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This study aimed to evaluate whether equol production status has an impact on the risk of locomotive syndrome in very elderly (≥85 years old) women. In this retrospective observational study, 116 very elderly women were recruited from those who lived in nursing homes for the elderly from June 2018 to November 2019. Equol production status was determined by measuring spot urine levels of equol, and risks of locomotive syndrome were evaluated by vulnerable fracture history and loco-check, a simple questionnaire comprising seven questions that can describe locomotive syndrome. Equol production (≥1 μmol/L in a spot urine sample) was found in 46 women (39.6%). Loss of equol production contributes to some lococheck items, which correlate with weakness of lower limb muscle strength (P < 0.05). In this study population, 57 women (49.1%) had previous vulnerable fractures. However, equol production status was not significantly related to the vulnerable fracture in this study population (P = 0.159). Equol production might contribute to the induction of locomotive syndrome, at least in part. However, equol deficiency as a mechanism of locomotive syndrome induction might not be the primary cause of a previous vulnerable fracture in very elderly women who live in nursing homes.

Ξ− atomic X-ray spectroscopy is one of the most useful methods for investigation of the Ξ–nucleus strong interaction. Since the X-ray energy is shifted and/or broadened due to the Ξ–nucleus strong interaction compared to those calculated from electromagnetic interaction alone, the measurement of the energy shift, ΔE, and the width, Γ, give us information on the Ξ–nucleus potential. A serious problem in the measurement is the significant background derived from in-flight Ξ− decay. A novel method of identifying stopped Ξ− events using the nuclear emulsion was developed to realize the first Ξ− atomic X-ray spectroscopy experiment as the J-PARC E07 experiment, which also aimed at searching for ΛΛ and Ξ− hypernuclei in the emulsion. The X-rays emitted from Ξ− Br and Ξ− Ag atoms were measured using germanium detectors. No clear peaks were observed in the obtained spectra. However, we succeeded in reducing the background to 1/170 by this method employing coincidence measurements using nuclear emulsion and X-ray detectors.

Lymphoscintigraphy with single-photon emission computed tomography (SPECT-CT) is useful in diagnosing lymphedema. However, there are multiple timings, techniques, and tracers utilized worldwide without any comparison. We examined and compared the image clarity with two different radiotracers, 99mTc-human serum albumin (HSA) and 99mTc-phytate (phytate), in the same patients. The study retrospectivity examined 46 limbs of 36 patients who underwent lymphoscintigraphy using HSA and phytate from January 2013 to September 2018. Tracer accumulation in the lymph nodes, linear pattern (LP), and dermal backflow (DBF) were qualitatively analyzed; contrast-to-noise ratios (CNR) of DBF and standardized uptake value ratio (SUVR) of LP were also quantitatively analyzed. Neither lymph node accumulation nor DBF identification showed significant difference. However, a significant difference was observed between the LP identification of the unaffected (p

Until the early 1990s, cyst nematodes were abundant pathogens in fields where hosts of Heterodera spp. were frequent members of crop rotations along California’s Central Coast. To mitigate damage caused by Heterodera schachtii and H. cruciferae, the soil fumigant 1,3-dichloropropene (1,3-D) was used by more than 43% of surveyed broccoli growers. Over the last few decades, use of 1,3-D and other nematicides has dramatically diminished, suggesting a decline in nematode disease pressure. The goal of this study was to examine the hypothesis that increased population densities of nematophagous fungi contribute to the low populations of Heterodera spp. in fields frequently cropped to their hosts. In 2016, soil samples were collected from 152 Brassica fields with a broad geographical distribution, from Santa Barbara County to Santa Cruz County. The average number of Heterodera cysts per 250 cm3 of soil ranged from 0.5 to 27.5, with 62% of the soils harboring no detectable cyst nematodes and only a few samples reaching a potentially damaging threshold level. A baiting experiment with H. schachtii and cabbage was performed in a greenhouse to detect nematophagous fungi associated with nematode females as their posterior end emerged and became exposed to the soil’s rhizosphere. An Illumina-based sequence analysis of these H. schachtii females identified several known nematophagous fungi, including members of the Hyalorbilia oviparasitica clade, Pochonia chlamydosporia, certain Fusarium spp., and others. These soils clearly harbor a diverse population of hyperparasitic fungi that could be biologically suppressing cyst nematodes below a damaging threshold. [Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

Allyl isothiocyanate (AITC) is a glucosinolate produced in cruciferous plant species. AITC is known to act as a pesticide on microorganisms, insects, and weeds. Synthetic AITC is registered as a biopesticide for agricultural soil treatment use in the United States and elsewhere in the world. Although a potent pesticide, reports on the weed and pathogen control efficacy of synthetic AITC applied as soil disinfectant are highly variable. Due to the low vapor pressure of AITC, questions remain as to whether pest and weed control efficacy can be improved by combining it with other chemicals. The objective of this study was to assess the control efficacy of AITC stand-alone applications vs. applications, in which AITC was combined with the standard-fumigants chloropicrin, 1,3-dichloropicrin, and methyl isothiocyanate. Two shank-applied on-farm field trials were conducted in cut flower [delphinium (Delphinium elatum), ranunculus (Ranunculus asiaticus)] fields, and two drip tape applied field trials in strawberry (Fragaria ×ananassa) fields in California. Weed pressure, weed seed viability, nematode survival, and pathogen survival of Pythium ultimum, fusarium wilt (Fusarium oxysporum), and verticillium wilt (Verticillium dahliae) were assessed. Cumulative yearly yield of marketable fruit was assessed in the strawberry field trials. The results of this study show that the use of AITC as a stand-alone treatment provided no consistent weed or pathogen control efficacy. However, our results also indicate that shank and drip applied multitactic fumigation approaches with AITC can efficiently control soil-borne diseases and weeds. These findings have potential implications, especially in those areas where certain fumigants are restricted due to regulations and/or availability.

A learning-based THz multi-layer imaging has been recently used for contactless three-dimensional (3D) positioning and encoding. We show a proof-of-concept demonstration of an emerging quantum machine learning (QML) framework to deal with depth variation, shadow effect, and double-sided content recognition, through an experimental validation., Comment: 2 pages, 5 figures, IRMMW-THz2022

The differential cross sections of the Σ^{-}p→Λn reaction were measured accurately for the Σ^{-} momentum (p_{Σ}) ranging from 470 to 650 MeV/c at the J-PARC Hadron Experimental Facility. Precise angular information about the Σ^{-}p→Λn reaction was obtained for the first time by detecting approximately 100 reaction events at each angular step of Δcosθ=0.1. The obtained differential cross sections show a slightly forward-peaking structure in the measured momentum regions. The cross sections integrated for -0.7≤cosθ≤1.0 were obtained as 22.5±0.68 [statistical error(stat.)] ±0.65 [systematic error(syst.)] mb and 15.8±0.83(stat)±0.52(syst) mb for 470p_{Σ}(MeV/c)550 and 550p_{Σ}(MeV/c)650, respectively. These results show a drastic improvement compared with past measurements of the hyperon-proton scattering experiments. They will play essential roles in updating the theoretical models of the baryon-baryon interactions.

In the autonomous driving era, automotive architecture has been rapidly progressing toward electronic control unit (ECU) integration and centralization. Advanced vehicle control is becoming increasingly important for safe driving. It requires microcontroller unit (MCU) integration, the highest automotive safety integrity level (ASIL), and network performance improvement. A 28-nm 600-MHz automotive flash MCU has been developed for next-generation automotive architecture. The MCU for vehicle control integrates three key features: a virtualization-assisted processor (VAP) for functional safety, a built-in self-test in the field (field-BIST) at a sleep resume (SR) BIST for functional safety, and a serial gigabit media independent interface (SGMII) for the in-vehicle network. The VAP helps the hypervisor to realize real-time virtualization to execute several different virtual machines without interference. The SR-BIST realizes random hardware failures per hour of 10−8 in various automotive applications. In the SGMII circuit, we used 5-V transistors for high reliability despite their narrow bandwidth. The automotive MCU satisfies the ISO26262 ASIL D system requirements with a low power consumption of 0.52 W. The VAP can realize the severe automotive control hard real time capability.

The lettuce downy mildew pathogen, Bremia lactucae, is an obligate oomycete that causes extensive produce losses. Initial chlorotic symptoms that severely reduce the market value of the produce are followed by the appearance of white, downy sporulation on the abaxial side of the leaves. These spores become airborne and disseminate the pathogen. Controlling lettuce downy mildew has relied on repeated fungicide applications to prevent outbreaks. However, in addition to direct economic costs, heterogeneity and rapid adaptation of this pathogen to repeatedly applied fungicides has led to the development of fungicide-insensitivity in the pathogen. We deployed a quantitative PCR assay-based detection method using a species-specific DNA target for B. lactucae coupled with a spore trap system to measure airborne B. lactucae spore loads within three commercial fields that each contained experimental plots, designated EXP1 to EXP3. Based upon these measurements, when the spore load in the air reached a critical level (8.548 sporangia per m3 air), we advised whether or not to apply fungicides on a weekly basis within EXP1 to EXP3. This approach saved three sprays in EXP1, and one spray each in EXP2 and EXP3 without a significant increase in disease incidence. The reduction in fungicide applications to manage downy mildew can decrease lettuce production costs while slowing the development of fungicide resistance in B. lactucae by eliminating unnecessary fungicide applications.

Isolates of the Fusarium oxysporum species complex have been characterized as plant pathogens that commonly cause vascular wilt, stunting, and yellowing of the leaves in a variety of hosts. F. oxysporum species complex isolates have been grouped into formae speciales based on their ability to cause disease on a specific host. F. oxysporum f. sp. fragariae is the causal agent of Fusarium wilt of strawberry and has become a threat to production as fumigation practices have changed in California. F. oxysporum f. sp. fragariae is polyphyletic and limited genetic markers are available for its detection. In this study, next-generation sequencing and comparative genomics were used to identify a unique genetic locus that can detect all of the somatic compatibility groups of F. oxysporum f. sp. fragariae identified in California. This locus was used to develop a TaqMan quantitative polymerase chain reaction assay and an isothermal recombinase polymerase amplification (RPA) assay that have very high sensitivity and specificity for more than 180 different isolates of the pathogen tested. RPA assay results from multiple field samples were validated with pathogenicity tests of recovered isolates.

This study determined the variability in population uniformity of an applied mixture of attenuated E. coli O157:H7 (attEcO157) on spinach leaves as impacted by sampling mass and detection technique over spatial and temporal conditions. Opportunistically, the survival and distribution of naturally contaminating pathogenic E. coli O157:H7 (EcO157), in a single packaged lot following commercial postharvest handling and washing, was also evaluated. From the main study outcomes, differences in the applied inoculum dose of 100-fold, resulted in indistinguishable population densities of approximately Log 1.1 CFU g−1 by 14 days post-inoculation (DPI). Composite leaf samples of 150 g and the inclusion of the spinach petiole resulted in the greatest numerical sensitivity of detection of attEcO157 when compared to 25 and 150 g samples without petioles (P

BACKGROUND AND PURPOSE: The hemodynamics associated with cerebral AVMs have a significant impact on their clinical presentation. This study aimed to evaluate the hemodynamic features of AVMs using 3D phase-contrast MR imaging with dual velocity-encodings. MATERIALS AND METHODS: Thirty-two patients with supratentorial AVMs who had not received any previous treatment and had undergone 3D phase-contrast MR imaging were included in this study. The nidus diameter and volume were measured for classification of AVMs (small, medium, or large). Flow parameters measured included apparent AVM inflow, AVM inflow index, apparent AVM outflow, AVM outflow index, and the apparent AVM inflow-to-outflow ratio. Correlation coefficients between the nidus volume and each flow were calculated. The flow parameters between small and other AVMs as well as between nonhemorrhagic and hemorrhagic AVMs were compared. RESULTS: Patients were divided into hemorrhagic (n = 8) and nonhemorrhagic (n = 24) groups. The correlation coefficient between the nidus volume and the apparent AVM inflow and outflow was .83. The apparent AVM inflow and outflow in small AVMs were significantly smaller than in medium AVMs (P

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

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

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

In an emulsion-counter hybrid experiment performed at J-PARC, a Ξ^{-} absorption event was observed which decayed into twin single-Λ hypernuclei. Kinematic calculations enabled a unique identification of the reaction process as Ξ^{-}+^{14}N→_{Λ}^{10}Be+_{Λ}^{5}He. For the binding energy of the Ξ^{-} hyperon in the Ξ^{-}-^{14}N system a value of 1.27±0.21 MeV was deduced. The energy level of Ξ^{-} is likely a nuclear 1p state which indicates a weak ΞN-ΛΛ coupling.

Downy mildew of spinach is caused by the obligate oomycete pathogen, Peronospora effusa. The disease causes significant economic losses, especially in the organic sector of the industry where the use of synthetic fungicides is not permitted for disease control. New pathotypes of this pathogen are increasingly reported which are capable of breaking resistance. In this study, we took advantage of new spinach genome resources to conduct RNA-seq analyses of transcriptomic changes in leaf tissue of resistant and susceptible spinach cultivars Solomon and Viroflay, respectively, at an early stage of pathogen establishment (48 hours post inoculation, hpi) to a late stage of symptom expression and pathogen sporulation (168 hpi). Fold change differences in gene expression were recorded between the two cultivars to identify candidate genes for resistance. In Solomon, the hypersensitive inducible genes such as pathogenesis-related gene PR-1, glutathione-S-transferase, phospholipid hydroperoxide glutathione peroxidase and peroxidase were significantly up-regulated uniquely at 48 hpi and genes involved in zinc finger CCCH protein, glycosyltransferase, 1-aminocyclopropane-1-carboxylate oxidase homologs, receptor-like protein kinases were expressed at 48 hpi through 168 hpi. The types of genes significantly up-regulated in Solomon in response to the pathogen suggests that salicylic acid and ethylene signaling pathways mediate resistance. Furthermore, many genes involved in the flavonoid and phenylpropanoid pathways were highly expressed in Viroflay compared to Solomon at 168 hpi. As anticipated, an abundance of significantly down-regulated genes was apparent at 168 hpi, reflecting symptom development and sporulation in cultivar Viroflay, but not at 48 hpi. In the pathogen, genes encoding RxLR-type effectors were expressed during early colonization of cultivar Viroflay while crinkler-type effector genes were expressed at the late stage of the colonization. Our results provide insights on gene expression in resistant and susceptible spinach-P. effusa interactions, which can guide future studies to assess candidate genes necessary for downy mildew resistance in spinach.

Background Spinach downy mildew caused by the oomycete Peronospora effusa is a significant burden on the expanding spinach production industry, especially for organic farms where synthetic fungicides cannot be deployed to control the pathogen. P. effusa is highly variable and 15 new races have been recognized in the past 30 years. Results We virulence phenotyped, sequenced, and assembled two isolates of P. effusa from the Salinas Valley, California, U.S.A. that were identified as race 13 and 14. These assemblies are high quality in comparison to assemblies of other downy mildews having low total scaffold count (784 & 880), high contig N50s (48 kb & 52 kb), high BUSCO completion and low BUSCO duplication scores and share many syntenic blocks with Phytophthora species. Comparative analysis of four downy mildew and three Phytophthora species revealed parallel absences of genes encoding conserved domains linked to transporters, pathogenesis, and carbohydrate activity in the biotrophic species. Downy mildews surveyed that have lost the ability to produce zoospores have a common loss of flagella/motor and calcium domain encoding genes. Our phylogenomic data support multiple origins of downy mildews from hemibiotrophic progenitors and suggest that common gene losses in these downy mildews may be of genes involved in the necrotrophic stages of Phytophthora spp. Conclusions We present a high-quality draft genome of Peronospora effusa that will serve as a reference for Peronospora spp. We identified several Pfam domains as under-represented in the downy mildews consistent with the loss of zoosporegenesis and necrotrophy. Phylogenomics provides further support for a polyphyletic origin of downy mildews. Electronic supplementary material The online version of this article (10.1186/s12864-018-5214-8) contains supplementary material, which is available to authorized users.