patients with refractory RA for whom disease activity was not adequately controlled even with multiple sequentially administered bDMARDs with different targets.Methods:We obtained the number of bDMARDs used and the various reasons for discontinuing therapy in our hospital from January 2005 to December 2019. Kaplan–Meier analysis was used to obtain the therapy continuation rate, and the log-rank test was used to examine the difference in therapy continuation rate. Refractory RA was defined as RA with inefficacy with 3 or more bDMARDs with different targets (1 or more tumor necrosis factor inhibitor, a selective costimulation modulator abatacept, and an interleukin 6 receptor inhibitor tocilizumab). We then examined patients with refractory RA who had received tofacitinib (TOF) or baricitinib (BAR) therapy after discontinuation of a series of bDMARDs due to unsatisfactory response. Various statistical tests were performed to identify predictors of ≥ 6-month continuation of JAK inhibitor therapy that achieves low disease activity without increases in prednisolone (PSL) use. Explanatory variables included characteristics of patients at initiation of TOF or BAR therapy: age, sex, disease duration, number of bDMARDs previously used, concomitant methotrexate dose, concomitant PSL dose, DAS28-ESR value, presence of rheumatoid factor or anti-CCP antibodies, and MMP-3 level.Results:A cumulative number of 782 bDMARDs were administered to 362 RA patients by December 2019. The most common reason for discontinuation was inefficacy (51.8%), followed by adverse events including deaths (30.1%), patients’ circumstances such as hospital transfer (9.2%), switch to biosimilars (5.2%), and remission (3.7%). The bDMARDs continuation rate and the number of bDMARDs used were 69.6% and 2.17 for 5 years and 53% and 2.83 for 10 years, respectively, if the switch was considered to be continuous due to insufficient effect. The 6-month continuation rates were not significantly different between TOF and BAR (60 patients [62.3%] vs. 39 patients [81.3%], respectively; P = 0.147). In patients with refractory RA, continuation rates were not significantly different between TOF and BAR (19 patients [42.1%] vs. 11 patients [54.5%], respectively; P = 0.86). Only TOF-treated patients, not BAR-treated patients, showed significant differences in disease duration (226.1 months in the continued group vs. 111.8 months in the discontinued group; P = 0.035) and concomitant PSL dose (0.71 mg vs. 4.0 mg, respectively, P = 0.045).Conclusion:There are not a few patients with refractory rheumatoid arthritis. These findings, albeit retrospective, suggest that low concomitant PSL dose and long disease duration at the time of TOF therapy initiation were factors for TOF continuation. Therapy continuation rate was decreased in patients with refractory RA, and further study on switching therapy between different JAK inhibitors is anticipated.References:[1]Souto A, Maneiro JR & Gomez-Reino JJ. Rate of diccontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care database. Rheumatology (Oxford), 55, 523-534, 2016Disclosure of Interests:None declared

Background With the advent of biologic agents, it has become possible to prevent progression of symptoms and joint destruction in rheumatoid arthritis (RA). However, less than half of patients achieve remission. The patient subgroup that benefits from a specific biologic agent remains unclear. Etanercept has been repeatedly reported to have a high long-term continuation rate, and can also be tapered once the therapeutic goal has been achieved. Identification of a patient subgroup that benefits from long-term use of etanercept would not only benefit the patients but would also reduce healthcare costs. Objectives The purpose of this study was to evaluate the characteristics of patients who benefited from long-term use of etanercept and patients who discontinued the drug due to loss of efficacy using our hospital records, and evaluated factors that may predict the difference in efficacy. Methods We compared RA patients who continued etanercept treatment for at least 3 years, without interruption for 3 months or longer for reasons other than remission, including patients who switched from other biologics (continuation group), and patients who discontinued treatment within 3 years of treatment initiation due to loss of efficacy (discontinuation group). All patients were treated at our hospital before October 31, 2017. Multiple regression analysis was used to determine factors that may predict long-term etanercept efficacy, using 10 patient background characteristics, including age at initiation of etanercept and DAS28ESR, as explanatory variables. Results At the time of evaluation, the 3 year continuation rate of etanercept by the Kaplan-Meier method was 49.7%. Reasons for discontinuation included adverse events (33.3%), loss of efficacy (50%), and patient preference (17.3%). The continuation group comprised 87 cases, including 5 cases where etanercept was discontinued due to remission. Initial dose was 50 mg, and relative dose intensity was 0.78 (95% confidence interval 0.66–0.89). The discontinuation group included 51 cases. Regarding patient characteristics at the time of etanercept initiation, age (continuation group 60.1 vs. discontinuation group 66.7, p=0.019), number of previously used biologics (continuation group 1.24 vs. discontinuation group 1.45, p=0.016), and disease duration (continuation group 110.2 months vs. discontinuation group 74.2 months, p=0.035) were statistically significant with α=0.05, suggesting potential utility in predicting long-term response. In contrast, combination therapy with methotrexate (p=0.259), rheumatoid factor, or anti-cyclic citrullinated peptide antibody positivity (p=0.086), and DAS28ESR (p=0.056) were not statistically significant. Conclusions Although this was a retrospective study, the results showed that young RA patients who have previously used few biologics, with long disease duration, may be more likely to benefit long-term from etanercept without loss of efficacy. Disclosure of Interest None declared

Background The emergence of biologics has led to innovation in the treatment of rheumatoid arthritis (RA). In the clinical setting, biologics are administered with careful consideration of complications and medical history in accordance with the treat-to-target recommendations. However, the progression of joint damage, the costs incurred before finding an effective biologic are serious concerns. It is therefore desirable to use biologics with long-term efficacy and less financial burden from the early stage. Objectives Participants were RA patients treated with one of three biologics having different mechanisms of action who achieved therapy targets with long-term treatment efficacy and consequently achieved either reduction or withdrawal of therapy. Patients9 background characteristics and long-term treatment patterns were evaluated. Methods Between November 2004 and October 2016, 196, 57, and 85 RA patients were treated with etanercept (ETN), tocilizumab (TCZ), and abatacept (ABT), respectively, in first- or second-line therapy. These patients were divided into the continuation group, who underwent therapy with the same agent for ≥3 years without disease flare (DAS28-ESR >3.2) persisting 3 months, and the discontinuation group, who experienced primary failure resulting in discontinuation of the therapy within 3 months. Student9s t test or Mann-Whitney9s U test were used to compare patients9 background characteristics between the two groups for each biologic. Further, log-rank test and Steel-Dwass test, respectively, were used to compare therapy continuation rates and reasons for discontinuation among the three biologics. Finally, relative dose intensity (RDI) was calculated to evaluate the treatment patterns of the individual biologics. Results The Kaplan-Meier method showed that the 3-year continuation rates of therapy with ETN, TCZ, and ABT were 54.2%, 23.8%, and 35.8%, respectively: the continuation rate of ETN was significantly higher than that of the other two agents. The numbers of patients treated with ETN, TCZ, and ABT were respectively 46, 9, and 14 in the continuation group and 16, 12, and 11 in the discontinuation group. The proportion of patients treated with ETN plus concomitant MTX was significantly higher in the continuation group than in the discontinuation group (P=0.0057). No significant differences were found in patients9 background characteristics (disease duration, rheumatoid or anti-cyclic citrullinated peptide positivity, number of biologics previously used, and DAS28-ESR). Mean RDI values (median value, 95% confidence interval) over a 3-year period were as follows: 0.95 (0.92, 0.83–1.06) for 25 mg/week ETN therapy; 0.78 (0.90, 0.66–0.89) for 50 mg/week ETN therapy; 0.84 (0.84, 0.76–0.89) for TCZ therapy; and 0.87 (0.94, 0.79–0.95) for ABT therapy. The cumulative costs for 3 years of the respective treatments were 19,700, 32,200, 27,300, and 39,000 euros (1 euro =115 Japanese yen). After targets were reached, the dose of ETN was maintained at 25 mg/week or reduced from 50 mg/week, while the TCZ and ABT therapies were continued over the long term with a longer dosing interval. Conclusions Treatment with ETN plus concomitant MTX showed high continuation rates, and long-term achievement of therapy targets was maintained at a lower dosage (and thus, lower costs). It is beneficial to choose this method over non-TNF inhibitors. Disclosure of Interest None declared

Summary Objective Inconsistent results have been found in prior studies investigating the accuracy of self‐reported waist circumference, and no study has investigated the validity of self‐reported waist circumference among Japanese individuals. This study used the diagnostic standard of metabolic syndrome to assess the accuracy of individual's self‐reported height, weight and waist circumference in a Japanese sample. Methods Study participants included 7,443 Japanese men and women aged 35–79 years. They participated in a cohort study's baseline survey between 2007 and 2011. Participants' height, weight and waist circumference were measured, and their body mass index was calculated. Self‐reported values were collected through a questionnaire before the examination. Results Strong correlations between measured and self‐reported values for height, weight and body mass index were detected. The correlation was lowest for waist circumference (men, 0.87; women, 0.73). Men significantly overestimated their waist circumference (mean difference, 0.8 cm), whereas women significantly underestimated theirs (mean difference, 5.1 cm). The sensitivity of self‐reported waist circumference using the cut‐off value of metabolic syndrome was 0.83 for men and 0.57 for women. Conclusions Due to systematic and random errors, the accuracy of self‐reported waist circumference was low. Therefore, waist circumference should be measured without relying on self‐reported values, particularly in the case of women.

Background Long noncoding RNAs (lncRNAs) have recently been known to play various important roles in maintaining molecular regulations. Significant amounts of lncRNAs HOTTIP, PVT1 and H19 are well known to be expressed in pancreatic cancer cells, however their association with efficacy of adjuvant chemotherapy for pancreatic cancer have not been fully investigated. The aim of this study was to evaluate expression of HOTTIP, PVT1 and H19 in the pancreatic cancer cells, and to clarify the predictive roles of those lncRNAs in pancreatic cancer patients who received adjuvant chemotherapy by S-1, an oral fluoropyrimidine or gemcitabine (GEM) after curative resection. Methods Pancreatic cancer patients who underwent curative resection followed by adjuvant chemotherapy by S-1 or GEM since 2005 to 2017 at Kanagawa Cancer Centre were enrolled in this study. In situ hybridization (RNA scope®) to detect each three lncRNAs was performed using tissue microarrays prepared from formalin-fixed and paraffin-embedded tissues of resected specimens. The relations between the expression of HOTTIP, PVT1 and H19 and clinicopathological characteristics were statistically analyzed. Results We analyzed 204 eligible pancreatic cancer patients. 114 patients received adjuvant chemotherapy by S-1, and 90 patients by GEM. The patients with higher expression of H19 were significantly associated with shorter relapse free survival (RFS) regardless of adjuvant chemotherapy regimens (p Conclusions The expression levels of PVT1 and HOTTIP in pancreatic cancer cells were associated with the efficacy of adjuvant chemotherapy for pancreatic cancer in the present study. The higher expression of H19 may serve as a significant predictive/prognostic marker for patients who received adjuvant chemotherapy by S-1 or GEM after curative resection. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background and Purpose L-DOPA is generally considered to alleviate the symptoms of Parkinson's disease by its conversion to dopamine. We have proposed that DOPA is itself a neurotransmitter in the CNS. However, specific receptors for DOPA have not been identified. Recently, the gene product of ocular albinism 1 (OA1) was found to exhibit DOPA-binding activity. Here, we have investigated whether OA1 is a functional receptor of DOPA in the nucleus tractus solitarii (NTS). Experimental Approach We examined immunohistochemical expression of OA1 in the NTS, and the effects of DOPA microinjected into the depressor sites of NTS on blood pressure and heart rate in anaesthetized rats, with or without prior knock-down of OA1 in the NTS, using shRNA against OA1. Key Results Using a specific OA1 antibody, OA1-positive cells and nerve fibres were found in the depressor sites of the NTS. OA1 expression in the NTS was markedly suppressed by microinjection into the NTS of adenovirus vectors carrying the relevant shRNA sequences against OA1. In animals treated with OA1 shRNA, depressor and bradycardic responses to DOPA, but not those to glutamate, microinjected into the NTS were blocked. Bilateral injections into the NTS of DOPA cyclohexyl ester, a competitive antagonist against OA1, suppressed phenylephrine-induced bradycardic responses without affecting blood pressure responses. Conclusion and Implications OA1 acted as a functional receptor for DOPA in the NTS, mediating depressor and bradycardic responses. Our results add to the evidence for a central neurotransmitter role for DOPA, without conversion to dopamine.

To evaluate the high-resolution computed tomography (CT) findings of primary lung cancer with cavitation and compare the findings in adenocarcinoma and squamous cell carcinoma.The high-resolution CT findings of tumours with cavitation were retrospectively evaluated in 60 patients. Forty-seven of the lesions were diagnosed as adenocarcinomas; 13 were diagnosed as squamous cell carcinomas. The diameters of the tumour and cavity, the maximum thickness of the cavity wall, shape of the cavity wall, the number of cavities, and the presence of ground-glass opacity, bronchial obstruction, intratumoural bronchiectasis, emphysema, and honeycombing were evaluated. The mechanisms of cavity formation were examined according to the pathological features.The maximum thickness of the cavity wall was significantly greater in squamous cell carcinomas than in adenocarcinomas (p=0.002). Ground-glass opacity and intratumoural bronchiectasis were significantly more common in adenocarcinomas than in squamous cell carcinomas (p0.001 and p=0.040, respectively). Regarding the pathological findings, intratumoural bronchiectasis with or without alveolar wall destruction contributed to a significant difference between adenocarcinoma and squamous cell carcinoma (p0.001; odds ratio [OR], 20.35; 95% confidence interval [CI], 3.87-107.10).The cavity wall tends to be thicker in squamous cell carcinomas than in adenocarcinomas. The presence of ground-glass opacity and intratumoural bronchiectasis is strongly suggestive of adenocarcinoma.

Lithium as an essential element for human life is still a subject of controversy. However, it is accepted that it does have profound neurological effects and is a valuable treatment for bipolar disease. Generally, it occurs in barely trace amounts in groundwater with few major exceptions. One of these is the Northern area of Chile where all potable water and many of the food stuffs contain high levels of lithium; between 100 and 10,000 times higher than most rivers in North America. Inevitably, the local population has been exposed to these levels in their drinking water for as long as the region has been populated. The present report details lithium levels in all the surface water sources of Northern Chile with comparison to that elsewhere. The implications for the local population are discussed and their situation compared to those exposed to other sources of lithium pollution.

The relationship between shear-force value and collagen architecture of connective tissue of the longissimus thoracis (LT) muscle of Japanese Black (n = 10) and Brown (Kumamoto) (n = 5) steers (body weight: 688.4 +/- 8.6 kg as average and standard error) was investigated. There were negative correlations between the shear-force value and lipid content (n = 15, R(2)= 0.3709, P < 0.01) and protein content and lipid content (n = 15, R(2)= 0.6748, P < 0.01). Shear-force value and collagen content (n = 15, R(2)= 0.4344, P < 0.01) were positively correlated. In scanning electron microscopic photographs of the macerated preparation, the perimysium of the high-lipid LT muscle was broken down compared with the low-lipid LT muscle. The endomysium in all LT muscle fibers showed similar architecture. The fine surface cover of reticular collagen fibers around an adipocyte was observed in the high-lipid LT muscle perimysium. These results suggested that the shear-force value of the LT muscle was related to change in collagen architecture and of the perimysium in particular.

The behaviour of Pu and other actinides in some characteristic processes of the NEXT process, i.e. the crystallization process and the U–Pu–Np co-recovery process, was investigated with referring to the experimental results obtained in our experimental facility, CPF. In the crystallization process, the existence of Pu(VI) in the dissolver solution brought the co-crystallization of Pu(VI) with U, and low DFPu. Such co-crystallization could be prevented by adjusting the Pu valence to Pu(IV). In the crystallization with the dissolver solution containing Pu(IV), meanwhile, DFCs showed significant low values, which might be caused by the formation and crystallization of some kinds of Cs compounds with Pu(IV). In the U–Pu–Np co-recovery process which had high [HNO3] feed solution obtained from the crystallization process, it was confirmed experimentally that almost all the Np could be extracted with U and Pu in the extraction section. Some considerable parameters, e.g. temperature, acidity of stripping solution, were pointed out for preventing the leakage of U and Pu to the solvent and for avoiding the Pu polymer formation in the stripping section using only diluted HNO3 as the stripping solution. Under the appropriate stripping condition taking account of these parameters, the calculation and experimental results showed that these elements could be stripped efficiently.

BackgroundThe hypothesis that fibre width is a major determinant of mesothelioma induction has been examined by comparative studies of two crocidolites from different sources. Fine fibres fromCapesouthAfricaand the thicker fibre found and used similarly inBolivia. It is well established that ‘thin’ fibre crocidolite fromCapeSouth Africais extremely mesotheliomagenic. Bolivian crocidolite has a much wider width distribution and relatively little mesothelioma inducing potential. MethodsWe analysed the mesothelioma demography inBoliviawhere local crocidolite has been used for decades This was compared with the mesothelioma demography in theItalianCityof Casale Monteferrato whereCapecrocidolite was processed for many decades in the Eternit Asbestos Cement plant producing numerous cases of mesothelioma.We also conducted a limited downwind study from the fiberizing part of the historical operating plant where products containing Bolivian crocidolite were made for sale and use inCochabamba. ResultsThe demographic study confirmed the absence of a significant mesothelioma excess inBolivia.Despite the extremely high fibre concentrations measured in the plant, no significant fibre levels were detected 100 meters away. Conclusion These preliminary findings undermine claims such as those made at Casale that crocidolite fibre can drift up to 15 km and remain airborne in quantities sufficient to contribute significantly to mesothelioma induction. We propose the difference in thickness and the attendant reduction in the percentage ofStantonfibres provides an explanation for the difference in mesothelioma patterns found in each city.

Proper nutritional management during the dry period is required to prevent metabolic disorders during the time of parturition and for potential increase milk yield during early lactation, especially under the heat of summer. The effect of prepartum diets on partitioning of nitrogen (N), calcium (Ca), phosphorus (P), magnesium (Mg) and potassium (K) during dry period and early lactation in summer was investigated. Nine cows were assigned to two groups and fed either control (group C: four cows) or high concentrate (group H: five cows) diets to meet 110% of their requirements before parturition. The proportion of concentrate in control diet was 35%, and that in the high concentrate diet was 45%. After parturition, all cows were fed the same diets ad libitum during lactation. Balance trials were conducted at 9, 8 and 7 days before parturition and at 12, 13 and 14 days after parturition. Before parturition, dry matter intake (DMI), DM and NFE digestibility in group C tended to be lower than those in group H. The retention of N (p

Heat stress causes oxidative stress, which decreases plasma levels of vitamin C, an antioxidative vitamin in pigs and poultry. We investigated the plasma vitamin C concentration in lactating cows exposed to a hot environment temperature. In the first experiment, plasma vitamin C concentrations of 8 lactating cows were measured in summer and autumn. The concentration was found to be significantly lower in summer. The second experiment was performed using 4 lactating cows in a crossover design. The ambient temperature was set at 18 °C in the control treatment and at 28 °C in the heat-stressing treatment. Milk yields and feed intake tended to be lower in the stressing than control treatment. Rectal temperature and respiration rate were significantly ( P P

Extraction of U(VI), TUE, and REE from acid process solution with solutions of mono-and bidentate neutral organophosphorus compounds (NOPCs), phenyloctyl(N,N-diisobutylcarbamoylmethyl)phosphine oxide (CMPO), 2-ethylhexyl (N,N-dibutylcarbamoylmethyl)phenylphosphinate (CMPP), and unsymmetrical phosphine oxide (UPO) was studied as influenced by γ-irradiation at different absorbed dose rates. In all cases extraction of the target radionuclides decreased with increasing absorbed dose of γ-radiation. The resistance of the NOPCs to radiolysis decreases as CMPO>CMPP>UPO owing to the difference in the structures of their molecules.

The volatility of tellurium and some other fission products was radiochemically studied in heated nitric acid solutions. As tracers 121Te produced by bremsstrahlung of an electron LINAC and other fission products produced by neutron irradiation were used. The distribution rate of radionuclides between the mother solution and the condensate, was considered as volatility, and was determined. The volatility of tellurium was found to be small and close to that of cesium. Volatilization tests were also performed in the presence of large amounts of solutes.

The solvus temperatures of the Laves phase were investigated in heat resistant 10Cr ferritic steels containing 2.3-4.7 mass% (Mo+W) and 0-1.7 mass% Re. The measured solvus data was approximately represented as a solvus curve in the pseudo-binary system of Fe-W (+Mo). The solvus temperatures increased with increasing content of Mo+W in the steels, for example, 1020 K for 2.3 mass% (Mo+W) steel, 1130 K for 3.7 mass% (Mo+W) and 1145 K for 4.7 mass% (Mo+W) steel. It was suggested from the measured solvus curve that the Laves phase precipitated at 923 K granularly in a 2 mass% W steel, but finely in a 4.5 mass% W steel. On the other hand, the solvus temperature did not change with the Re addition up to 1.7 mass%.

Summary Background A new sensitive method for the detection of skin cancer micrometastases in lymph nodes is based on amplification of keratin 19 (K19) mRNA by reverse transcriptase–polymerase chain reaction (RT–PCR). Objectives To compare results of RT–PCR with those of histological examination in terms of the detection rate of skin cancer micrometastases. Methods Twenty-six lymph nodes obtained from 13 patients with squamous cell carcinoma (SCC), eccrine porocarcinoma and Paget's disease were investigated by histological examination (haematoxylin and eosin sections) and RT–PCR. RT–PCR was performed on extracted RNA by using K19 primer pairs. RT–PCR products were visualized by ethidium bromide staining and confirmed by non-radioactive hybridization with K19-specific probes. Results All of 10 histologically positive lymph nodes yielded the expected 460-bp band. Of the 16 histologically negative lymph nodes, one (6%) was found by RT–PCR to express K19 mRNA, indicating the presence of micrometastases which could not be detected by histological examination. A serial dilution study using RNA extracted from SCC cells mixed with RNA extracted from normal lymph node cells showed a detection sensitivity of K19 RT–PCR of 10−5 µg cancer cell RNA in 1 µg lymph node RNA. Nested RT–PCR showed a detection sensitivity of one tumour cell in 106 lymphocytes. Conclusions These results demonstrate the usefulness of K19 RT–PCR for the detection of skin cancer micrometastases in lymph nodes.

¶Background. We report a rare case of germinoma mainly located in the septum pellucidum. Case description. A 19-year-old man presented with germinoma located in the septum pellucidum manifesting as amnesia and right hemiparesis. Magnetic resonance imaging demonstrated a heterogeneously enhanced mass in the septum pellucidum and abnormal T2-weighted signals in the left basal ganglia. An anterior transcallosal approach was performed to remove the mass in the septum pellucidum. The histological diagnosis was germinoma. Radiotherapy and chemotherapy were given. He was discharged with slight amnesia and right hemipareis. Interpretation. Intracranial germinoma can arise from the septum pellucidum.

To sophisticate the nuclear fuel recycling processes, the transfer percentages for Pd, Mo, Te, and Sb should be determined. Each element solution containing NaNO3 or HNO3 was fed consistently into the thin film evaporator regulated in vac and at 50 °C. The analyte percentages in the inside of the lid, in the condenser, and in the distillate were 10-1%/m2, 10-3%/m2, and 10-3% (DF = 105), respectively. The Mo percentage in the condenser was lower by a factor of 10 than those of other elements investigated. The NO3- percentages were nearly constant despite increasing HNO3 concentrations, however, the ratios decreased with increasing NaNO3 concentrations.

Organic superconductors have been usually obtained by the bandwidth control of antiferromagnetic insulator. In order to find another parameter to control the electronic state, the band filling control has been applied to obtain the carrier-controlled organic conductors. As a result, the systematic band filling control for four kinds of organic conductors has been succeeded. The obtained crystals were (a) 2:1 salts, λ-ET 2 (GaCl 4 1− ) 1− x (CoCl 4 2− ) x [ET=bis(ethylenedithio)tetrathiafulvalene], doping to the antiferromagnetic insulator, (b) 2:1 salts, δ′-ET 2 (GaCl 4 ) 1− x (CoCl 4 ) x , doping to the non-magnetic insulator, (c) 3:1 salts, α-ET 3 (CoCl 4 ) 1− x (GaCl 4 ) x (TCE), doping to the charge ordered salt, and (d) 3:2 salts, β′-ET 3 (CoCl 4 ) 2− x (GaCl 4 ) x , doping to the half-filled band insulator. For both 2:1 salts, (a) and (b), the semiconducting behaviors have transferred to relatively conductive semiconducting ones by doping. The largest change of transport property is observed for (d) β′-phase from semiconducting behavior of parent material to metallic ones [β′-ET 3 (CoCl 4 ) 2− x (GaCl 4 ) x ( x =0.88, 0.66)] down to 140 and 100 K, respectively. These systematic band filling control suggests that the doping to the 1/2-filled band insulator is most effective.

A simple inexpensive analog transmission system is realized using a dual-channel-color LED assembly, a plastic optical fiber, a dual-channel-color sensor assembly, and a crosstalk elimination circuit. The transmission system, covering DC to 10 kHz, has a distortion factor of less than 2% and a crosstalk of less than -40 dB, and is suitable for use in factory communications.

Crocidolite is a fibrous mineral with unusual crystallography in that the fiber width varies according to geographical origin. The fibers from the mining areas of Western Australia and the Cape Province, in South Africa are ‘thin’ compared to those from Bolivian and some other mines. Regardless, the mineral is a well known causative agent for mesothelioma. The literature contains many reports of the disease occurring as a consequence of so called environmental exposures due to what some believe to be ‘low’ dose, ambient exposure. However, closer examination of these exposure conditions generally reveals an unrecognized (or simply ignored) strong domestic (para-occupational) exposure component. Oftentimes, the importance of such domestic exposures is not considered since they too are thought to be too low to contribute to risk. We have, for the first time, applied state of the art measurement methods to evaluate domestic (shake out) conditions created by workers in a historical unregulated crocidolite-cement based operating plant in Bolivia. Our results show that exposures can reach levels more usually associated with historic occupational exposures. The reason for studying the exposures in such a plant is that epidemiological studies have shown that ‘thin’ crocidolite fibers are associated with a high mesothelioma risk while exposure to the ‘thick’ Bolivian fibers are associated with a much lessened mesothelioma risk.

In order to search and clarify the mechanism of organic superconductors, it is of importance to control the electronic state systematically and elucidate the electronic phase diagram. In organic conductors, bandwidth control is usually applied to change the electronic states from insulating, superconducting, to metallic state. By the chemical bandwidth control with introducing Se atoms, the antiferromagnetic insulator, λ-ET 2 GaCl 4 , newly prepared, shifts to the semiconductor, λ-(us-BEDT-STF) 2 GaCl 4 , and superconductor, λ-BETS 2 GaCl 4 . It is clarified that λ-type organic superconductor has been obtained by the chemical bandwidth control of the antiferromagnetic insulator. In this paper, our recent successful results of band filling control in organic conductors are also reported.

A new type of analog data transmission system using a plastic fiber is proposed, where a direct intensity modulation scheme has been employed together with a differential amplifier to compensate for the transmission error caused by the optical fiber bending loss. This system was experimentally applied to transmit analog data of dimensions detected by the displacement sensor attached to the robot arm tip to the robot basement through the plastic optical fiber installed in the robot arm body.

In this article, we introduce a fuzzy logic controller to the driving strategy of a hybrid electric vehicle (HEV). The decision making of this fuzzy logic controller is useful to nonlinear and uncertain systems such as electric vehicle applications, and the fuzzy logic controller is immune to various vehicle load and road conditions. To construct the proper rule base of the fuzzy logic controller, the torque-producing, pollutant-emission, and fuel-consumption characteristics of the diesel engine and the hybrid system are clarified through dynamo testing. Then, the driving patterns of the driver and vehicle load on the service course are investigated. These results are also reflected in constructing the rule bases of the proposed fuzzy logic controller. To prove the usefulness of the proposed fuzzy logic controller, actual road tests of the parallel HEV are carried out. Note that the battery maintains its nominal voltage through 20 days of running without extra charging process.

From the aspects of economical competitiveness, proliferation resistance, and minimizing waste problems, PNC has proposed an improved recycle concept for the FBR fuel cycle, termed Advanced Fuel Recycle System. Reprocessing in this system is based on the well-known PUREX flowsheet and features a “single cycle Pu/U co-extraction flowsheet” with lower decontamination factor (DF) than that in the conventional process. This feature is practical because of the FBR's low neutronic sensitivity to impurities. Such a simplified extraction process without purification cycles should substantially reduce not only the number of process components but also the quantities of liquid to be treated in other related processes, so it will lead to the proportional reduction in waste processing, waste itself, and all other related equipments and facilities. This should improve overall economics. One method being examined to further reduce the liquid throughputs and simplify the process is to apply the crystallization technique to dissolver solution. Overall, with this proposed concept, proliferation resistance will be significantly improved because plutonium is always recovered as a mixture with the uranium and DF of the plutonium product is low. Reprocessing and fabrication processes are integrated into one fuel cycle plant in this system further contributing to these improvements.

We have constructed the linkage map with precise genetic analysis of the Syrian hamster, Mesocricetus auratus, according to the restriction landmark genomic scanning (RLGS) spot mapping method. Although only 3.2-6.6% of the total RLGS spots between the two strains, ACN and BIO 14.6, showed genetic variance, 572 loci were found to be polymorphic. Out of 569 RLGS loci and 3 other loci, 531 were mapped with the backcross (ACN x BIO 14.6) F1 x BIO 14.6. The cumulative map was 1111.6 cM, indicating that the spots/loci are located throughout the genome at 1.94 cM intervals on average. Thus, RLGS provides us with a rapid tool to construct the genetic map of any species, even if it has less genetic variation.