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Human DNA present in faecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is presently unclear how much personal information can be reconstructed from such reads, and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable efficient use of human genetic information in stool samples, such as for research and forensics. Here we used genomic approaches to reconstruct personal information from the faecal metagenomes of 343 Japanese individuals with associated human genotype data. Genetic sex could be accurately predicted based on the sequencing depth of sex chromosomes for 97.3% of the samples. Individuals could be re-identified from the matched genotype data based on human reads recovered from the faecal metagenomic data with 93.3% sensitivity using a likelihood score-based method. This method also enabled us to predict the ancestries of 98.3% of the samples. Finally, we performed ultra-deep shotgun metagenomic sequencing of five faecal samples as well as whole-genome sequencing of blood samples. Using genotype-calling approaches, we demonstrated that the genotypes of both common and rare variants could be reconstructed from faecal samples. This included clinically relevant variants. Our approach can be used to quantify personal information contained within gut metagenome data.

Understanding the genetic effects on non-coding RNA (ncRNA) expression facilitates functional characterization of disease-associated genetic loci. Among several classes of ncRNAs, microRNAs (miRNAs) are key post-transcriptional gene regulators. Despite its biological importance, previous studies on the genetic architecture of miRNA expression focused mostly on the European individuals, underrepresented in other populations. Here, we mapped miRNA expression quantitative trait loci (miRNA-eQTL) for 343 miRNAs in 141 Japanese using small RNA sequencing and whole-genome sequencing, identifying 1275 cis-miRNA-eQTL variants for 40 miRNAs (false discovery rate < 0.2). Of these, 25 miRNAs having eQTL were unreported in the European studies, including 5 miRNAs with their lead variant monomorphic in the European populations, which demonstrates the value of miRNA-eQTL analysis in diverse ancestral populations. MiRNAs with eQTL effect showed allele-specific expression (ASE; e.g. miR-146a-3p), and ASE analysis further detected cis-regulatory variants not captured by the conventional miRNA-eQTL mapping (e.g. miR-933). We identified a copy number variation associated with miRNA expression (e.g. miR-570-3p, P = 7.2 × 10−6), which contributes to a more comprehensive landscape of miRNA-eQTLs. To elucidate a post-transcriptional modification in miRNAs, we created a catalog of miRNA-editing sites, including 10 canonical and 6 non-canonical sites. Finally, by integrating the miRNA-eQTLs and Japanese genome-wide association studies of 25 complex traits (mean n = 192 833), we conducted a transcriptome-wide association study, identifying miR-1908-5p as a potential mediator for adult height, colorectal cancer and type 2 diabetes (P < 9.1 × 10−5). Our study broadens the population diversity in ncRNA-eQTL studies and contributes to functional annotation of disease-associated loci found in non-European populations.

Novel biomarkers of rheumatoid arthritis (RA), in addition to antibodies against cyclic citrullinated peptides, are required. Metabolome analysis is a promising approach to identify metabolite biomarkers for clinical diagnosis. We adopted a comprehensive non-targeted metabolomics approach combining capillary electrophoresis time-of-flight mass spectrometry (TOFMS) and liquid chromatography TOFMS. We constructed metabolomics profiling of 286 plasma samples of a Japanese population [92 RA patients, 13 systemic lupus erythematosus (SLE) patients and 181 healthy controls). RA case–control association tests showed that seven metabolites exhibited significantly increased levels in RA samples compared with controls (P < 1.0 × 10−4; UTP, ethanolamine phosphate, ATP, GDP, ADP, 6-aminohexanoic acid and taurine), whereas one exhibited a decreased level (xanthine). The plasma levels of these eight metabolites were not significantly different between seropositive and seronegative RA patients (P > 0.05; n = 68 and 24, respectively). The four nucleotide levels (UTP, ATP, GDP and ADP) were significantly higher in the non-treatment patients in comparison between patients with and without treatment (P < 0.014; n = 57 and 35, respectively). Furthermore, we found that none of the four nucleotide levels showed significant differences in SLE case–control association tests (P > 0.2; 13 patients with SLE and the 181 shared controls) and psoriatic arthritis (PsA) case–control association tests (P > 0.11; 42 patients with PsA and 38 healthy controls), indicating disease specificity in RA. In conclusion, our large-scale metabolome analysis demonstrated the increased plasma nucleotide levels in RA patients, which could be used as potential clinical biomarkers of RA, especially for seronegative RA., Plasma nucleotide levels are new biomarkers for RA

Biological disease-modifying anti-rheumatic drugs (bDMARDs) against pathogenic proinflammatory cytokines and lymphocytes, such as tumour necrosis factor-α (TNF-α), interleukin-6, T cells and B cell...

ObjectiveThe causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome’s role in RA pathology by a comprehensive metagenome-wide association study (MWAS).MethodsWe conducted MWAS of the RA gut microbiome in the Japanese population (ncase=82, ncontrol=42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample). Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis).ResultsPhylogenetic case–control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola) in the RA case metagenome. The non-linear machine learning method efficiently deconvoluted the case–control phylogenetic discrepancy. Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls. A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case–control comparison. A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results. No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls.ConclusionOur shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome’s role in RA aetiology.

A 26-year-old woman with Takayasu's arteritis (TAK) experienced back and neck pain during tocilizumab (TCZ) treatment. The levels of C-reactive protein were normal, and ultrasonography revealed no significant changes. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement in the walls of several arteries. Contrast computed tomography showed arterial inflammation in the same lesion. After increasing the dose of prednisolone and TCZ, all signal enhancements decreased and continued to decrease, as observed on days 76 and 132. Thus, DWIBS may be a novel imaging modality for assessing the disease activity of TAK, particularly during follow-up.

ObjectiveThe relationship between autoimmune diseases and the gut microbiome has been intensively studied, and several autoimmunity-associated bacterial taxa have been identified. However, much less is known about the roles of the gut virome in autoimmune diseases.MethodsHere, we performed a whole gut virome analysis based on the shotgun sequencing of 476 Japanese which included patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis and healthy control subjects.ResultsOur case–control comparison of the viral abundance revealed that crAss-like phages, which are one of the main components of a healthy gut virome, significantly decreased in the gut of the patients with autoimmune disease, specifically the patients with RA and SLE. In addition, Podoviridae significantly decreased in the gut of the patients with SLE. To understand how these viruses affected the bacteriome, we performed a quantitative virus–bacterium association analysis and clustered regularly interspaced short palindromic repeat-based virus–bacterium interaction analysis. We identified a symbiosis between Podoviridae and Faecalibacterium. In addition, multiple bacterial targets of crAss-like phages were identified (eg, Ruminococcus spp).ConclusionOur data suggest that the gut virome can affect our body either directly or via bacteria. Our analyses have elucidated a previously missing part of the autoimmunity-associated gut microbiome and presented new candidates that contribute to the development of autoimmune diseases.

MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA–target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (∼1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA–target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (nTotal = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 × 10−8). Our result highlighted that miRNA–target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers.

Ising machines have attracted attention, which is expected to obtain better solutions of various combinatorial optimization problems at high speed by mapping the problems to natural phenomena. A slot-placement problem is one of the combinatorial optimization problems, regarded as a quadratic assignment problem, which relates to the optimal logic-block placement in a digital circuit as well as optimal delivery planning. Here, we propose a mapping to the Ising model for solving a slot-placement problem with additional constraints, called a constrained slot-placement problem, where several item pairs must be placed within a given distance. Since the behavior of Ising machines is stochastic, the obtained solution does not always satisfy the slot-placement constraint, which is different from the conventional methods such as the conventional simulated annealing. To resolve the problem, we propose an interpretation method in which a feasible solution is generated by post-processing procedures. Using an Ising machine computer, feasible solutions could be obtained up to 50 times faster than the conventional simulated annealing without degrading accuracy for constrained slot-placement problems with 6 x 6 slots and 27 items at the maximum.

Background Severe infections that complicate rheumatoid arthritis may cause significant morbidity and mortality. The Modified Health Assessment Questionnaire (MHAQ) is one of the scores most used for measuring the functional status of rheumatoid arthritis (RA) patients. However, the relationship between the MHAQ score and severe infection risk has not been well studied [1]. Objectives To examine the relationship between disease-associated functional status (MHAQ) and severe infection events (SIE) in rheumatoid arthritis patients. Methods We used data from the “MiRAi” cohort in Japan. In total, 2174 RA outpatients were examined at the Osaka Minami Medical Center between January 2012 and October 2017. The risk factors were identified and evaluated by multivariate logistic regression, linearity analysis. Interactions of SIE risk between MHAQ and treatment were also observed. Results The cohort contributed to 8206 patient-years of follow-up. Overall, 251 SIEs were observed and the incidence of SIE was 3.0 infections per 100 patient-years. The mean age at first observation was 61.7 years and the mean disease duration was 10.3 years. The use of glucocorticoids (GCs), methotrexate (MTX), and biologic and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs/tsDMARDs) was 59.2%, 63.8%, and 40.3%, respectively. The mean Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Disease Activity Scores of 28 joints (DAS28), and MHAQ at first observation were 9.76±6.39, 10.1±6.87, 2.67±0.96, and 0.43±0.58, respectively. Disease duration, the MHAQ score, and prednisolone dose (p=0.015, 0.007, and Conclusion An increased MHAQ score was lineally associated with SIE, and did not show significant interactions with bDMARD/tsDMARD use or the oral glucocorticoid dose. Therefore, the MHAQ score is considered to be a strong, independent risk factor for infection in RA patients. Reference [1] Yamanaka H, Askling J, Berglind N, Franzen S, Frisell T, Garwood C, Greenberg JD, Ho M, Holmqvist M, Novelli Horne L, et al: Infection rates in patients from five rheumatoid arthritis (R017, 3(2):e000498A) registries: contextualising an RA clinical trial programme. RMD Open 2017, 3(2):e000498. Disclosure of Interests Yuji Yoshida: None declared, Shiro Ohshima Grant/research support from: AbbVie, Eisai, Asahikasei, Speakers bureau: AbbVie, Eisai, Bristol-Meyers, Novartis, Astellas, Nippon-Kayaku, Pfizer, UCB, Ayumi, Daiichi-Sankyo, Takeda, Tanabe-Matsubishi, Chugai, Eri Oguro: None declared, Kentaro Kuzuya: None declared, Yasutaka Okita: None declared, Hidetoshi Matsuoka: None declared, Satoru Teshigawara: None declared, Maiko Yoshimura: None declared, Kentaro Isoda: None declared, Yoshinori Harada: None declared, Jun Hashimoto: None declared, Yukihiko Saeki: None declared

Background: One of the most important complications of biological disease-modifying antirheumatic drugs (bDMARDs) is severe infection, and management of patients who develop severe infection during treatment with bDMARDs is a great concern. However, no consensus exists regarding bDMARDs readministration following treatment for bDMARDs-associated infection. Objectives: We elucidated risk factors associated with severe infection recurrence in patients who developed severe infections during bDMARDs therapy. Severe infection was defined as an infection requiring hospitalization. Moreover, we analyzed whether bDMARDs readministration after severe infection in patients with rheumatoid arthritis (RA) was a risk for severe infection recurrence. Methods: The study sample comprised patients with RA who were examined and prescribed bDMARDs at Osaka Minami Medical Center between January 2010 and December 2017, as part of the MiRAi cohort. The patients who developed severe infections during bDMARDs treatment were followed-up for 12 months. Logistic regression analysis was performed using baseline disease activity, baseline treatment, and disease activity and treatment during the 12-month period. Results: Severe infections developed in 164 of a total of 1192 patients who were treated with bDMARDs during the study period, and the severe infection rate was 5.73/100 patients-years. Among the 164 patients, bDMARDs were readministered in 130 (79.3%), whereas treatment with bDMARDs was discontinued in 34 patients (20.7%). We observed 31 cases of patients with severe infections during the follow-up period (18.9/100 patients-years), of which 20 patients (15.4/100 patients-years) belonged to the bDMARDs readministration group and 11 (32.4/100 patients-years) belonged to the bDMARDs discontinuation group. The adjusted odds ratio (OR) for severe infection recurrence within 12 months in the bDMARDs readministration group was 0.39 [95% confidence interval (CI) 0.16–0.96]. At 12 months after infection, high-dose prednisolone treatment (adjusted OR 1.35, 95%CI 1.08–1.69), high C-reactive protein level (adjusted OR 1.28, 95%CI 1.02–1.62), and low serum albumin levels (adjusted OR 0.30, 95%CI 0.01–0.89) were associated with high risk of severe infection recurrence (Figure). Conclusion: Patients who developed severe infection during bDMARDs treatment were at an extremely high risk for severe infection irrespective of the readministration or discontinuation of bDMARDs after infection. Discontinuation of bDMARDs, high dose of prednisolone 12 months after infection, high levels of C-reactive protein 12 months after infection, and low levels of albumin 12 months after infection were identified as risk factors for severe infection recurrence in these patients. However, bDMARDs readministration did not increase the risk of severe infection recurrence. Reference: [1] Ramiro et al, Ann Rheum Dis 2017;76:1093-1101. Disclosure of Interests: Eri Oguro: None declared, Yuji Yoshida: None declared, Kentaro Kuzuya: None declared, Yasutaka Okita: None declared, Hidetoshi Matsuoka: None declared, Satoru Teshigawara: None declared, Maiko Yoshimura: None declared, Kentaro Isoda: None declared, Yoshinori Harada: None declared, Shiro Ohshima Grant/research support from: AbbVie, Eisai, Asahikasei, Speakers bureau: AbbVie, Eisai, Bristol-Meyers, Novartis, Astellas, Nippon-Kayaku, Pfizer, UCB, Ayumi, Daiichi-Sankyo, Takeda, Tanabe-Matsubishi, Chugai, Jun Hashimoto: None declared, Yukihiko Saeki: None declared

A 66-year-old woman with symptoms of fatigue and headache was diagnosed with giant cell arteritis (GCA). Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) revealed the strong accumulation of FDG in the descending aorta, abdominal aorta, bilateral subclavian artery, and total iliac artery. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement at the descending aorta and abdominal aorta. We repeated FDG-PET and DWIBS 2 months after the initiation of therapy with prednisolone. In line with the FDG-PET findings, the signal enhancement of the aortic wall completely vanished on DWIBS. DWIBS may be a novel useful tool for the diagnosis and follow-up of GCA treatment.

Objectives To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism. Methods The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the “NinJa” Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A. Results The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305–3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879–2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1β and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor. Conclusions These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits.

Background Tocilizumab (TCZ), an inhibitor of interleukin-6 (IL-6), has been widely used to treat rheumatic diseases such as rheumatoid arthritis (RA) and juvenile idiopathic arthritis. Recently, TCZ was approved for use in patients with giant cell aortitis and Takayasu aortitis. However, TCZ treatment sometimes obscures changes in the conventional biomarkers for infection such as serum levels of C-reactive protein (CRP) and procalcitonin (PCT). Presepsin (P-SEP), a subtype of soluble CD14, has been recently identified as a biomarker for sepsis. In addition, we have reported the usefulness of P-SEP for the diagnosis of bacterial infection in RA patients because it is less affected by the disease activity. Objectives To examine the usefulness of P-SEP in RA patients complicated with bacterial infections during TCZ treatment. Methods In this study, 49 RA patients with bacterial infections (i+RA), 76 RA patients without bacterial infections (RA) and 23 healthy controls (HC) were enrolled. The presence of infection was strictly diagnosed by bacteriological examinations, typical clinical characteristics such as fever (38.0°C) and/or CRP elevation and/or increased white blood cell count, and improvements of these manifestations with antibiotics. Serum P-SEP levels were measured by an immunoassay. The CRP and PCT levels were measured simultaneously. Results The median serum P-SEP levels were 186.0 [interquartile range (IQR), 134.0–236.0], 691.0 [IQR, 345.5–842.0], 154.5 [IQR, 145.8–165.5] l, and 161.0 [IQR, 146.5–166.0] pg/mL for TCZ (n=25), i+TCZ (pre-antibacterial treatment; n=7), i+TCZ (post-antibacterial treatment; n=7) and the HC group, respectively. The P-SEP levels of the i+TCZ group were significantly elevated compared with those of the TCZ group (p Conclusions These results suggest that serum P-SEP levels are less affected by TCZ treatment compared with other conventional inflammatory biomarkers such as CRP and PCT. Moreover, P-SEP levels are useful for the assessment of bacterial infections in RA patients treated with TCZ. Reference [1] Tsuji S, et al. Mod Rheumatol2017;27(4):718–720. Disclosure of Interest None declared

Background and purpose Interferons (IFN), such as IFNα and IFNγ, are known to play a pivotal role for the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). These IFNs enhance the expression of mCD64. We recently have reported a tight correlation between mCD64 expression levels and SLE disease activity index (SLEDAI) (r=0.68, p Method mCD64 expression levels were assessed quantitatively by using flow cytometry in five patients with NPSLE. The mCD64 expression levels were compared with SLEDAI and other conventional SLE activity markers, such as anti-dsDNA antibody, complements and cerebrospinal fluid (CSF) IL-6. Result The NPSLE events included three headaches, two aseptic meningitis and one acute confusion. At the active phase of these NPSLE events, mCD64 expressions were significantly enhanced at the median of 38 541 (range 31,693–73,287) molecules/cell compared to the treated inactive phase. Additionally, mCD64 expression was significantly higher in CSF IL-6 high (more than 4.3 pg/ml) group than the low group (p=0.011). The mCD64 expression levels were significantly decreased at the inactive phase of the NPSLE after treatment (p=0.027) shown in figure 1. The changes of mCD64 expression levels correlated with SLEDAI (r=0.74, p=0.014). Conclusions mCD64 expression may be a potential biomarker for evaluating not only the disease activity but also the response of treatment in NPSLE.

Background Adult-onset Still9s disease (AOSD) is a systemic inflammatory disease of unknown etiology. Overproduction of multiple inflammatory cytokines and subsequent hyperactivation of monocytes/macrophages are prominent characteristics of AOSD. However, there are no convenient and precise methods for evaluating monocyte/macrophage activation in AOSD. We previously reported that monocyte CD64 (mCD64) expression could be quantitatively measured by flow cytometry and its expression was tightly correlated with the activity of systemic lupus erythematosus. Objectives We examined the association between mCD64 expression and AOSD disease activity. Methods This was a prospective, single-center, observational study conducted between January 2013 and December 2016. Eleven active AOSD patients who fulfilled the Yamaguchi9s criteria for AOSD and had the modified Pouchot score of ≥2 were enrolled. The mCD64 expression levels were quantitatively measured by flow cytometry and individually assessed both before (Pouchot score ≥2) and after treatment (score 0). Other disease-related laboratory data, such as C-reactive protein, ferritin, and white blood cell count, were simultaneously measured. As a control, 16 active systemic lupus erythematosus (SLE) patients (SLE disease activity index ≥6), 22 active rheumatoid arthritis (RA) patients (disease activity score with 28-joint counts >3.2), and 20 healthy controls (HC) (female, 55%; mean age, 38.7±9.1 years) were enrolled. Statistical analysis was performed by the Mann-Whitney and Wilcoxon-paired tests. Results The median mCD64 expression levels were 73,339 [interquartile range (IQR), 45,861–88,181] and 16,443 (IQR, 45,891–88,181) molecules/cell before and after treatment, respectively. Thus, mCD64 expression levels were significantly decreased during the inactive phase compared with those in the active phase in AOSD (p=0.0001). The mCD64 expression levels were significantly higher in patients with active AOSD than in those with active SLE [34,648 (IQR, 44,204–24,657) molecules/cell, p=0.001], active RA [25,167 (IQR, 35,778–22,301) molecules/cell, p Conclusions These results suggest that mCD64 expression levels are highly upregulated in AOSD and tightly correlated with disease activity. The mCD64 expression level may be a useful biomarker for assessing the disease activity of AOSD. References Rau M, et al. J Rheumatol. 2010 Nov;37(11):2369–76. Kikuchi-Taura A, et al. Lupus. 2015 Sep;24(10):1076–80. Pouchot J, et al. Medicine. 1991;70:118–36. Disclosure of Interest None declared

A 72-year-old man presented with persistent oligoarthritis and positive results for rheumatoid factor and was suspected of having rheumatoid arthritis (RA). However, the musculoskeletal ultrasonography (MSUS) findings were not consistent with those of typical RA. He had undergone surgery for carpal tunnel syndrome, which allowed both histopathological and microbiological examinations to be performed. A synovial tissue culture was positive for Sporothrix schenckii, and he was diagnosed with sporotrichal tenosynovitis. He received anti-fungal therapy, and the sporotrichal tenosynovitis resolved. This case suggests that MSUS is a useful modality, and sporotrichal tenosynovitis, though rare, should be considered in the differential diagnosis of RA.

Background and aims Lupus nephritis (LN) is one of the most serious clinical manifestations of systemic lupus erythematosus (SLE). Recently, we have reported that the expression levels of CD64 on monocyte (mCD64), a high-affinity receptor for IgG (FcgRI), correlate with the disease activity of SLE (Lupus 2015;24:1076–80). However, the relation between lupus nephritis (LN) and mCD64 expression is yet to be elucidated. The aim of this study is to investigate whether or not mCD64 expression level correlates with the activity of LN. Methods We quantitatively measured the mCD64 expression levels by flow cytometry in eight SLE patients with biopsy proven LN before and after treatment. All patients fulfilled the 1997 American College of Rheumatology classification criteria for SLE. The mCD64 expression levels of the individual patients were measured both at active (presence of proteinuria >0.5 g/day and/or active urinary sediment) and inactive phase (absence of proteinuria and active urinary sediment). The changes were analysed statistically (Wilcoxon signed-rank test). Results The mean±SD of mCD64 expression levels before and after treatment were 42 463±15 466 and 19 190±1696 molecules/cell, respectively (p Conclusions The mCD64 expression level correlates with the activity of LN, although a larger scale study is needed to confirm the results.

In questionnaire studies for evaluating objects such as manufacturing products, evaluators are required to respond to several evaluation items for the objects. When the number of objects is large, a part of the objects is often assigned randomly to each evaluator, and the response becomes a matrix with missing components. To handle this kind of data, we consider a model by using a dummy matrix representing the existence of the missing components, which can be interpreted as an extension of the GMANOVA model. In addition, to cope with the case where the numbers of the object and evaluation items are large, we consider a ridge-type estimator peculiar to our model to avoid instability in estimation. Moreover, we derive a C p criterion in order to select the tuning parameters included in our estimator. Finally, we check the validity of the proposed method through simulation studies and real data analysis.

We think there are many valuable techniques which is able to improve the environmental performance in the traditional old house. Therefore, we investigated the space layout and environmental performance of IGURATSUKURI houses in KAMO area. As a result, we clarified some space layout techniques for climate characteristics of IGURATSUKURI houses, as follows: 1) technique to keep out the seasonal wind in winter and let in the seasonal wind in summer, 2) technique to use rooms in winter and summer, 3) technique to control sunlight by a double roof.

2004年9月5日に紀伊半島南東沖で発生した地震（Mj7.4）は南海トラフ軸付近で発生した津波を伴う大地震である。この地震の発震機構は南北方向に圧縮軸を持つ逆断層型で、フィリピン海プレート内あるいは上部マントルで発生したものと解釈されている。我々はこの地震の詳細な余震分布とその時空間推移を調査するため、自己浮上式海底地震計（OBS）による余震観測を実施した。余震観測は2004年9月から2005年8月までの期間、断続的に3回にわたって実施された。震源決定に用いた1次元P波の速度構造はOBSの観測海域で実施された速度構造探査結果を参照して求めた。また震源の決定精度を向上させるため、PS変換波を用いた堆積層補正をおこなった。その結果、気象庁一元化震源に比べ詳細かつ高精度な余震分布を得ることができた。OBS観測から求めた余震の震源は気象庁一元化震源と比較すると、深さは20kmほど浅く5～30kmに分布し、震央については全体的に南東方向に10kmほどシフトした。気象庁一元化震源では余震活動は主にトラフ軸より陸側に分布するように見えていたが、主たる余震活動はトラフ軸沿いで発生していることがわかった。また、余震活動は深さ5～10 kmの比較的浅い地震群と、深さ15～30kmの比較的深い地震群の2群に分かれていることが見出された。前者は余震域の中央部から北部にかけてのフィリピン海プレート内およびその上部の付加体内で発生しており、後者は前震および本震の破壊域と思われる海溝軸下の上部マントルで発生していることがわかった。さらに、浅い地震群の中にいくつかの地震クラスターが見出された。これらの地震クラスターは付加体からフィリピン海プレート内までほぼ鉛直に下降しているとみられる。これら余震域の中で発見された地震クラスターは、超低周波地震の発生源となっている付加体の分岐断層との関係において興味が持たれる。

This paper focuses on the attempt to formulate the prescription prediction logic based on the medical data analysis towards the future computer-assisted-diagnosis for Kampo medicine. We constructed and evaluated prediction models for some frequently-used prescriptions using six kinds of machine learning algorithms including artificial neural network, multinomial logit, random forest, support vector machine, k-nearest neighbor, and decision tree. The possibility of prescription prediction and the necessary amount of data required for robust prediction are clarified.

Background There is little evidence on prediction of clinical response to biologics in patients with RA. Recently, it has been suggested that clinical response to tumor necrosis factor (TNF) inhibitors was related to periodontal conditions, which might be affected by infection with Porphyromonas gingivalis ( P.g. ). Additionally, serum antibody responses to P. g were associated with RA and periodontitis.Newly established test of antibody against hemin binding protein 35 (HBP) of P.g. , which has an ability specifically bind to P.g. containing protein HBP, can be available. Objectives To evaluate whether serum antibody responses to P.g. antigens and periodontal conditions are associated with clinical response to biologics in patients with RA. Methods 20 patients with severe RA enrolled in this study were treated with biologics according to the usual regimen. Clinical background and disease parameters were assessed at entry. DAS28-CRP was evaluated at 6 months (reassessment) after the initiation of biologics. Periodontal conditions were also assessed at entry. Serum levels of antibodies against P.g. sonicated extracts (SE) and HBP of P.g. were determined by enzyme-linked immunsorbent assay, respectively. Results Their mean (SD) age was 57.2 (13.4) years. Patients were predominantly women (85%) with mean disease duration of 8.2 (6) years.10 patients were treated with TNF-i, 7 with IL-6 blocker and 3 with CTLA4-Ig, respectively. Most patients had active disease with DAS28-CRP 4.2 (0.9) at baseline, and showed an improvement of DAS28-CRP 2.87 (0.82) at reassessment. Seven patients (35%) achieved remission (DAS28-CRP

In this paper, we propose a new model construction method utilizing application specific physical information and present its application to SRAM yield calculation. The physical information is extracted as statistical distributions from past simulation results automatically. Experimental results show our method achieves 700x speed up over non modeling method and more than 10x speed up over the conventional modeling method. It requires only 5.3 samples to model a fifth order full cross term polynomial with 21 coefficients and is free from over-fitting and singular matrix problem. This modeling method can be a general approach to create models with application specific physical information.

Many applications on multiprocessors have their own locality in communication. Since convectional networks don't necessarily make full use of these localities, it sometimes causes local congestion of networks and large latency. In this paper, we propose a new network architecture (ToF-net). It has topological and routing flexibility with low latency. Also, the ASIC that we developed to organize it is presented. According to our estimation, the ToF-Net has the advantage of less latency and higher throughput with increasing locality or packet length over conventional networks such as 3-D torus and hypercube. >

Background An increased risk of respiratory infections among rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ) has been known through clinical trials and by postmarketing surveillance. So far, little data is available from detailed analysis of respiratory infections among RA patients with long-term follow-up of TCZ treatment in daily clinical practice. Objectives To study the frequency, degree of laboratory data of respiratory infections, and the frequency of patients who discontinued TCZ because of respiratory infection among RA patients treated with TCZ for average 2.7 years. Methods One hundred and seventeen RA patients (mean age 56±12.5 years: 85% women) have been treated with TCZ (8mg/kg) for more than 24 weeks in our hospital after June 2008. Respiratory infection (bronchitis, pneumonia and tuberculosis) was detected by chest radiography, pulmonary CT and clinical records indicating the use of antibiotics. Frequency of respiratory infections, the titer of WBC and C-reactive protein (CRP) and cessation period of TCZ were described. Results 117 RA patients were treated with TCZ. Mean treatment duration was 2.66±1.43 years [7 months∼5.5 years]. Mean prednisolone use was 5.1±5.2 mg and 59.4% were concomitantly used methotrexate at the beginning of the start of TCZ. Mean baseline DAS28-CRP was 4.55±1.26. Respiratory problems occurred in 23 patients. Bronchitis occurred in 13 cases among 11 patients, pneumonia occurred in 12 cases for 10 patients, 1 patient was considered as methotrexate-induced pneumonia and upper respiratory tract tuberculosis was found in 1 patient. Mean WBC count and CRP for bronchitis patients were 6,650±3,470/mm 3 and 2.4±3.0 mg/L, respectively. Mean WBC count and CRP for pneumonia patients were 10,420±6,780/mm 3 and 10.3±20.8 mg/L, respectively. The titer of CRP was normal for the entire observation period for respiratory problems in 84.6% of bronchitis cases, and 41.7% of pneumonia cases. All bronchitis and pneumonia cases responded to antibiotics. Admission to hospital was necessary only for pneumonia cases (75%). In most of the cases restart of TCZ was possible. In cases of pneumonia, mean cessation period of TCZ was average 4.8 weeks [0∼18 weeks, median 3 weeks]. TCZ was withdrawn in 2 cases, that is the upper respiratory tract tuberculosis case and a repeated pneumonia case. Conclusions Masked early symptoms and laboratory abnormalities of pneumonia in patients with RA during TCZ treatment are sometimes described in literature. We confirmed this fact by following patients for average 2.7 years. Our analyses, composed of 117 patients, showed about half of the pneumonia patients of RA with TCZ treatment did not show elevation of CRP for the entire period of pneumonia. These facts indicate that appropriate treatment for respiratory infections among RA patients treated with TCZ is linked to putting diagnostic weight on symptoms and careful image examination. References Yanagawa Y, et al. BMJ Case Rep. published online 23 May 2012. Acknowledgements The authors thank Ms. Ayumi Kondou for her excellent secretarial assistance. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3072

An ultrathin MgO/Fe seed layer was introduced to manipulate the crystal orientation and crystallinity of Fe/MgO/Fe trilayers. The crystallographic properties and magnetic properties of the trilayer are investigated. It is concluded that the texture of the MgO layer is strongly dependent on the texture of the Fe layer. (001) oriented Fe layer can assist the growth of (001) oriented MgO barrier upon annealing. A 0.5 nm MgO seed layer can introduce (001) orientation in the following Fe layer. It is also found that the crystal orientation of the Fe/MgO/Fe trilayer is independent of the initial Fe seed layer thickness. However, the crystallinity of both the Fe layer and the MgO layer is dependent on the initial Fe seed layer.

The annealed copper and JIS S15C steel were fatigue-tested under rotating bending and the growth behavior of microcracks was examined through an optical microscope. The distribution of crack size was found to be described by either a single straight line or a broken line on the Weibull plot. The appearance of the break is due to the coalescence of pretty large cracks of the size from about 100 to 200μm. The maximum crack size plotted against the ratio of a given cycle number to that to failure, N/Nf, increased discontinuously around N/Nf≅0.4 in copper. On the other hand, it rose continuously in the most part of fatigue process in S15C steel and a sudden ascent on this curve occurred around N/Nf≅0.6-0.8. Such a discontinuous increase in the maximum crack size is also due to the coalescence of pretty large cracks mentioned above. These results indicate that the fatigue process is controlled mainly by the gradual growth and connection of microcracks less than about 100-200μm in size in S15C steel, while the discontinuous joining of pretty large cracks dominates the fatigue process in copper.The relation between the maximum crack size and the cycle ratio, N/Nf, was almost independent of cyclic stress level in copper, while it was definitely influenced by this in S15C steel. The magnitude of cumulative cycle ratio in the double repeated fatigue tests under two step stress amplitudes, which had been found to be dependent on the kind of materials, was reasonably interpreted through such crack growth behaviors.The Frenche's damage lines were found to be located at N/Nf≅0.1 and 0.50 in copper and S15C steel, respectively. The cracks of about 120μm in size were formed at these lines in both materials.