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New information and communication technologies (ICTs) are contributing to the advancement and popularization of distance learning, and its use by educational institutions is accelerating. Some characteristics of distance learning are remarkable, such as its quantity, scalability, ability to serve many students at the same time, scope, lower costs, and so on. Some of these characteristics refer to a type of innovation called frugal, which is the ability to "do better with fewer resources for more people", that is, create significantly more value and minimize the use of resources. The objective of this research was to analyze the characteristics of distance learning through the theoretical lens of frugal innovation using the conceptual model of frugal innovation. The characteristics listed in the Rossetto model were researched qualitatively and quantitatively to obtain a solid conclusion, as this model uses a scale to identify and measure frugal innovation. The Rossetto model was developed and tested using the results of five collections of data from three different countries (Brazil, the United States of America, and India), with the entire development and refinement processes being subjected to an exploratory factor analysis (EFA) and a confirmatory factor analysis (CFA). The final validation of the scale was based on data from 1130 companies. The mixed (qualitative and quantitative) methodological procedures were used to analyze the data obtained from the field research. The qualitative analysis consisted of verifying the characteristics of frugal innovation through Rossetto's conceptual model, and exploratory factor analysis was chosen for the quantitative analysis. Ten of the characteristics of the model sought, analyzed in three dimensions, identified, and strongly indicated that ODL can be considered as a frugal innovation, convincing and confirming that ODL has as main characteristics of the FI such as cost reduction, focus on essential functionalities and improved performance in relation to face-to-face teaching and thus, highlighting that the main value created is to do better with fewer resources than traditional teaching for a greater number of students served.

Funding Acknowledgements Type of funding sources: None. Background/Introduction A novel leadless pacemaker enables atrioventricular synchronous pacing. However, there have been still difficulties to obtain high atrioventricular (AV) synchrony due to a mechanical sensing algorithm. We’ve reported a new sensing method for acquiring high AV synchrony regardless of heart rate. Our hypothesis is that this novel sensing method might facilitate better AV synchrony. Purpose The purpose of this study is to investigate the feasibility of our novel sensing method for the patients that ventricular activity completely depends on the ventricular pacing. Methods This study is a retrospective study conducted by 2 centers. From the 1st December, 2021 to the 31th October, 2022, leadless pacemakers with atrioventricular synchronous pacing were implanted to 32 patients in 2 centers. Among the 20 patients with sinus rhythm and complete AV block were analyzed. Two groups were compared in this study. Novel sensing setting was programmed during the hospitalization in Group 1, composed by 9 patients. Auto A3 threshold and auto A3 window end are turned off. An intentionally prolonged A3 window end and a low A3 threshold are programmed in a novel sensing method. Conventional setting (auto A3 threshold, auto A3 window end and auto A4 threshold were turned on) was programmed during the hospitalization in Group 2, composed by 11 patients. Device check was performed at the first outpatient clinic within 3 months after the implantation. Results Overall, 20 patients were analyzed. Baseline characters are described in Table 1. BMI (23.5±0.9 vs 20.4±0.8, p Conclusion Novel sensing method might be a feasible sensing method to obtain higher AV synchrony than conventional algorithm. Further prospective studies will be required.

The majority of people with HIV live in sub-Saharan Africa, where HIV epidemics are generalized. For these epidemics to develop, populations need to be mobile. However, population-level mobility has not yet been studied in the context of the development of generalized HIV epidemics. Here we do so by studying historical migration data from Botswana which has one of the most severe generalized HIV epidemics worldwide; in 2021, HIV prevalence was 21%. The country reported its first AIDS case in 1985 when it began to rapidly urbanize. We hypothesize that, during the development of Botswana’s epidemic, the population was highly mobile and there were substantial urban-to-rural and rural-to-urban migratory flows. We test this hypothesis by conducting a network analysis using a historical time series (1981 to 2011) of micro-census data from Botswana. We found 10% of the population moved their residency annually, complex migration networks connected urban with rural areas, and there were very high rates of rural-to-urban migration. Notably, we also found mining towns were both important in-flow and out-flow migration hubs; consequently, there was a very high turnover of residents in towns. Our results support our hypothesis, and together, provide one explanation for the development of Botswana’s generalized epidemic.

Summary We examined the effectiveness of coordinators’ interventions to prevent secondary fractures in patients with fragility fractures. These coordinator-based interventions improved bone density assessment implementation and treatment rates, and enhanced treatment persistence rates in the early stages following fractures. Introduction This study aimed to determine the efficiency of coordinator-based osteoporosis intervention in fragility fracture patients during a 2-year period. Methods A prospective intervention randomized control study was conducted at seven medical facilities from January 2015 to March 2017. Postmenopausal women and men over 50 years old with fragility fractures were randomly divided into the coordinator intervention (LI; 70 patients) and without intervention (non-LI; 71 patients) groups. The osteoporosis treatment rate, osteoporosis treatment persistence rate, fall rate, fracture incidence rate, and bone density measurement rate 3 months, 6 months, 1 year, and 2 years after registration were compared between the two groups. Non-parametric tests were used to analyze data at each inspection period. Results The osteoporosis treatment initiation rate was significantly higher in the LI group than in the non-LI group (85.7% vs. 71.8%; p = 0.04). The LI group had significantly higher bone density assessment implementation rates than the non-LI group at the time of registration (90.0% vs. 69.0%; p = 0.00) and 6 months after registration (50.0% vs. 29.6%; p = 0.01), but not 1 or 2 years after registration. In addition, no significant differences in fall or fracture incidence rates were found between the two groups. Conclusion The coordinator-based interventions for fragility fractures improved bone density assessment implementation and treatment rates and enhanced treatment persistence rates in the early stages following bone fractures. The findings suggest that liaison intervention may help both fracture and osteoporosis physicians for the evaluation of osteoporosis and initiation and continuation of osteoporosis medication.

International audience

Summary Background UNAIDS has prioritised Malawi and 21 other countries in sub-Saharan Africa for fast-tracking the end of their HIV epidemics. UNAIDS' elimination strategy requires achieving a treatment coverage of 90% by 2030. However, many individuals in the prioritised countries have to travel long distances to access HIV treatment and few have access to motorised transportation. Using data-based geospatial modelling, we investigated whether these two factors are barriers to achieving HIV elimination in Malawi and assessed the effect of increasing bicycle availability on expanding treatment coverage. Methods We built a data-based geospatial model that we used to estimate the minimum travel time needed to access treatment, for every person living with HIV in Malawi. We constructed our model by combining a spatial map of health-care facilities, a map that showed the number of HIV-infected individuals per km2, and an impedance map. We quantified impedance using data on road and river networks, land cover, and topography. We estimated travel times for the existing coverage of 70%, and the time that HIV-infected individuals would need to spend travelling in order to achieve a coverage of 90%, whether driving, bicycling, or walking. Findings We identified a quantitative relationship between the maximum achievable coverage of treatment and the minimum travel time to the nearest health-care facility. At 70% coverage, health-care facilities can be reached within approximately 45 min if driving, 65 min if bicycling, and 85 min if walking. Increasing coverage above 70% will become progressively more difficult. To reach 90% coverage, many HIV-infected individuals (who have yet to initiate treatment) will need to travel for almost twice as long as those already on treatment. Bicycling, rather than walking, in rural areas would substantially increase the maximum achievable coverage. Interpretation The long travel times needed to reach health-care facilities coupled with little motorised transportation in rural areas are substantial barriers to reaching 90% coverage in Malawi. Increased bicycle availability could help eliminate HIV. Funding US National Institute of Allergy and Infectious Diseases.

International audience; SARS-CoV-2 transmission models have been fairly inaccurate in their predictions for Africa. Here, based on an analysis of surveillance data from Namibia, we conclude that it is necessary to include spatial demography, and travel, in SARS-CoV-2 transmission models in order to make more accurate predictions for COVID-19 epidemics in Africa.

Summary Generalised HIV epidemics in sub-Saharan Africa show substantial geographical variation in prevalence, which is considered when designing epidemic control strategies. We hypothesise that the migratory behaviour of the general population of countries in sub-Saharan Africa could have a substantial effect on HIV epidemics and challenge the elimination effort. To test this hypothesis, we used census data from 2017 to identify, construct, and visualise the migration network of the population of Botswana, which has one of the most severe HIV epidemics worldwide. We found that, over 12 months, approximately 14% of the population moved their residency from one district to another. Four types of migration occurred: urban-to-urban, rural-to-urban, urban-to-rural, and rural-to-rural. Migration is leading to a marked geographical redistribution of the population, causing high rates of population turnover in some areas, and further concentrating the population in urban areas. The migration network could potentially be having a substantial effect on the HIV epidemic of Botswana: changing the location of high-transmission areas, generating cross-country transmission corridors, creating source–sink dynamics, and undermining control strategies. Large-scale migration networks could present a considerable challenge to eliminating HIV in Botswana and in other countries in sub-Saharan Africa, and should be considered when designing epidemic control strategies.

BackgroundDifficult-to-treat rheumatoid arthritis (D2T RA) is defined as RA in which disease activity is uncontrolled despite the use of two or more biologics or Janus kinase inhibitors (JAKi) with different mechanisms of action (MOA).ObjectivesTo explore the optimal treatment strategy for D2T RA, we evaluated the drug retention, efficacy, and reasons for discontinuation of biologics or JAKi used for patients with D2T RA in a longitudinal multicenter cohort.MethodsRA patients with clinical disease activity index (CDAI) >10 despite the use of at least two biologics or JAKi with different MOA and further treated with biologics or JAKi were included. The drug retention rates of biologics (TNFi, IL-6Ri, and CTLA4-Ig) or JAKi were estimated at 12 months using the Kaplan-Meier method and adjusted for potential confounders (age, sex, disease duration, concomitant MTX and PSL use, and the number of switched biologics or JAKi) using Cox proportional hazards models.ResultsA total of 251 treatment courses (TCs) from 167 patients were included (TNFi: 97 TCs, IL-6Ri: 67 TCs, CTLA4-Ig: 27 TCs, JAKi: 60 TCs). Baseline characteristics showed no difference in age, sex, disease duration, ACPA positivity, CDAI, and concomitant MTX and PSL use between the four groups. Drug retention excluding non-toxic reasons and remission was significantly higher in patients treated with JAKi or IL-6Ri than in patients treated with TNFi or CTLA4-Ig (P=0.00172). Multivariate analysis using Cox proportional hazards models demonstrated that discontinuation of the drug was associated with the use of TNFi or CTLA4-Ig (HR: 3.29, 95%CI: 1.15-9.42, P=0.027) and concomitant PSL use (HR: 1.14, 95%CI: 1.04-1.26, P=0.0084). In terms of disease activity evaluated with CDAI, no difference was observed between the four groups at 3 months (P=0.90), at 6 months (P=0.77), and at 12 months (P=0.75).ConclusionIn patients with D2T RA, JAKi or IL-6Ri may have treatment advantages compared with TNFi or CTLA4-Ig.References[1] EULAR definition of difficult-to-treat rheumatoid arthritis.Nagy G, Roodenrijs NMT, Welsing PM, Kedves M, Hamar A, van der Goes MC, Kent A, Bakkers M, Blaas E, Senolt L, Szekanecz Z, Choy E, Dougados M, Jacobs JW, Geenen R, Bijlsma HW, Zink A, Aletaha D, Schoneveld L, van Riel P, Gutermann L, Prior Y, Nikiphorou E, Ferraccioli G, Schett G, Hyrich KL, Mueller-Ladner U, Buch MH, McInnes IB, van der Heijde D, van Laar JM.Ann Rheum Dis. 2021 Jan;80(1):31-35.[2] Prevalence and predictive factors of difficult-to-treat rheumatoid arthritis: the KURAMA cohort.Watanabe R, Hashimoto M, Murata K, Murakami K, Tanaka M, Ohmura K, Ito H, Matsuda S.Immunol Med. 2021 May 25:1-10.Disclosure of InterestsRyu Watanabe Speakers bureau: Eli Lilly, Mitsubishi Tanabe, Pfizer, Sanofi, AbbVie, Asahi Kasei, Eisai, Bristol-Myers Squibb, UCB Japan, Chugai, Janssen, Astellas, Nippon Shinyaku, Daiichi Sankyo, Gilead Sciences Japan, and Boehringer ingelheim., Tadashi Okano Speakers bureau: Asahi Kasei, Astellas, Abbvie, Amgen, Ayumi, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Janssen, Kyowa Kirin, Mitsubishi Tanabe, Novartis, Ono, Pfizer, Sanofi, Takeda, UCB, Grant/research support from: Asahi Kasei, Abbvie, Chugai, Eisai, Mitsubishi Tanabe, Shinsuke Yamada: None declared, Wataru Yamamoto: None declared, Koichi Murata Speakers bureau: Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd.; Asahi Kasei Pharma Corp.; and Mitsubishi Tanabe Pharma Co., and Daiichi Sankyo Co. Ltd., Kosaku Murakami: None declared, Kosuke Ebina Speakers bureau: AbbVie, Amgen, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Pfizer, Sanofi, and UCB Japan., Grant/research support from: AbbVie, Amgen, Asahi-Kasei, Astellas, Chugai, Eisai, Mitsubishi-Tanabe, Ono Pharmaceutical, Teijin Pharma, and UCB Japan, Yuichi Maeda Speakers bureau: Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol Myers Squibb, and Mitsubishi Tanabe Pharma Corporation., Sadao Jinno Speakers bureau: AbbVie G.K., Asahi Kasei Pharma., Bristol-Myers Squibb., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., and Mitsubishi Tanabe Pharma, and Ono Pharmaceutical Co, Iku Shirasugi: None declared, Yonsu Son: None declared, Hideki Amuro Speakers bureau: Chugai Pharmaceutical Co.,Ltd, Masaki Katayama: None declared, Ryota Hara: None declared, Kenichiro Hata Speakers bureau: AbbVie, Asahi-Kasei, Chugai, Janssen, Mitsubishi-Tanabe, Eisai, Ayaka Yoshikawa: None declared, Motomu Hashimoto Grant/research support from: Abbvie, Asahi-Kasei, Brystol-Meyers, Eisai, Eli Lilly, Novartis Pharma.

Purpose This study’s primary objective is to propose actors’ embeddedness as a source for governance and upgrading within the GVC (Global Value Chain) framework. Design/methodology/approach This study uses co-word analysis to study the GVC scientific production. The analysis is conducted using controversies mapping from the Theory of Scientific and Technological Change (TSTC). Findings Two theoretical gaps were identified. First, governance and upgrading have more than one definition. Second, value and network are upgrading strategies. This article proposes the use of the Montenegro and Bulgacov (2014) framework to translate governance and upgrading respectively as network governance and strategic outcomes. Embeddedness matters because it is a stable theoretical concept (Granovetter, 1985) that can be a link between network governance and strategic results. Originality/value The study’s main contribution is to propose relativist embeddedness as a source of governance and upgrading. The second contribution is to present an ANT-based framework to study governance and its strategic results. Resumo Objetivo O objetivo principal deste estudo é propor a inserção de atores como fonte de governança e melhoria na estrutura da cadeia global de valor (CGV). Metodologia Este estudo utiliza análise de coocorrência de palavras para estudar a produção científica referente à CGV. A análise é realizada utilizando o mapeamento de controvérsias da Teoria da Mudança Científica e Tecnológica (TSTC, na sigla em inglês). Resultados Duas lacunas teóricas foram apontadas devido à evolução na teoria da CGV. A primeira é a de que a governança e a melhoria têm mais de uma definição e a segunda, de que valor e rede são estratégias de melhoria. Este artigo propõe o uso da estrutura de Montenegro e Bulgacov (2014) para transladar a governança e a melhoria, respectivamente, como governança em rede e resultados estratégicos. A inserção é importante porque é um conceito teórico estável (Granovetter, 1985) que pode ser um elo entre a governança em rede e os resultados estratégicos. Contribuições A principal contribuição deste estudo é a proposta de uma inserção relativista como fonte de governança e melhoria. A segunda contribuição é apresentar uma estrutura baseada na Teoria Ator-Rede (TAR), modelada para estudar a governança e seus resultados estratégicos.

Muito se discute sobre as organizações sociais na academia e no mercado de trabalho, mas não existe um acordo conceitual comum sobre a compreensão dos conceitos. O objetivo deste artigo é, por meio de uma pesquisa bibliométrica, obter as definições de empreendedorismo social, empresas sociais e negócios sociais e desmistificar estes conceitos, além de incentivar os acadêmicos e pesquisadores a desenvolverem pesquisas nestas áreas. De acordo com o objetivo e finalidade deste projeto, a pesquisa adotou a abordagem qualitativa, a forma de raciocínio lógico utilizada foi o método indutivo e em relação à natureza das fontes utilizadas a pesquisa é classificada como bibliográfica. Pode-se concluir que. além, destas empresas poderem contribuir em áreas que são, a princípio, responsabilidade dos governos municipal, estadual e federal, mas estas esferas não têm condições de manter um serviço de qualidade para a população, permitindo assim que outras organizações sociais possam substituir os governos nestes serviços e atender uma população necessitada.

We examined the effects of the coordinator-based intervention on quality of life (QOL) in the aftermath of a fragility fracture, as well as factors predictive of post-fracture QOL. The coordinator-based interventions mitigated the decrease in QOL. Secondary fracture after primary fracture, however, was a significant predictor of lower QOL.This study aimed to determine the effects of the coordinator-based intervention on QOL in the aftermath of a fragility fracture, as well as factors predictive of post-fracture QOL, in an Asian population.Patients with new fractures in the intervention group received the coordinator-based intervention by a designated nurse certified as a coordinator, within 3 months of injury. QOL was evaluated using the Japanese version of the EuroQol 5 Dimension 5 Level (EQ-5D-5L) scale before the fracture (through patient recollections) and at 0.5, 1, and 2 years after the primary fracture.Data for 141 patients were analyzed: 70 in the liaison intervention (LI) group and 71 in the non-LI group. Significant intervention effects on QOL were observed at 6 months after the fracture; the QOL score was 0.079 points higher in the LI group than in the non-LI group (p=0.019). Further, the LI group reported significantly less pain/discomfort at 2 years after the fracture, compared to the non-LI group (p=0.037). In addition, secondary fractures were found to significantly prevent improvement and maintenance of QOL during the recovery period (p=0.015).Short-term intervention effects were observable 6 months after the primary fracture, with the LI group mitigated the decrease in QOL. Few patients in the LI group reported pain/discomfort 2 years after the fracture, but there is uncertainty regarding its clinical significance. Secondary fracture after initial injury was a significant predictor of lower QOL after a fracture.

BackgroundRecently, the disease activity of rheumatoid arthritis (RA) was improved due to the ‘treat-to-target’ strategy. However, some patients remain various symptoms despite recommended treatment was performed. Then, the term of ‘difficult-to-treat RA (D2TRA)’ is widely recognized. It is unknown how the difference of type of biological disease-modifying anti rheumatic dugs (bDMARDs)/Janus kinase inhibitor (JAKi) will affect clinical efficacy in patients with D2TRA. Moreover, the risk factor to inhibit the clinical response in patients with D2TRA is unknown.ObjectivesThe aim of this study was to evaluate the treatment response in patients with D2TRA who were treated with interleukin 6 receptor inhibitor (IL-6Ri), abatacept and JAKi.MethodsThis study used the multicenter database included 673 RA patients treated with bDMARDs/JAKi (tocilizumab 240, sarilumab 67, abatacept 146, tofacitinib 101, baricitinib 83, upadacitinib 20, peficitinib 14, filgotinib 2). Two hundred forty-two patients were treated as first line bDMARDs/JAKi (IL-6Ri 117, abatacept 63, JAKi 62), 211 patients were treated as second line bDMARDs/JAKi (IL-6Ri 117, abatacept 37, JAKi 57), 220 patients were treated as third and more bDMARDs/JAKi. In these 220 patients, 82 patients did not meet D2TRA criteria (IL-6Ri 42, abatacept 15, JAKi 25) and 138 patients met D2TRA criteria (IL-6Ri 31, abatacept 31, JAKi 76). In all patients, we analyzed 138 patients with D2TRA (113 female, mean age was 63.1 ± 13.7 years). Drug retention rate and effectiveness of bDMARDs/JAKi in patients with D2TRA were evaluated for 24 weeks. Multivariate linear regression analysis was performed to clarify the risk factors to inhibit the clinical response.ResultsDrug retention rate of patients with D2TRA at 24 weeks was 67.7% in IL-6Ri group, 74.2% in abatacept group, 61.8% in JAKi group. Drug retention rate in patients with D2TRA was not different between groups (IL-6Ri vs abatacept: p=0.86, IL-6Ri vs JAKi group: p=0.39, abatacept vs JAKi group: p=0.33). DAS28-CRP at 4, 12, 24 weeks decreased in all group (Figure 1). Abatacept showed lower improvement ratio of DAS28-CRP at 24 weeks compared to IL-6Ri group (IL-6Ri vs abatacept: p 1.2 with a score < 3.2) was 52.4% patients in IL-6Ri, 17.4% patients in abatacept, 29.8% patients in JAKi. SDAI and CDAI at 4, 12, 24 weeks decreased in all group (Figure 1). There were no diferences between the groups in improvement ratio of SDAI (IL-6Ri vs abatacept: p=0.11, IL-6Ri vs JAKi: p=0.81, abatacept vs JAKi: p=0.08) and CDAI (IL-6Ri vs abatacept: p=0.31, IL-6Ri vs JAKi: p=0.82, abatacept vs JAKi: p=0.13) at 24 weeks. HAQ was 1.42, 1.15, 1.39 at baseline, 1.27, 1.07, 1.22 at 4 weeks, 1.17, 1.07, 1.17 at 12 weeks, 1.26, 1.06, 1.14 at 24 weeks in IL-6Ri group, abatacept and JAKi, respectively. Multivariate linear regression analysis revealed that high HAQ (β=0.28, p=0.02) and high dosage of glucocorticoid (β=0.67, pTable 1.Multivariate linear regression analysis of risk factor to inhibit the clinical response in patients with D2TRA.β95% CIpAge (years)-0.037-0.025, 0.0170.74male-0.047-0.788, 0.4860.64Disease durations (years)-0.048-0.028, 0.0170.63RF (IU/ml)-0.082-0.0004, 0.00020.41Anti CCP antibody (U/ml)0.111-0.0005, 0.0020.26DAS28-CRP-0.063-0.265, 0.1420.55HAQ0.2790.059, 0.7170.02MTX (mg/day)0.136-0.018, 0.0810.21Glucocorticoid dose (mg/day)0.6690.174, 0.324< 0.01Type of bDMARDs/JAKi-0.088-0.415, 0.1510.36ConclusionDrug retention rate and clinical efficacy of D2TRA patients were not different among IL-6Ri, abatacept and JAKi. DT2RA patient with functional disorder and high dosage of glucocorticoid were risk factor to inhibit the clinical response.Disclosure of InterestsNone declared

BackgroundSome cases of creatine kinase (CK) elevation caused by Janus kinase (JAK) inhibitor treatment for rheumatoid arthritis (RA) have been reported in clinical trials1. However, the frequency and patients’ background characteristics in clinical practice are unknown.ObjectivesThe correlation between JAK inhibitor treatment for RA and changes in CK levels in clinical practice were investigated using a multicenter database.MethodsThe multicenter database of JAK inhibitors was used, and 103 (tofacitinib 46, baricitinib 44, upadacitinib 11, peficitinib 1, filgotinib 1) of 265 RA patients were followed up at 24 weeks, and their CK levels were evaluated. The time-dependent change of CK was evaluated by sex and analyzed by the Wilcoxon signed-rank test. The percentage abnormal from the standard titer was calculated. The factors related to an elevated CK at 24 weeks were investigated using patients’ background characteristics at the time of starting JAK inhibitors by univariate analysis.ResultsWomen accounted for 85.4% of the patients, the median age was 68 years, disease duration was 15 years, and the mean DAS28ESR was 5.00. The CK levels of both men and women were significantly elevated at 4 weeks and maintained until 24 weeks (men, women: 63, 62 (0 weeks), 101, 95 (4 weeks), 119, 96 (12 weeks), 155, 99 (24 weeks), U/L, PTable 1.Characteristics at the time of starting JAK inhibitors related to elevated creatine kinase levels at 24 weeksUnivariateData at stating JAK inhibitorsR valueP valueCreatine kinase0.653Gender, men0.2470.012Steinbrocker stage-0.2150.039Steinbrocker class-0.2770.008modified health assessment questionnaire-0.2680.008Creatinine0.2890.003eGFR-0.2310.019LDH0.2010.041Glucocorticoid use-0.4090.008Analyzed by Spearman rank correlation coefficientFigure 1.Time-dependent changes of CK in all RA patientsConclusionCK was significantly elevated at 4 weeks and maintained until 24 weeks. However, no patients complained of muscle pain and stopped JAK inhibitors. Patients with high CK, low eGFR, high LDH, or maintained activities of daily living at the time of starting JAK inhibitors tended to have high CK levels at 24 weeks.References[1]Fleischmann, R. et al. Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis & rheumatology (Hoboken, N.J.) 71, 1788-1800, doi:10.1002/art.41032 (2019).Disclosure of InterestsNone declared

BackgroundIn patients with rheumatoid arthritis (RA) who have residual synovitis even after using biological disease modified anti-rheumatic drug (bDMARDs), joint destruction may progress1,. The enhanced treatment such as shortening the dosing interval or dose escalation of bDMARDs are recommended for these patients, if allowed in package inserts 2, 3.ObjectivesWe investigated the effects of enhanced treatment in RA patients with residual synovitis under treatment with standard dose of bDMARDs.MethodsForty RA patients treated with standard dose of infliximab, tocilizumab or golimumab were included in this study. Ultrasound (US) examination was performed at the bilateral first to fifth metacarpophalangeal (MCP) joints, first interphalangeal (IP) and second to fifth proximal interphalangeal (PIP) joints, wrist joints (three parts of radial, medial and ulnar) and first to fifth metatarsophalangeal (MTP) joints, by using HI VISION Ascendus (Hitachi Medical Corporation, Japan) with a multifrequency linear transducer (18-6 MHz). Residual synovitis was defined as Power Doppler score (PD) ≥2. In patients with residual synovitis, we recommended enhanced treatment. The patients were divided into 3 groups, PD≥2/ET+ group (patients agreed enhanced treatment), PD≥2/ET- group (patients rejected enhanced treatment), and PDResultsThere were 9 patients in PD≥2/ET+ group and 31 patients in PD0.99) (Figure 1).Figure 1.Disease activity, ultrasound assessment and radiographic change from baseline (BL) to 1-year follow-up in RA patients with residual synovitis who had enhanced treatment (PD≥2/ET+) and those without active synovitis (PD*Each parameter at BL and 1-year was statistically analyzed by Wilcoxin signed rank test only in PD≥2/ET+ group.**Difference in two groups at BL was statistically analyzed by Student t test or Mann-Whitney U test.SDAI: simplified disease activity index, HAQ: health assessment questionnaire, PD: Power Doppler, MMP-3: matrix metalloproteinase 3, mTSS: modified Total Sharp Score.ConclusionIn RA patients with the residual synovitis under treatment with standard dose of bDMARDs, enhanced treatment decreased the synovitis and suppressed the joint destruction.References[1]Nguyen H, Ruyssen-Witrand A, Gandjbakhch F, Constantin A, Foltz V, Cantagrel A. Prevalence of ultrasound-detected residual synovitis and risk of relapse and structural progression in rheumatoid arthritis patients in clinical remission: a systematic review and meta-analysis. Rheumatology (Oxford). 2014 Nov;53(11):2110-8.[2]Ogata A, Tanaka Y, Ishii T, Kaneko M, Miwa H, Ohsawa S; SHINOBI study group. A randomized, double-blind, parallel-group, phase III study of shortening the dosing interval of subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis and an inadequate response to subcutaneous tocilizumab every other week: Results of the 12-week double-blind period. Mod Rheumatol. 2018 Jan;28(1):76-84.[3]Takeuchi T, Miyasaka N, Tatsuki Y, Yano T, Yoshinari T, Abe T, Koike T. Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis. Ann Rheum Dis. 2011 Jul;70(7):1208-15.Disclosure of InterestsNone declared

BackgroundPatients with rheumatoid arthritis (RA) who have sarcopenia and stiff or painful joints might be at increased risk of falls and fractures.ObjectivesThe present study aimed to prospectively identify the incidence of clinical fractures and associated risk factors in patients with RA in a cohort study named the TOMORROW (UMIN000003876) that started in 2010.MethodsWe evaluated anthropometric parameters, bone mineral density (BMD), disease activity, RA medication at entry and observed the incidence of clinical fractures during ten years in 202 patients with RA (mean age, 58.6 y; medication with biological agents, 54.9%) and 202 age- and sex-matched non-RA volunteers (Vo) (mean age, 57.4 y). We compared the incidence of clinical fractures between patients with RA and Vo for ten years, and analyzed the risk factors for clinical fractures using Cox proportional hazard model.ResultsThe incidences of clinical fractures were 0.036 and 0.024/person-year in patients with RA and Vo, respectively. Cox proportional hazard model revealed that low BMD at the thoracic vertebrae (< 0.7 g/cm2) and history of fractures at entry were significantly associated with the incidence of clinical fractures (Hazard ratio [HR]1.737, p=0.020 and HR1.514, p=0.047, respectively) in all participants. RA morbidity, however, was not (HR1.398, p=0.112). In patients with RA, medication with GC at entry was a significant risk factor for clinical fractures (HR1.898, p=0.017). Additionally, a mean GC dose (≥ 2 mg/day) at entry and during the ten-year period increased risk for fractures (HR 2.189, p=0.004, 1.866, p=0.022, respectively).ConclusionRA per se was not a risk factor for clinical fractures in this cohort. Low BMD at the thoracic vertebrae at entry and the use of GC with even low dose at entry and during ten years were significantly associated with an increased frequency of clinical fractures among patients with RA.Disclosure of InterestsNone declared

BackgroundPatients with rheumatoid arthritis (RA) who have muscle weakness and stiff or painful joints might be at increased risk of falls and fractures.ObjectivesThe present study prospectively investigates correlations between decreasing doses of glucocorticoid (GC) and the incidence of clinical fractures in patients with RA based on the ten-year findings of the TOMORROW study (UMIN000003876) that started in 2010.MethodsWe evaluated anthropometric parameters, bone mineral density, disease activity, RA medication, and the incidence of clinical fractures over a period of ten years in 202 patients with RA (mean age, 58.6 years; mean disease duration, 14.0 years). We also investigated the effects of GC doses on the incidence of clinical fractures over the same period in patients with RA using multivariate regression analysis.ResultsThe incidence of clinical fractures for ten years in patients with RA was 0.036/person-year. There were 89 patients (44.1%) treated with GC at least once during ten years. The incidences of clinical fractures in patients with RA treated with and without GC during ten years were 0.052 and 0.026/person-year, respectively. After adjusting for fracture risk factors including age, sex, smoking, and body mass index, cox proportional hazard model revealed that GC dose of ≥ 2 mg/day at baseline was a significant risk factor for clinical fractures (Hazard ratio [HR]:2.430; 95%CI, 1.040-5.675, p=0.040). Although the risk for clinical fractures did not decrease by just reducing the dose of GC (HR:4.505; 95%CI, 0.589-34.457, p=0.147), it was significantly lower if the dose of GC could be reduced to zero during ten years (HR:0.407; 95%CI, 0.194-0.857, p=0.018).ConclusionMedication with even low dose of GC are apparently significantly associated with an increased frequency of clinical fractures among patients with RA. However, if the dose of GC was reduced to free during ten years, the clinical fracture risk could become lower. We concluded that we should decrease the dose of GC to free after controlling disease activity of RA.Disclosure of InterestsNone declared

BackgroundThe treatment option including biological DMARDs (BIO) and JAK inhibitor (JAK) was expanded, and the number of patients reached to the treatment target are increasing in rheumatoid arthritis (RA). On the other hand, it is also true that some patients are still using prednisolone (PSL). Recently, ultrasound has played a role of sensitive imaging modality in the diagnosis and follow-up of patients with RA. It is known that residual synovitis was found in ultrasound even in patients with clinical remission.ObjectivesWe investigated the differences of ultrasonographic intra-articular synovitis findings between treatment drugs in patients with RA.MethodsFrom January 2017 to August 2020, 750 RA patients who underwent ultrasound examination were included. A US examination was performed at the bilateral first to fifth metacarpophalangeal (MCP) joints, first interphalangeal (IP) and second to fifth proximal interphalangeal (PIP) joints, wrist joints (three part of radial, medial and ulnar) and first to fifth metatarsophalangeal (MTP) joints, by using HI VISION Ascendus (Hitachi Medical Corporation, Japan) with a multifrequency linear transducer (18-6 MHz). The gray scale and power Doppler findings were assessed by the semi-quantitative method (0-3). All patients were divided into with or without BIO / JAK, methotrexate (MTX) and PSL. Then, patients were matched using the propensity score adjusted for gender, age, RA disease duration, disease activity, CRP value, and MMP-3 value. The total gray scale and power Doppler score (GSUS / PDUS) were compared between treatment drugs of RA by using propensity score matching methods.ResultsThe average age of 750 RA patients were 64.5 years and an average disease duration of RA was 13.9 years and females were 581 (77.5%). There were 517 patients (68.9%) treated with BIO/JAK and 233 patients treated without BIO/JAK. The 205 patients in each group were matched. GSUS were 10.6±11.1 vs 9.2±10.4 (p=0.218) and PDUS 7.4±9.2 vs 6.5±9.0 (p=0.328). Ultrasound residual synovitis was not different between with or without BIO/JAK in matched patients. There were 525 patients (70.0%) treated MTX, the average MTX dose was 9.3 mg, and 225 patients treated without MTX. The 203 patients with or without MTX in each group were matched. GSUS were 9.7±10.6 vs 11.4±12.0 (p=0.119) and PDUS 6.6±8.8 vs 8.1±10.1 (p=0.117). Ultrasound residual synovitis was not different between with or without MTX in matched patients. There were 111 patients (14.8%) treated PSL, the average dose was 4.0mg, and 639 patients treated without PSL. The 105 patients with or without PSL in each group were matched. GSUS were 15.7±13.9 vs 11.6±10.6 (p=0.018) and PDUS 11.5±11.4 vs 8.1±9.6 (p=0.021). Ultrasound residual synovitis was more severe treated with PSL than without PSL in matched patients.ConclusionIn a comparison between RA patients matched backgrounds such as disease activity, there was no difference in ultrasound residual synovitis between patients with or without BIO/JAK and MTX. However, there was significant difference in patients with or without PSL. This suggests that PSL use suppresses clinical symptoms but does not improve synovitis. Thus, it should be noted that joint destruction may progress in patients treating with PSL.References[1]Grassi W, Okano T, Di Geso L, Filippucci E. Imaging in rheumatoid arthritis: options, uses and optimization. Expert Rev Clin Immunol. 2015;11:1131-46.[2]Nguyen H, Ruyssen-Witrand A, Gandjbakhch F, Constantin A, Foltz V, Cantagrel A. Prevalence of ultrasound-detected residual synovitis and risk of relapse and structural progression in rheumatoid arthritis patients in clinical remission: a systematic review and meta-analysis. Rheumatology (Oxford). 2014;53:2110-8.AcknowledgementsWe wish to thank Atsuko Kamiyama, Tomoko Nishimura for clinical assistant, Setsuko Takeda, Emi Yamashita, Yuko Yoshida, Emi Ohtani, Yuka Domae, Asami Yagami, Shingo Washida for their special efforts as a sonographer and collecting data.Disclosure of InterestsTadashi Okano Speakers bureau: Asahi Kasei, Astellas, Abbvie, Amgen, Ayumi, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Janssen, Kyowa Kirin, Mitsubishi Tanabe, Novartis, Ono, Pfizer, Sanofi, Takeda, UCB, Grant/research support from: Asahi Kasei, Abbvie, Chugai, Eisai, Mitsubishi Tanabe, Kenji Mamoto: None declared, Yutaro Yamada: None declared, Koji Mandai: None declared, Shohei Anno: None declared, Masahiro Tada: None declared, Kentaro Inui Speakers bureau: Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Takeda Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Abbvie GK, Pfizer Inc., Eisai Co.,Ltd., Chugai Pharmaceutical Co., Ltd., Grant/research support from: Janssen Pharmaceutical K.K., Astellas Pharma Inc., Sanofi K.K., Abbvie GK, Takeda Pharmaceutical Co. Ltd., QOL RD Co. Ltd., Mitsubishi Tanabe Pharma, Ono Pharmaceutical Co. Ltd., Eisai Co.,Ltd.,, Tatsuya Koike Speakers bureau: Takeda Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical, Eisai, Abbott Japan, Teijin Pharma, Banyu Pharmaceutical and Ono Pharmaceutical, Hiroaki Nakamura: None declared

BackgroundClinical feature of Janus kinase (JAK) inhibitor is recognized as not only suppress inflammation but also improve patient-reported outcomes (PRO) such as pain and health assessment questioner (HAQ) in patients with rheumatoid arthritis (RA). This representative clinical feature was known as a results of phase 3 trial compared to TNF inhibitor. One of the mechanisms of JAK in RA is to suppresses interleikin-6 (IL-6). However, the effect for PRO in JAK inhibitor compared to IL-6 inhibitor have not been known.ObjectivesWe investigated the effect for patient-reported outcomes such as pain and HAQ in patients with RA treated with JAK inhibitor compared to IL-6 inhibitor.MethodsThis study was analysed a multicenter database included RA patients treated with biological disease-modifying anti rheumatic dugs (bDMARDs) and JAK inhibitors. In 307 patients treated with IL-6 inhibitor (tocilizumab 240 and sarilumab 67) and 220 patients with JAK inhibitor (tofacitinib 101, baricitinib 83, upadacitinib 20, peficitinib 14 and filgotinib 2), 155 patients were treated as first-line bDMARDs/JAK inhibitor (IL-6R inhibitor 104 and JAK inhibitor 51). In this first-line patients, patients treated with IL-6R inhibitor and JAK inhibitor were matched using the propensity score adjusted for gender, age, RA disease duration, baseline charactristics of disease activity, CRP level, and MMP-3 level. The beaseline data and the change of clinical and laboratory data at 4, 12 and 24 weeks were compared between IL-6 inhibitor and JAK inhibitor.ResultsThirty-six patients in each group were matched and analyzed. The average age was 62.4 and 62.6 years and the average disease duration of RA was 13.2 and 10.1 years in IL-6 inhibitor and JAK inhibitor. The baseline characteristics were not significantly different in both groups. At week 4, tender joint count (TJC) was significantly improved in JAK inhibitor than IL-6 (IL-6: -1.86 vs JAK: -4.12, p= 0.036) and HAQ was significantly improved in JAK inhibitor than IL-6 (IL-6: -0.04 vs JAK: -0.27, p= 0.041). Moreover, Clinical Disease Activity Index (CDAI) was also improved in JAK inhibitor than IL-6 (IL-6: -6.6 vs JAK: -10.9, p= 0.026) at week 4. However, pain VAS and patient global VAS were not significantly different in each group in week4. TJC, HAQ and CDAI was not different in both groups at week 12 and week 24. On the other hand, ESR was significantly decreased in IL-6 inhibitor than JAK inhibitor at week 4, 12 and 24 (IL-6: -26.6 vs JAK: -14.1, p=0.018 at week 4, IL-6: -32.7 vs JAK: -16.5 p=0.004 at week 12, IL-6: -31.3vs JAK: -17.7 p=0.014 at week 24).ConclusionIn a comparison between IL-6 inhibitor and JAK inhibitor as a first-line molecular-targeted drug matched baseline charactristics of disease activity, TJC and HAQ was improved in JAK inhibitor earlier than IL-6 inhibitors. JAK inhibitor suppress multi cytokine that might be the reason why JAK inhibitor improve pain. Improvement of patient reported outcome in JAK inhibitor was found also in comparison with IL-6 inhibitor.References[1]Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017;376:652-62.[2]Fleischmann R, Pangan AL, Song IH, et al. Upadacitinib Versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol. 2019;71:1788-1800.AcknowledgementsWe wish to thank Atsuko Kamiyama and Tomoko Nishimura for clinical assistant, and all member of Team RA.Disclosure of InterestsTadashi Okano Speakers bureau: Asahi Kasei, Astellas, Abbvie, Amgen, Ayumi, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Janssen, Kyowa Kirin, Mitsubishi Tanabe, Novartis, Ono, Pfizer, Sanofi, Takeda, UCB, Grant/research support from: Asahi Kasei, Abbvie, Chugai, Eisai, Mitsubishi Tanabe, Tatsuya Koike Speakers bureau: Takeda Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical, Eisai, Abbott Japan, Teijin Pharma, Banyu Pharmaceutical and Ono Pharmaceutical, Kentaro Inui Speakers bureau: Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Takeda Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Abbvie GK, Pfizer Inc., Eisai Co.,Ltd., Chugai Pharmaceutical Co., Ltd., Grant/research support from: Janssen Pharmaceutical K.K., Astellas Pharma Inc., Sanofi K.K., Abbvie GK, Takeda Pharmaceutical Co. Ltd., QOL RD Co. Ltd., Mitsubishi Tanabe Pharma, Ono Pharmaceutical Co. Ltd., Eisai Co.,Ltd., Masahiro Tada: None declared, Kenji Mamoto: None declared, Yutaro Yamada: None declared, kazuki Orita: None declared, Koji Mandai: None declared, Shohei Anno: None declared, Takahiro Iida: None declared, Hiroaki Nakamura: None declared

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

BackgroundRecently, the disease activity of rheumatoid arthritis (RA) was improved due to the ‘treat-to-target’ strategy. However, some patients remain various symptoms despite recommended treatment was performed. Then, the term of ‘difficult-to-treat RA (D2TRA)’ is widely recognized. Janus kinase inhibitor (JAKi) might be effective for D2TRA patients, because JAKi can simultaneously block the function of multiple cytokines.ObjectivesThe aim of this study was to evaluate drug retention rate and effectiveness of JAKi in patients with D2TRA.MethodsThis study included 220 RA patients (tofacitinib 101, baricitinib 83, upadacitinib 20, peficitinib 14, filgotinib 2) treated with JAKi. Sixty-two patients were treated as first line bDMARDs/JAKi (1st group), 57 patients were treated as second line bDMARDs/ JAKi (2nd group), 101 patients were treated as third and more bDMARDs/ JAKi. In these 101 patients, 25 patients did not met D2TRA criteria (non-D2TRA group) and 76 patients met D2TRA criteria (D2TRA group). Drug retention rate and effectiveness of JAKi were evaluated during 24 weeks in each group.ResultsUsage rate of methotrexate was lower and dosage of glucocorticoid was higher in D2TRA group than in other groups (Table 1). Drug retention rate at 24 weeks was 87.1% (54/62) in 1st group, 80.1% (46/57) in 2nd group, 88% (22/25) in non-D2TRA group, 61.8% (47/76) in D2TRA group. Drug retention rate was lower in D2TRA group compared to 1st group, 2nd group and non-DT2RA group (pTable 1.Baseline characteristics of RA patients1st group (n=62)2nd group (n=57)non-D2TRA group (n=25)D2TRA group (n=76)Age (years)64.9 ± 14.866.1 ± 11.564.6 ± 16.163.0 ± 15.0Female (%)75.879.096.080.3Disease durations (years)10.4 ± 11.717.6 ± 17.622.6 ± 22.416.3 ± 15.7RF (IU/ml)296.3 ± 1153.8314.9 ± 1037.7262.4 ± 375.9305.9 ± 819.6RF positive ratio (%)81.878.479.275.7Anti CCP antibody (U/ml)221.8 ± 327.2157.8 ± 258.795.9 ± 101.6191.8 ± 250.6Anti CCP antibody positive ratio (%)79.679.672.283.3CRP (U/ml)1.5 ± 2.11.1 ± 2.01.6 ± 1.61.8 ± 2.9MMP-3 (ng/ml)185.7 ± 167.6146.7 ± 122.1190.1 ± 152.6268.0 ± 451.2DAS28-CRP4.3 ± 1.24.1 ± 1.33.9 ± 1.44.4 ± 1.3SDAI21.8 ± 12.221.7 ± 13.118.4 ± 13.023.9 ± 12.8CDAI20.3 ± 11.320.7 ± 12.717.6 ± 12.822.1 ± 12.2HAQ1.1 ± 0.81.2 ± 1.00.9 ± 0.81.4 ± 1.1MTX use (%)69.463.25647.4MTX (mg/day)10.7 ± 3.410.4 ± 3.58.8 ± 3.59.0 ± 4.3Glucocorticoid use (%)29.136.81646.1Glucocorticoid dose (mg/day)3.3 ± 2.13.0 ± 1.53.5 ± 1.95.1 ± 2.8ConclusionDrug retention rate of JAKi in treatment of D2TRA group were lower than that of 1st group, 2nd group, and non-D2TRA group. Clinical efficacy of JAKi in D2TRA group were not significantly different to 2nd group and non-D2TRA group. However, HAQ improvement was weak in D2TRA group.Disclosure of InterestsNone declared

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

BackgroundTo investigate if FRAX in patients with RA can predict the incidence of new clinical fractures for 10 years by using the 10-year data of the TOMORROW study (UMIN000003876) which is a prospective cohort study.ObjectivesTo investigate if FRAX in patients with RA can predict the incidence of new clinical fractures for 10 years by using the 10-year data of the TOMORROW study (UMIN000003876) which is a prospective cohort study.MethodsWe calculated ten-year probability of major osteoporotic fracture (FRAX) in 208 RA patients and 205 sex- and age-matched volunteers (Vo), and compared FRAX with the incidence of clinical fractures for 10 years.ResultsThe mean FRAX were 14.5 and 8.8% in 175 RA patients and 168 Vo, respectively, in whom we could calculate FRAX at baseline and complete to investigate the incidence of clinical fractures for 10 years from baseline. The mean FRAX in RA patients was significantly higher than that in Vo (PConclusionFRAX and the incidence of clinical fractures for 10 years were significantly higher in RA patients than them of Vo. We confirmed that FRAX was the risk factor for clinical fractures in actual clinical practice.Disclosure of InterestsNone declared

BackgroundRomosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. Romosozumab has an excellent therapeutic effect on patients with osteoporosis. However, there are few reports investigated the efficacy and the effect of various factors relative to osteoporosis in real-world.ObjectivesWe evaluated bone mineral density (BMD) and bone metabolism marker (BMM) change in osteoporosis patients treated with romosozumab, and assessed the effect of various factors, such as preosteoporosis treatment, history of fragility fracture and combination of vitamin D.MethodsThis study included 141 osteoporosis patients (132 female, mean age: 78.8 ± 7.5 years, mean hight: 151.1 ± 7.5 cm, mean weight: 50.9 ± 8.9 kg) treated with romosozumab. BMD measurements using dual energy X-ray absorptiometry (DXA) and BMM measurements using N-terminal propeptide of type 1 collagen (P1NP) were evaluated at 0, 4, 6, and 12 months after treatment. DXA were performed at the lumbar spine (n=92), at proximal femoral and femoral neck (n=92), and at distal third radius (n=49). We evaluated the influence of preosteoporosis treatment, history of fragility fracture and combination of vitamin D for BMD change.ResultsBMD at lumbar spine (5.2%: pConclusionRomosozumab improved BMD at lumbar and femoral independently regardless of preosteoporosis treatment, history of fragility fracture and combination of vitamin D.References[1]Felicia Cosman et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med 2016; 375:1532-1543, DOI: 10.1056/NEJMoa1607948Disclosure of InterestsNone declared

BackgroundUNAIDS has prioritized Malawi and 21 other countries in sub-Saharan Africa (SSA) for “fast-tracking” the end of their HIV epidemics. To achieve elimination requires treating 90% of people living with HIV (PLHIV); coverage is already fairly high (70–75%). However, many individuals in SSA have to walk to access healthcare. We use data-based geospatial modeling to determine whether the need to travel long distances to access treatment and limited transportation in rural areas are barriers to HIV elimination in Malawi. Additionally, we evaluate the effect on treatment coverage of increasing the availability of bicycles in rural areas.MethodsWe build a geospatial model that we use to estimate, for every PLHIV, their travel-time to access HIV treatment if driving, bicycling, or walking. We estimate the travel-times needed to achieve 70% or 90% coverage. Our model includes a spatial map of healthcare facilities (HCFs), the geographic coordinates of residencies for all PLHIV, and an “impedance” map. We quantify impedance using data on road/river networks, land cover, and topography.FindingsTo cross an area of one km2 in Malawi takes from ~60 seconds (driving on main roads) to ~60 minutes (walking in mountainous areas); ~80% of PLHIV live in rural areas. At ~70% coverage, HCFs can be reached within: ~45 minutes if driving, ~65 minutes if bicycling, and ~85 minutes if walking. Increasing coverage above ~70% will become progressively more difficult. To achieve 90% coverage, the travel-time for many PLHIV (who have yet to initiate treatment) will be almost twice as long as those currently on treatment. Increasing bicycle availability in rural areas reduces round-trip travel-times by almost one hour (in comparison with walking), and could substantially increase coverage levels.InterpretationGeographic inaccessibility to treatment coupled with limited transportation in rural areas are substantial barriers to reaching 90% coverage in Malawi. Increased bicycle availability could help eliminate HIV.FundingNational Institute of Allergy and Infectious Diseases

Economic, political, and technological uncertainties require organizations to prepare adequately for new events that occur each day. Economic crisis, changes in the policies of each country and technological developments are classic examples of these changes in organizations. Seasonality is one of the economic phenomena that occur, and different forms of management are required. The seasonality that is described as a systematic and temporal imbalance of the tourist phenomenon that does not need to be regular, caused by the climate or by the vacation periods, and is based on the consumer behavior that can be expressed in terms of the number of visitors, traffic, highways, jobs, and tickets at attractions. Therefore, through a careful analysis of seasonality, it is possible that the losses are predicted, and the negative impact is not so grotesque on the company. For this, it is good that the manager uses the cost assessment methods to assume the seasonality of sales and thus be able to guard against the negative effects of the same. The objective of this research is to understand how owners of micro and small businesses in coastal cities consider themselves entrepreneurs or not and how they deal with obstacles such as seasonality through cost management. The methodology used was based on an exploratory and bibliographic research with a qualitative approach, seeking to analyze the triad: Entrepreneurship, Seasonality and Cost Management. The field research was applied through a semi-structured questionnaire to the sample of 100 Microentrepreneurs in the trade of goods and services in Caraguatatuba and São Sebastião, central cities of the North Coast of São Paulo. The main results show that most of the interviewed entrepreneurs perceive a certain impact caused by seasonality, understand the use of Cost Management to improve their processes and are adapted to one of the main costing methods highlighted by the bibliography.

A temática “dados pessoais” está em alta devido ao lançamento da Lei Geral de Proteção de Dados (LGPD), também conhecida como Lei nº 13.709/2018, e trata de qualquer relação entre o tratamento de informações classificadas como dados pessoais por qualquer meio, seja pessoa física ou jurídica, a proteção de dados pessoais. Este novo cenário para as empresas e organizações exigirá diversas adaptações e ajustes nos processos que envolvam dados pessoais, um diagnóstico inicial, para verificar se estes processos estão adequados ou não a LGPD, será necessário para orientar e organizar os procedimentos. Isso posto, este artigo tem o objetivo de levantar e discutir os modelos ou frameworks existentes na literatura para diagnosticar se os processos estão adequados ou não a LGPD. O objetivo desta pesquisa foi alcançado, pois identificou-se e discutiu-se dois modelos ou frameworks existentes na literatura para diagnosticar se os processos estão adequados ou não a LGPD. A importância destes frameworks é grande, pois facilita e organiza os diagnósticos dos processos das empresas em relação ao LGPD.

Multiple phylogenetic studies of HIV in sub-Saharan Africa have shown that mobility-driven transmission frequently occurs: many communities export and import strains. Mobility-driven transmission can result in source-sink dynamics: one community can sustain a micro-epidemic in another community in which transmission is too low to be self-sustaining. In epidemiology, the basic reproduction number (R0) is used to specify the sustainability threshold. R0 represents the average number of secondary infections generated by one infected individual in a community in which everyone is susceptible. If R0 is greater than 1, transmission is high enough to sustain an epidemic; if R0 is less than 1, it is not. Here, we discuss the conditions that are needed (in terms of R0) for source-sink transmission dynamics to occur in generalised HIV epidemics in sub-Saharan Africa, present an example of where these conditions could occur (ie, Namibia), and discuss the necessity of considering mobility-driven transmission when designing control strategies. Additionally, we discuss the need for a new generation of HIV transmission models that are more realistic than the current models. The new models should reflect not only geographical variation in epidemiology and demography, but also the spatial-temporal complexity of population-level movement patterns.