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Background:Residual synovitis can be detected by sensitive modalities such as ultrasonography in patients with rheumatoid arthritis in clinical remission. On the other hand, a previous study has shown that ultrasound-guided treatment provides modest benefit compared to a conventional strategy aiming clinical remission in early patients. It is still unclear how discordant clinical remission is from imaging remission by ultrasonography in patients treated with biologic agentsObjectives:To clarify the discordance between clinical remission and imaging remission in patients with rheumatoid arthritis treated with biologic agents.Methods:Patients with rheumatoid arthritis who were treated with biologic agents and in clinical remission defined as disease activity score for 28 joints (DAS28)Results:A total of 41 patients were enrolled with 22 patients treated with tumor necrosis factor (TNF)-α inhibitors and 19 with interleukin (IL)-6 inhibitors. The mean age, female ratio, the mean disease duration, and the mean duration of clinical remission were 60 years old, 87%, 5.1 years and 11.5 years. The imaging remission by ultrasonography was observed only in 51.2 %. When patients were divided according to biologic agents, baseline characteristics including median age, disease duration and clinically remission duration were comparable between both groups, while the rates of seropositivity and the stage of radiological progression was higher in IL-6 group (seropositivity, p=0.04; radiological progression, p=0.02). The mean DAS28 was 1.93 in the TNFα group and 1.02 in the IL-6 group. The discordance of clinical remission and imaging remission was observed in 28.6% of the TNFα group and 71.4% of the IL-6 group (p=0.03). The residual synovitis scores of GS and PD in 44 joints were significantly lower in the TNFα than the IL-6 group (GS, 1.1±1.8 vs 4.7 ± 4.6, pConclusion:Our results showed that there was substantial discordance between clinical remission and imaging remission, especially in the patients treated with IL-6 inhibitors. In patients treated with biologic agents, clinical remission should be assessed more stringently than the usual 2.6, and ulltrasound-guided management may be useful.References:[1]Smolen JS, et al. Ann Rheum Dis 2020;0:1–15.[2]Iwamoto T, et al. Arthritis Care Res (Hoboken). 2014;66(10):1576-81[3]Tanaka Y. Ann Rheum Dis 2010;69:1286 –91[4]Kaneko Y, et al. Ann Rheum Dis 2018;77:1268–1275[5]Brown AK, et al. Arthritis Rheum 2008;58: 2958 – 67.Acknowledgments:We would like to thank Harumi Kondo for their assistance.Disclosure of Interests:Yasushi Kondo: None declared, Yuko Kaneko Speakers bureau: Dr. Kaneko reports personal fees from AbbVie, personal fees from Astellas, personal fees from Ayumi, personal fees from Bristol-Myers Squibb, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Hisamitsu, personal fees from Jansen, personal fees from Kissei, personal fees from Pfizer, personal fees from Sanofi, personal fees from Takeda, personal fees from Tanabe-Mitsubishi, personal fees from UCB, Shuntaro Saito: None declared, Yuichiro Ohta: None declared, Komei Sakata: None declared, Yumiko Inoue: None declared, Chihiro Takahashi: None declared, Kazuoto Hiramoto: None declared, Jun Inamo: None declared, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd.

The electronic health record is a primary source of information for all professional groups participating in ICU rounds. We previously demonstrated that, individually, all professional groups involved in rounds have significant blind spots in recognition of patient safety issues in the electronic health record. However, it is unclear how team dynamics impacts identification and verbalization of viewed data. Therefore, we created an ICU rounding simulation to assess how the interprofessional team recognized and reported data and its impact on decision-making.Each member of the ICU team reviewed a simulated ICU chart in the electronic health record which contained embedded patient safety issues. The team conducted simulated rounds according to the ICU's existing rounding script and was assessed for recognition of safety issues.Academic medical center.ICU residents, nurses, and pharmacists.None.Twenty-eight teams recognized 68.6% of safety issues with only 50% teams having the primary diagnosis in their differential. Individually, interns, nurses, and pharmacists recognized 30.4%, 15.6%, and 19.6% of safety items, respectively. However, there was a negative correlation between the intern's performance and the nurse's or the pharmacist's performance within a given team. The wide variance in recognition of data resulted in wide variance in orders. Overall, there were 21.8 orders requested and 21.6 orders placed per case resulting in 3.6 order entry inconsistencies/case. Between the two cases, there were 145 distinct orders place with 43% being unique to a specific team and only 2% placed by all teams.Although significant blind spots exist in the interprofessional team's ability to recognize safety issues in the electronic health record, the inclusion of other professional groups does serve as a partial safety net to improve recognition. Electronic health record-based, ICU rounding simulations can serve as a test-bed for innovations in ICU rounding structure and data collection.

Background Twenty eight joints that are usually evaluated for disease activity score of rheumatoid arthritis (RA) do not include ankles and metatarsophalangeal joints. Although foot synovitis of patients in remission is clinically important in that it associates to relapse and worse physical function,1 composite markers without an assessment of foot have demonstrated poor performance in detecting foot synovitis.2 Objectives The aim of this study was to investigate the frequency and impact of residual synovitis in ankles and feet in patients with RA. Methods Patients with RA who underwent both physical examination and ultrasonography (US) on 44 joints including hands, fingers, ankles, and metatarsophalangeal joints between April 2016 and January 2018 in Keio University Hospital were enrolled. We compared patients with swollen joints of feet and ankles and those without, and then analysed those who did not have swollen joints by physical examination but were detected to have synovitis by US. Results Sixty one patients were enrolled in the study. The mean age was 58.5 years old, the disease duration was 7.1 years, and 85% were female. Among them, 21 patients had joint swelling in feet and ankles and 40 patients did not by physical examination. The patients in the former group showed significantly higher disease activity (DAS28 4.0 vs 2.4, p Conclusions The residual synovitis in ankles and feet did not reflect in remission criteria by DAS28 but did by Boolean criteria. It caused a discordance in global assessments between patient and estimator. References [1] Wechalekar MD, Lester S, Hill CL, Lee A, Rischmueller M, Smith MD, Walker JG, Proudman SM. Active Foot Synovitis in Patients With Rheumatoid Arthritis: Unstable Remission Status, Radiographic Progression, and Worse Functional Outcomes in Patients With Foot Synovitis in Apparent Remission. Arthritis Care Res (Hoboken)2016;68(11):1616–1623. [2] Wechalekar MD1, Lester S, Proudman SM, Cleland LG, Whittle SL, Rischmueller M, Hill CL. Active foot synovitis in patients with rheumatoid arthritis: applying clinical criteria for disease activity and remission may result in underestimation of foot joint involvement. Arthritis Rheum2012;64(5):1316–22. Disclosure of Interest None declared

Background The 2010 rheumatoid arthritis (RA) classification criteria has been verified to classify patients early as having RA more efficiently than the 1987 criteria. However, sensitivity of this criteria decreased remarkably in patients whose rheumatoid factor (RF) and anticitrullinated antibodies (ACPA) were both negative. Modern imaging technique including ultrasound (US) and magnetic resonance imaging (MRI) are more sensitive than physical examination for detecting joint inflammation objectively, however, US may offer only slight additional value when assessing patients with positive ACPA and RF. Reliability and value of inflammatory findings detected by US and MRI in seronegative, undifferentiated arthritis (UA) patients are still unclear. Objectives To clarify benefits of US and MRI for predicting futuristic diagnosis of RA in UA patients with neither ACPA nor RF. Methods Consecutive, untreated, early arthritis patients who underwent both US and contrast enhanced MRI of 22 sites including bilateral wrists, MCP and PIP joints were enrolled. Synovitis and tenosynovitis were defined as inflammatory findings of US and MRI. Concordance between swollen joint counts (SJC) by experienced physician, inflammatory findings of US and MRI were assessed. We defined UA as non-fulfilment of the 2010 RA classification criteria and the clinical diagnosis pf RA as the initiation of disease modifying anti-rheumatic drugs. Results Seventy one patients were included in the analysis. Fifty eight (82%) were female, the median age was 63 years old, and the mean symptom duration 3 months. Forty eight (67.6%) did not fulfil the 2010 criteria being defined as UA, among which thirty six were seronegative. In all patients, the concordance of detecting inflammation was quite high between MRI and US (κ: 0.67–0.70). In 36 seronegative UA patients, SJC detected by physical examinations were fewer than US or MRI (2.2 vs 3.9, p Conclusions Our study suggested that both US and MRI inflammation findings are reliable with a good concordance and can be useful as predictor for futuristic development of RA in UA patients without ACPA and RF. References [1] Kaneko Y, et al. Rheumatology (Oxford). 2011Jul;50(7):1268–74. [2] Zufferey P, et al. Joint Bone Spine. 84(3): 299–303, 2017 [3] Kawashiri S, et al. Mod Rheumatol (2013) 23:36–43 [4] Hirata A, et al. Arthritis Care Res (Hoboken). 2017Jun;69(6):801–806. Disclosure of Interest None declared

Background Ataxia-telangiectasia mutated (ATM) is a protein kinase associated with ataxia-telangiectasia (AT), which is an autosomal recessive disorder due to defective functional activity of ATM. Telangiectasia, seen in AT, is also well known as one of the major characteristics of systemic sclerosis (SSc). ATM plays an important role not only in DNA damage repairing system, but also in the process of regulation of oxidative stress. 1 Moreover, it has been reported that oxidative stress may contribute to disease process of SSc 2 3 . Based on these background, we hypothesised that ATM may play a substantial role in the pathogenesis of SSc. However, the possible association between ATM activity and SSc development is not fully understood. Objectives To clarify the role of ATM in the pathogenesis of SSc, we demonstrated the expression and activation level of ATM in circulating immune cells and analysed the association with clinical characteristics of the patients. Methods Whole blood samples were collected from twenty-four patients with SSc and 12 healthy controls (HC). Expression levels of total ATM and active phosphorylated ATM (pATM) were examined in each immune cell subset (neutrophil, monocyte, T cell, B cell and NK cell) by mean fluorescence intensity (MFI) using flow cytometer. Each MFI level of ATM and pATM was compared between patients with SSc and HC, and was analysed the correlation with clinical characteristics of SSc patients, retrospectively collected from patients’ records. Results The expression level of pATM was significantly lower in monocytes, neutrophils, and T cells in SSc as compared with HC (1887 ±128 vs 2386±181, p=0.03; 10265±861 vs 16087±1218, p=0.0004; 1326±73 vs 1675±103, p=0.009; respectively), whereas no significant difference in total ATM level was observed in each cell subset between two groups. Notably, the expression levels of pATM in monocytes of the patients with interstitial lung disease (ILD) was lower than that of the patients without ILD (1663 ±136 vs 1999±96, p=0.05). Furthermore, there was a tendency of correlation between pATM level in monocyte and parameters of pulmonary function test, such as forced vital capacity. No significant differences and/or correlation between pATM expression level in other cell subsets and clinical parameters of the patients, such as SSc subtype, SSc-specific autoantibodies, presence of pulmonary arterial hypertension, gastrointestinal involvement, digital tip ulcer, pitting scar and modified Rodnan skin score were observed. Conclusions In SSc, phosphorylated level of ATM in monocytes, neutrophils, and T cells was significantly lower than that of HC. Importantly, we found that ATM activation was impaired in monocyte of the SSc patients with ILD. These results collectively suggest that the loss of ATM activation in monocytes may contribute to the disease process of SSc, and is possibly due to DNA damage and oxidative stress. References [1] Guo Z, et al. Science. 2010;330:517–521. [2] Sambo P, et al. J Invest Dermatol. 1999;112:78–84. [3] Gabrielli A, et al. Open Rheumatol J. 2012;6:87–95. Disclosure of Interest None declared

Background In advanced non-small cell lung cancer (NSCLC), small biopsy specimens from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are often the only available material from cancer tissue for the analysis of programmed death ligand-1 (PD-L1) expression. We aim to assess the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression at ≥ 1% and ≥ 50% on EBUS-TBNA samples compared with their corresponding surgically resected tumor. Methods We retrospectively reviewed all patients who underwent EBUS-TBNA followed by surgical resection of NSCLC between July 2006 and September 2016. Demographic information and periprocedural/surgical data were collected. The archived specimens were retrieved and assessed for PD-L1. A positive PD-L1 stain was defined using two separate cutoff points: ≥ 1% and ≥ 50% of tumor cell positivity. EBUS-TBNA aspirates were compared with the surgically resected specimen to calculate the sensitivity, specificity, PPV, and NPV. Results Sixty-one patients were included. For PD-L1 ≥ 1%, the sensitivity, specificity, PPV, and NPV were 72%, 100%, 100%, and 80%, respectively. For PD-L1 ≥ 50%, the sensitivity, specificity, PPV, and NPV were 47%, 93%, 70%, and 84%, respectively. The concordance rates for PD-L1 ≥ 1% and ≥ 50% were 87% and 82%, respectively. Conclusions A PD-L1 cutoff of ≥ 1% on EBUS-TBNA has a strong correlation with resected tumor specimen. For PD-L1 ≥ 50%, there is a significant decrease in the sensitivity and PPV of EBUS-TBNA specimen when compared with resected tumor. When analyzing for PD-L1 expression using a cutoff of ≥ 50%, EBUS-TBNA specimens may misclassify the status of PD-L1.

The design, synthesis, and application of [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis of sulfur(VI) fluorides, is described. The utility of AISF is demonstrated in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl fluorides under mild conditions. Additionally, a single-step preparation of AISF was developed that installed the bis(fluorosulfonyl)imide group on acetanilide utilizing an oxidative C–H functionalization protocol.

Table S2â 1. Factors associated with frailty (1 point increase) among male elderly survivors in the RIAS study, 2011â 2015. (PDF 160Â kb)

Table S1. The Kihon Checklist in Japan. The checklist included a multidimensional 20-item index concerning lifestyle, motor abilities, nutrition, oral function, seclusion, and forgetfulness. (PDF 130Â kb)

Table S2â 2. Factors associated with frailty (1 point increase) among female elderly survivors in the RIAS study, 2011â 2015. These two tables were the results from a linear regression in the linear regression models. (PDF 155Â kb)

A persistent air leak (PAL) can be caused by either an alveolar-pleural fistula (APF) or bronchopleural fistula (BPF). Complications from PAL lead to an increase in morbidity and mortality, prolonged hospital stay, and higher resource utilization. Pulmonary physicians and thoracic surgeons are often tasked with the difficult and often times frustrating diagnosis and management of PALs. While most patients will improve with chest tube thoracostomy, many will fail requiring alternative bronchoscopic or surgical strategies. Herein, we review the bronchoscopic and surgical diagnostic and treatment options for PAL as it pertains to the field of interventional pulmonology and thoracic surgery.

Objective. To determine whether results of the nasopharyngeal FilmArray respiratory panel (NP-FARP) influenced antibiotic decisions. Methods. We reviewed the medical records of nonintensive care unit (ICU) inpatients that had an NP-FARP performed at our institution between June 2013 and June 2014. The inpatient records were reviewed 48 hours after the NP-FARP for the following data: demographic information; NP-FARP, serum procalcitonin, and methicillin-resistant Staphylococcus aureus nasal swab (MRSA NS) results; antibiotics prior and post-48 hours of the NP-FARP result; and the current immunosuppression status. Clinical outcome data were not obtained. Patients were categorized into those who had a positive (+) or a negative (−) NP-FARP. We further subdivided these two categories into groups A, B, and C based on the antibiotic modifications 48 hours after their NP-FARP result. Group A included patients who were never initiated on antimicrobial therapy. Patients whose antibiotics were discontinued or deescalated were placed in group B. Patients with antibiotic escalation or continuation without change constituted group C. We compared and analyzed groups A, B, and C in the (+) and (−) NP-FARP cohorts. Results. A total of 545 patients were included. There were 143 (26%) patients with positive and 402 (74%) patients with negative NP-FARPs. Comparison of groups A, B, and C between those with a (+) and (−) NP-FARP were as follows: (+) A and (−) A, 28/143 (20%) and 84/402 (21%); (+) B and (−) B, 59/143 (41%) and 147/402 (37%); and (+) C and (−) C, 56/143 (39%) and 171/402 (43%), respectively. We found no statistically significant differences between groups (+) A versus (−) A, (+) B versus (−) B, and (+) C versus (−) C with respect to age, gender, MRSA NS result, procalcitonin result, or concurrent immunosuppression. Conclusion. In non-ICU inpatients, NP-FARP alone or in combination with procalcitonin or MRSA NS did not influence antibiotic decisions during the study period.

Pyoderma gangrenosum is a chronic sterile skin disorder that is frequently seen in association with systemic disorders such as inflammatory bowel disease. Extracutaneous pyoderma gangrenosum is rare and most commonly occurs in the lungs. It is particularly unusual for extracutaneous pyoderma gangrenosum to manifest prior to skin findings and without an associated systemic disorder. A 19-year-old white man presented with shortness of breath and a productive cough. His skin exam was normal. Unenhanced chest computed tomography showed peripheral consolidations, areas of cavitation, nodules and bilateral pleural effusions. A bronchoalveolar lavage and an autoimmune panel were unremarkable. Right lung wedge biopsies via thoracostomy was performed and showed pulmonary pyoderma gangrenosum. He was treated with corticosteroids and has returned back to his baseline. This is the first case of pulmonary pyoderma gangrenosum without any associated underlying systemic disorder and without any cutaneous manifestations to date. Serial follow-ups are necessary to assess for the development of an associated systemic disorder or skin lesions.

There is various potentially hazardous aerosol suspended in atmospheric air, such as virus, exhaust gas, PM 0.1 and 2.5, endospore of bacteria, etc. One of the important issue is a monitoring technology to protect from such the hazardous aerosol from out living sphere. For this purpose, we have tried to develop a sampling mechanism, which is suitable for longtime continuous monitoring purpose. In this work, we have proposed and experimentally demonstrated new sampling method, which was utilized with liquid-gat. By testing the device using a carbon toner as a model of carbon particulate in atmospheric air, we confirmed that the liquid-gate sampling worked successfully.

Background In systemic sclerosis (SSc), systemic remodeling, microvascular injuries and production of autoantibodies are well known as disease hallmarks. However, the master regulator of these characteristics is still unclear. Microparticle (MP) is a small membrane vesicle, released from various kinds of cells, and distributes systemically through circulation1). Recent reports revealed that MP contains various growth factors, proteases and cytokines including TGF-b2), suggesting that MP can contribute to immune and mesenchymal responses as a conveyor3). and involve with disease process of SSc. Although, the possible involvement of MPs in the pathogenesis of SSc is indicated, the detailed association of MPs including MP subsets with SSc is not well clarified. Objectives To elucidate the association between circulating MP subsets and patients9 characteristic of SSc. Methods Thirty-six patients with SSc and 13 healthy controls were involved in this study. Platelet-rich plasma containing microparticles was isolated from whole blood using gradient centrifugation and analyzed using flow cytometer. MP was defined as particles smaller than 1.0 μm diameter using Megamix®, and identified each MP subsets based on expression of cell type-specific surface markers; platelet (CD31+CD41+), endothelial cell (CD31+CD41-) and monocyte (CD14+CD45+) using fluorescence-tagged antibodies. Clinical information was retrospectively collected from patients9 records, and the correlation with the number of each MP subset was analyzed. Results Mean age of 36 patients with SSc was 60.9±1.8 years, 94% was female, and mean disease duration was 11.2±9.5 years. Patients with diffuse cutaneous SSc (dcSSc) was 6 (17%). As for the proportion of MP subsets, platelet-derived MP (PMP) was the largest subset, followed by endothelial cell-derived MP (EMP) and monocyte-derived MP (MoMP) in all samples. In patients with SSc, the number of total MP and all MP subsets were higher than those in healthy controls (p Conclusions These results suggest that MP subsets are associated with extended fibrotic phenotype in patients with SSc, and might be utilized as novel biomarkers. References Bayer C et al. Nat Rev Rheumatol. 6:21–9, 2010. Antonyak MA et al. Method Mol Biol. 1165:147–73, 2014. Budoni M et al. Cell Transplant. 22:369–79, 2013. Disclosure of Interest None declared

Background Rheumatoid arthritis (RA) is a systemic connective tissue disease and characterized by inflammation of synovium of multiple joints, however, its pathogenesis is still unclear (1). Physiologically, microparticle (MP) is categorized as a membrane microvesicle which contains various humoral factors such as cytokines or growth factors and 0.1–1 μm in size (2). And MPs can distribute systemically through circulation. MP is released from almost all cell types and induced by stimulation, stress or apoptosis (3). Thus, we hypothesized that MPs derived from various cells can distribute to the lesion of RA and be associated with systemic disease process of RA. Objectives To clarify the source of MPs in circulation of RA and elucidate their role in the pathogenesis and the possibility for application as a novel disease marker. Methods Twenty patients with RA and 13 healthy controls were involved. Using gradient centrifugation, platelet-rich plasma was isolated from whole blood and applied to flow cytometry. MP is defined as a vesicle less than 1 mm in diameter and Megamix® was used to set a gating condition to detect microparticles (4). Sources of MP (MP subsets) were identified by the expression of cell-specific markers using flow cytometry with fluorescence-conjugated antibodies as follows; platelets MP: CD41 + CD31 + MP, endothelial cell MP: CD41 - CD31 + MP, immune cell MP: CD45 + CD41 - MP, MP derived other cells: CD41 - CD31 - CD45 - MP. Correlation between clinical information and proportion of MP subsets was also analyzed. Comparisons between two groups were examined by Mann-Whitney U-test with Bonferroni correction. Significant difference was defined as corrected p value ( Pc ) Results Mean age of 20 patients with RA was 56±14 years, 95% was female, disease duration was 8.5±8.0 years, and DAS28-ESR was 2.0±1.1. Methotrexate was administered to 75% and average dose was 8.0±2.4 mg/week. Platelet-derived MP covered the largest proportion in all groups. Interestingly, proportion of immune-cell-derived MP was higher ( Pc Pc Conclusions Proportion of circulating immune-cell-derived MPs, especially monocyte-derived MPs, increased in RA and correlate with disease activity. These results suggest that monocyte-derived MPs can be measured as a novel biomarker and involved in the disease process of RA. References Smolen JS et al. Lancet 388: 2023–2038, 2016. van der Pol E et al. 64: 676–705, 2012. Buzas EI et al. Nat Rev Rheumatol 10: 356–364, 2014. Chandler WL et al. J Thromb Haemost 9:1216–1224, 2011. Disclosure of Interest None declared

Background Ultrasonography (US) is a useful modality that can directly visualize RA joint inflammation. Recently, brightness of thickened synovium is considered to associate with local synovitis. However the accuracy of US findings with the local pathophysiology remains uncertain since synovial biopsy could be heterogeneous depending on the biopsy site and can be influenced by various medications. On another front, synovial fluid (SF) is homogenous, easy to access and contains abundant inflammatory cytokines and growth factors, which play an important role in the local pathogenesis of RA. However, the association between SF proteins and joint US findings is not clear. Objectives To clarify whether synovitis detected by US including synovial hypertrophy, vascularity and brightness reflect local joint molecular pathophysiology. Methods Forty-four RA patients were recruited. All patients were performed standardized US examination of knee joint. US images were evaluated by semi-quantitative scoring (synovial hypertrophy; grey scale (GS) US, vascularity; power Doppler (PD) US) and quantitative analysis by using Image J (National Institutes of Health, MD, Maryland USA). The average of the pixels of synovial tissue area (GS quant), PD signal area (PD quant) and mean gray values of synovium (Brightness) in 3 areas of the knee joint were calculated. US guided SF aspiration was performed on the same day and concentrations of cytokines and growth factors were measured by Cytometric Beads Array. (BD Biosciences, NJ, USA) Results Median age, disease duration and DAS28-ESR were 64 years, 1.5 years and 5.2 respectively. Mean GSUS and PDUS were 2.3 and 2.0. Nineteen patients were untreated. US inflammatory findings especially PD quant were well correlated with corresponding SF IL-6, IL-8, IL-1β and IL-10.(range of rho;0.40–0.72, p Conclusions Our results suggest that not only US PD signals but also synovial brightness is a useful indicator for joint inflammation rather than synovial hypertrophy itself in treated RA patients. References Naredo E et al. Arthritis Rheum 2008; 58: 2248–56. Kelly S et al. Arthritis Res Ther. 2015 Mar 13;17:58. Disclosure of Interest None declared

Background and Aims CD4 + T cells play a crucial role in pathological process of Systemic Lupus Erythematosus (SLE). Recently, we found that T-bet is an important factor for shift to glycolysis in activated CD4 + T cells in vitro . In this study, we examined the mechanism by which T-bet in CD4 + T cells involved in pathogenesis of SLE. Methods Peripheral blood mononuclear cells were obtained from 19 healthy controls (HCs), 30 patients with bio-naive active RA and 60 patients with SLE. The expression of CXCR3, T-bet, mTORC1 phosphorylation and IFN-γ production in CD4 + T cells were measured by flow cytometry, and assessed the association with clinical characteristics. Results We found that the ratio of CD28 - CXCR3 int T-bet hi cells in patients with SLE was significantly higher compared to HCs. CD4 + CD28 - CXCR3 int T-bet hi cells mainly consisted of CD45RA - CCR7 - effector memory cells and were significantly activated with pronounced IFN-γ production. Interestingly, the ratio of CD4 + CD28 - CXCR3 int T-bet hi cells was significantly correlated with the number of immunosuppressants previously used for the SLE patients, that is treatment-resistant. Phosphorylation of mTORC1, which is important for shift to glycolysis, in CD4 + T cells from patients with SLE was significantly increased compared to HCs. T-bet expression was significantly correlated with mTOC1 phosphorylation and IFN-γ production in CD4 + T cells from patients with SLE. Conclusions These results indicated that CD4 + CD28 - CXCR3 int T-bet hi cells might be related to refractory to established therapies in patients with SLE. In addition, these cells are constitutively activated accompanied with shift to glycolysis through IFN-γ-mTORC1-T-bet pathway, which is a potential target for patients with SLE.

Background and aims To elucidate the diversity of systemic lupus erythematosus (SLE), we stratified SLE patients based on immunophenotyping. Methods Peripheral blood mononuclear cells were obtained from 80 active SLE patients (with one or more BILAG category A, or two or more BILAG category B). Circulating B, T and dendritic cells were defined based on flow cytometric analysis for human immune system termed ”the Human Immunology Project”. Based on these results, the immunophenotype was visualised by principal component analysis and SLE patients classified into subgroups by cluster analysis. Results Principal component analysis indicated that the immunophenotype of active SLE patients was consistent with T and B cell axes. Among these correlations, Th17 and Treg cells were statistically close, and showed positive correlation (p Conclusions Our study indicates that SLE patients can be divided into three subgroups based on T cell heterogeneity. This heterogeneity should be taken into consideration not only in basic research but also in patient selection in clinical trials for development of new drugs.

Background and aims The aim of this study was to assess the peripheral immune cell phenotypes in a correlation with clinical findings in patients with systemic lupus erythematosus (SLE). Methods Peripheral blood mononuclear cells were obtained from 143 SLE patients and 26 healthy donors (HD). Circulating B, T and dendritic cells were defined based on flow cytometric analysis for human immune system termed “the Human Immunology Project” proposed by the National Institutes of Health (NIH) and the Federation of Clinical Immunology Societies (FOCIS). Results The proportions of CD3 + CD4 + CXCR5 + ICOS + T follicular helper (Tfh) cells, but not CD3 + CD4 + CXCR3 + CCR6 - Th1 and CD3 + CD4 + CXCR3 - CCR6 + Th17 cells, were higher in SLE than the HD. The proportions of CD19 + CD20 + IgD + CD27 + central memory B cells and CD19 + CD20 + IgD - CD27 - effector B cells were higher in SLE. The largest difference relative to the HD was observed in the proportion of CD19 + CD20 - CD27 + CD38 + plasmablasts, which was higher in SLE and correlated with BILAG index. The proportion of Tfh cells correlated with serum IgG level, and the proportion of activated Tfh cells correlated with serum anti-Sm antibody level. Among helper T cell subsets (Th1, Th17, Treg and Tfh), Tfh cells only showed positive correlation with the proportion of plasmablast (r=0.24, p=0.02). Conclusions Peripheral immuno-phenotyping confirmed the importance of Tfh-plasmablasts axis in patients with SLE, i.e. activation of Tfh cells correlated with autoantibody production while plasmablast did with disease activity of SLE. Our findings supported the relevance of Tfh-plasmablasts axis as a potential therapeutic target for SLE.

Background and aims Aberrant and persistent production of type I interferon (IFN) is known to play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), and plasmacytoid dendritic cells (pDCs) are the major source of type I IFN upon toll-like receptor 7 (TLR7) and TLR9 stimulation. However the respective impacts of TLR7 and TLR9 responses on type I IFN production in SLE has not been addressed.To investigate the precise function of pDCs in SLE patients, we shed light upon the differential regulation of TLR7/9 responses during type I IFN production from pDCs. Methods PBMCs from SLE patients and healthy controls were analysed in the presence of a TLR7 agonist loxoribine and a TLR9 agonist CpG2216. The IFN-α production in Lin-HLA-DR+CD123+CD11c- pDCs was detected by flow cytometry. Results We demonstrated that TLR7-mediated IFN-α production were up-regulated and were positively correlated with disease activity, conversely, TLR9-mediated IFN-α production were down-regulated in SLE. The differential regulation of TLR7/9 responses of pDCs was not dependent on expression levels of TLR7/9. Furthermore, in vitro experiments revealed that up-regulation of TLR7 response was caused by pre-treatment with type I IFNs, conversely, down-regulation of TLR9 response was caused by pre-treatment with type II IFN. Conclusions This is the first report demonstrated the differential regulation of TLR7- and TLR9- mediated IFN-α production from pDCs in SLE, namely, caused by priming effects of type I and type II IFNs. Taken together, TLR7-, but not TLR9-, mediated IFN-α production contributes the pathogenesis of SLE, and TLR7 could be a potential therapeutic target for SLE.

No abstract available. Article truncated after 150 words. History of Present Illness A 65 year old woman was admitted for gastrointestinal bleeding as evidence by hematochezia. At the time of admission she denied any respiratory symptoms other than mild dyspnea. However, she rapidly developed respiratory failure, was transferred to the ICU and required emergent intubation. PMH, FH, SH She has a history of rheumatoid arthritis with a cervical spine fusion. There is also a history of sarcoidosis and she was receiving prednisone 30 daily up until the time of admission. There is no significant family history. She does not smoke or drink. Physical Examination Afebrile. Pulse 78. BP 105/65 mm Hg. Respirations: 28. SpO2 96% while receiving an FiO2 of 60% at the time of transfer to the ICU. Neck: No jugular venous distention. Lungs: Scattered rales and rhonchi. Cardiovascular: Regular rhythm. Abdomen: no hepatosplenomegaly. Radiography A portable chest x-ray taken after intubation is shown in figure 1…

No abstract available. Article truncated at 150 words. History of Present Illness A 69 year old man was admitted to the intensive care unit with shortness of breath and atrial fibrillation with a rapid ventricular response. PMH, FH, SH He has a history of peripheral vascular disease, end-stage renal disease and is receiving chronic hemodialysis. Physical Examination Afebrile. Pulse 135 and irregular. BP 105/65 mm Hg. SpO2 96% while receiving oxygen at 2L/min by nasal cannula. HEENT: Unremarkable. Neck: Jugular venous distention to the angle of the jaw while the head is elevated at 45 degrees. Lungs: Decreased breath sounds at the right base. Cardiovascular: Irregularly, irregular rhythm. 2-3+ pretibial edema. Abdomen: no hepatosplenomegaly. Radiography The admission chest x-ray is shown in figure 1. Which of the following is the best interpretation of the chest x-ray given the clinical situation? 1. Hepatomegaly elevating the right diaphragm 2. Large right pleural effusion 3. Paralyzed right diaphragm 4. Right lower ...

Confronted with the need to significantly raise the productivity of remotely located chemistry CROs Pfizer embraced a commitment to continuous improvement which leveraged the tools from both Lean Six Sigma and queue management theory to deliver positive measurable outcomes. During 2012 cycle times were reduced by 48% by optimization of the work in progress and conducting a detailed workflow analysis to identify and address pinch points. Compound flow was increased by 29% by optimizing the request process and de-risking the chemistry. Underpinning both achievements was the development of close working relationships and productive communications between Pfizer and CRO chemists.

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No abstract available. Article truncated after 150 words. History of Present Illness A 22 year old man was admitted with fever for 2 weeks. He had a history of acute lymphocytic leukemia (ALL) and had received a stem cell transplant in (SCT) in May 2013. PMH, SH, FH Other than the ALL and STC transplant there was no significant PMH, SH, or FH. The STC was uneventful. Physical Examination T 38.6°C with a pulse of 110 beats/min. Otherwise the physical examination was unremarkable. CT scan A CT scan of the thorax was performed in a search for the source of the fever (Figure 1). Figure 1. Admission thoracic CT scan showing an abnormality. The remainder of the CT scan was unremarkable. Which of the following best describes the CT abnormality? 1. Chest wall abnormality in the left chest 2. Focal area of consolidation in the left lung 3. Focal area of consolidation in the right lung 4. Mass …

Systemic sclerosis (SSc), a systemic, connective tissue disease, is characterized by excessive fibrosis of skin and multiple internal organs associated with microvascular injury and autoantibody production. However, the disease process is still under investigation. Among circulating blood cells, the roles of lymphocytes and monocytes were well-examined, however, other cellular components are not well-focused. Platelets play a significant role in hemostasis physiologically. However, recent studies have revealed that platelets contain humoral factors such as cytokines, chemokines and growth factors and can distribute systemically through circulation. We hypothesized that platelets could contribute to the pathogenesis through the release of these factors. To elucidate the role of platelets in SSc, activation status and phenotype of circulating platelets in patients and association with clinical characteristics were examined. Twenty-one patients with SSc who fulfilled 2013 classification criteria of American College of Rheumatology and European League Against Rheumatism and 16 healthy controls were involved. Platelets or platelet-derived microparticles (MPs) were defined as vesicles in platelet-rich plasma which is more or less than 1mm in diameter by forward and side scatter, respectively, and positive staining with anti-CD41 antibody using flow cytometry. Activation status of platelets was examined by the expression of activation markers on platelets such as P-selectin (CD62P) or activated glycoprotein IIb/IIIa (PAC1). Production of microparticles (MPs) is defined as ratio of proportion of MP to that of platelets. Association or correlation between proportion of activated platelets and clinical characteristics or parameters of patients with SSc was also examined. For the further phenotypic analysis of platelets, expression of selected surface markers on platelets such as membrane-bound transforming growth factor (TGF)-beta, CD147 (emmprin), CD142 (tissue factor), CD31 (platelet endothelial cell adhesion molecule (PECAM)-1) was examined using flow cytometry. Furthermore, release reaction of platelets was evaluated by release of platelet factor 4 (PF4) in culture supernatant of coculture with skin fibroblasts using enzyme-linked immunosorbent assay (ELISA). As for the characteristics of 21 patients, male was 14 %, proportion of diffuse cutaneous SSc was 24 %, mean age was 63 ± 13 years, and mean disease duration was 16 ± 13 years. In SSc, both proportion of CD62P+ or PAC1+ activated platelets (P < 0.05, P < 0.05, respectively) and production of MP were higher in SSc (P < 0.05) compared to those in healthy controls. Of these, proportion of CD62P+ platelets and MP production were correlated each other (r = 0.88, P < 0.05). When activation status of platelets was compared to clinical parameters, only proportion of CD62P+ platelets was higher in diffuse cutaneous SSc and correlated with modified Rodnan skin score (mRSS) (P < 0.05). Phenotype of platelets was also altered based on the upregulation of expression of selected surface markers on platelets, such as membrane-bound TGF-beta and CD147. Interestingly, proportion of membrane-bound TGF-beta+ platelets was positively correlated with that of CD62P+ activated platelets and furthermore, proportion of membrane-bound TGF-beta+ platelets was correlated with mRSS (P < 0.05). Functionally, release reaction of platelet was enhanced in platelets from patient with SSc compared to healthy controls (P < 0.05). In conclusion, circulating platelets in SSc were activated and their phenotype is altered in circulation. Furthermore, activation status of platelets is associated with skin fibrotic phenotype, suggesting that circulating platelets reflects and can contribute to the disease process of SSc. Also, phenotype of platelets can be a novel biomarker of the disease. Disclosures No relevant conflicts of interest to declare.

Nitrofurantoin-induced lung toxicity is relatively common, but rare histologic patterns sometimes occur that may make diagnosis difficult. We present the case of a 69-year-old woman taking prophylactic nitrofurantoin for urinary tract infections, who developed granulomatous interstitial pneumonia. She improved with cessation of nitrofurantoin, without other therapy. To our knowledge, this is the fourth reported case of granulomatous interstitial pneumonia associated with nitrofurantoin, and the first to show complete resolution with cessation of the drug alone, without steroids. It is important to recognize that idiosyncratic reactions to nitrofurantoin can produce a wide spectrum of histologic patterns. Of these patterns, granulomatous interstitial pneumonia is a rarely evidenced manifestation (possibly because few cases undergo a confirmatory lung biopsy). Recognition of granulomatous interstitial pneumonia as a manifestation of nitrofurantoin toxicity can aid in early identification of the reaction and prompt withdrawal of the drug, both of which are essential to prevent long-term complications.

To study the effect of ultrafiltration on the radiocarbon ages of relatively poorly preserved bones in Japan, we analyzed the 14C dates of high-molecular-weight (HMW) gelatin samples and compared them with those of other extracted organic fractions, unfiltered gelatin samples extracted from NaOH-treated or NaOH-untreated collagen, and XAD-purified hydrolysates of animal fossil bones (∼4600 BP; gelatin yield of 2–4%) from the Awazu underwater archaeological site, Shiga, Japan. NaOH-treated, unfiltered gelatins and XAD-purified hydrolysates showed statistically similar 14C ages to those of HMW gelatins. The 14C ages of the HMW gelatins were the oldest and similar to those of wood collected from the same layer as the bones, and the NaOH-treated, unfiltered gelatins gave 14C ages within the acceptable margins of error; therefore, ultrafiltration was effective for accurate 14C dating, while NaOH-treated gelatin without ultrafiltration was also sufficient to obtain accurate 14C dates on the animal bones. The 14C ages of human skeletons (∼750 BP; gelatin yield of 2–11%) from 5 individuals excavated from an archaeological site in Yuigahama, Kamakura, Japan, showed statistically the same 14C ages as NaOH-treated, unfiltered gelatins and HMW gelatins within the margins of error, although HMW gelatins were likely to give slightly older ages than unfiltered gelatin with a yield of less than ∼3%. These results indicate that unfiltered gelatins extracted from fossil bones of gelatin yield more than ∼3% can produce accurate 14C ages without the need for ultrafiltration. Ten bone fragments from 3 humans showed the same 14C ages for each individual, suggesting that any bone part from an individual can be used to obtain a representative age. The 14C ages of tooth enamels of 2 individuals were 35 and 70 yr older than their bone ages. Death dates obtained from these age gaps agreed with those determined by morphology.

The radionuclide 55 Fe was determined in sam- ples of radioactive wastes from the water cleanup system of the IEA-R1 nuclear research reactor. In order to validate the results, the 55 Fe activity concentration was measured in eight waste samples and in six simulated samples con- taining the most important interfering radionuclides. A simple method was employed to separate and purify 55 Fe from other radionuclides present in these samples, com- bining co-precipitation with ammonium hydroxide and purification with anionic ion-exchange resin, which enables 55 Fe to be quantified either by liquid scintillation counting (LSC) or by X-ray spectrometry using a low-energy ger- manium spectrometer (LEGe). Both measurement methods were used so that the separation and purification process could be confirmed by comparison of spectra with and without the utilization of anionic ion-exchange resin. Activity and interferences were compared in the results obtained from LSC and LEGe measurement methods.

The first extensive study on

A circularly polarized (CP) antenna is proposed, where four metalines are used as radiation elements. This CP antenna supports a negative phase constant current, leading to a small antenna height of approximately 1/100 wavelength. The same antenna characteristics are reproduced even when the feed point position is changed for beam-steering in the azimuth plane, because the metalines are arrayed symmetrically with respect to the antenna center point. Thus, this CP antenna works as a reconfigurable antenna. The radiation pattern and VSWR are analyzed and discussed.

During interprofessional intensive care unit (ICU) rounds each member of the interprofessional team is responsible for gathering and interpreting information from the electronic health records (EHR) to facilitate effective team decision-making. This study was conducted to determine how each professional group reviews EHR data in preparation for rounds and their ability to identify patient safety issues. Twenty-five physicians, 29 nurses, and 20 pharmacists participated. Individual participants were given verbal and written sign-out and then asked to review a simulated record in our institution’s EHR, which contained 14 patient safety items. After reviewing the chart, subjects presented the patient and the number of safety items recognised was recorded. About 40%, 30%, and 26% of safety issues were recognised by physicians, nurses, and pharmacists, respectively (p = 0.0006) and no item recognised 100% of the time. There was little overlap between the three groups with only 50% of items predicted to be recognised 100% of the time by the team. Differential recognition was associated with marked differences in EHR use, with only 3/152 EHR screens utilised by all three groups and the majority of screens used exclusively only by one group. There were significant and non-overlapping differences in individual profession recognition of patient safety issues in the EHR. Preferential identification of safety issues by certain professional groups may be attributed to differences in EHR use. Future studies will be needed to determine if shared decision-making during rounds can improve recognition of safety issues.

We succeeded in obtaining the depth profile of

Ion-exchange resins and activated charcoal beds are employed for purification of the cooling water that is pumped through the core of pool type nuclear research reactors. Once expended, these media are replaced and become radioactive wastes that contain low concentrations of long-lived fission and activation products, uranium isotopes and transuranium elements. Determination of the radioactive inventory is of paramount importance in the management of such radioactive wastes, which, besides high-energy photon emitters that can be identified and quantified directly by gamma-ray spectrometry, also contain pure alpha, pure beta and low-energy photon emitters whose quantitative determination require radiochemical separation. These later are collectively known as difficult to measure (DTM) radionuclides. A characterization program embracing the DTM radionuclides is currently in progress for spent ion-exchange resins and activated charcoal beds that were definitively withdrawn from the water cleanup system of the IEA-R1 nuclear research reactor. Radiochemical methods used in the characterization program include separations with specific anionic resins, chromatographic extractions and co-precipitation, which enabled the measurement of the activity concentrations of 90Sr, 234U, 235U, 238U, 238Pu, 239+240Pu, 241Pu, 241Am and 244Cm. An enhanced retention of uranium and transuranium elements was observed in the activated charcoal compared to the ion-exchange resins as a result of the tendency of actinides to undergo hydrolysis in aqueous solutions.

We investigated the uncertainty in patient set-up margin analysis with a small dataset consisting of a limited number of clinical cases over a short time period, and propose a method for determining the optimum set-up margin. Patient set-up errors from 555 registration images of 15 patients with prostate cancer were tested for normality using a quantile-quantile (Q-Q) plot and a Kolmogorov-Smirnov test with the hypothesis that the data were not normally distributed. The ranges of set-up errors include the set-up errors within the 95% interval of the entire patient data histogram, and their equivalent normal distributions were compared. The patient set-up error was not normally distributed. When the patient set-up error distribution was assumed to have a normal distribution, an underestimate of the actual set-up error occurred in some patients but an overestimate occurred in others. When using a limited dataset for patient set-up errors, which consists of only a small number of the cases over a short period of time in a clinical practice, the 2.5% and 97.5% intervals of the actual patient data histogram from the percentile method should be used for estimating the set-up margin. Since set-up error data is usually not normally distributed, these intervals should provide a more accurate estimate of set-up margin. In this way, the uncertainty in patient set-up margin analysis in radiation therapy can be reduced.

The FilmArray respiratory panel (FARP) reliably and rapidly identifies 17 viruses and 3 bacterial pathogens. A nasopharyngeal swab FARP (NP FARP) is performed for many patients with respiratory symptoms. For patients who are acutely ill or immunocompromised or fail to improve, a bronchoalveolar lavage sample FARP (BAL FARP) is performed in addition to the NP FARP. To date, no studies have compared the yield of a BAL FARP with that of an NP FARP. We retrospectively studied all patients who had a BAL FARP within 7 days after an NP FARP between June 2013 and May 2014. Demographic information, comorbidities, FARP results, and all microbiologic data from BAL fluid were collected. Eighty-six patients had a BAL FARP performed within 7 days (mean, 1.6; median, 1) after an NP FARP. Of these, 66 (77%) had concordant BAL and NP FARP results: 15 (23%) had the same pathogen identified from the NP and BAL FARPs, and 51 (77%) had concordant negative FARP results. In 18 of the 86 patients (21%), a pathogen was detected from the NP FARP; of these, 15 (83%) had a concordant match on a subsequent BAL FARP, and the remaining 3 had negative BAL FARPs. In 17 of the 86 patients (20%), pathogens were identified from the BAL FARPs that were not detected by the NP FARPs; of these, 16 (94%) had initial negative NP FARPs. The data suggest that once a pathogen is identified by an NP FARP, a subsequent BAL FARP is unlikely to add new microbiologic information. However, a BAL FARP may provide new, useful microbiologic information when performed within 7 days after a negative NP FARP.

The stereoselective oxidation of (—)-isolongifolanol (1) with a longifolene skeleton by Aspergillus niger (NBRC 4414) as a biocatalyst and suppressive effect on umuC gene expression by chemical mutagens furylfuramid and AFB1 of the SOS response in Salmonella typhimurium TA1535/pSK1002 were investigated. Compound 1 was converted to a new terpenoid, (-)-(2S,8R)-8,12-dihydroxy-isolongifolanol (2). Its structure was determined by NMR, IR, specific rotation and mass spectrometry. The metabolites suppressed the SOS-inducing activity of furylfuramid and AFB1 in the umu test. Compound 1 suppressed 51% of the SOS-inducing activity against furylfuramid at < 1.0 mM. Compound 2 suppressed 15% and 24% of the SOS-inducing activity against furylfuramid and AFB1 at < 1.0 mM respectively.

The present study investigated the influence of 241Am on microbial growth and the degradation of organic waste. Leachate samples collected in a lysimeter were periodically analyzed for bacterial growth, under both aerobic and anaerobic conditions. 241Am inhibited bacterial growth, and the degradation of organic matter was delayed in comparison with the control. Minimal inhibitory concentration assays and survival curves revealed that it inhibits the growth of Pseudomonas putida F1. The assay also revealed that 241Am is more toxic than 238U, Zn2+ and Cd2+. This study further led to the finding of four new radionuclide-tolerant bacterial strains: Flavobacterium spp., Pseudomonas gladioli, Chryseobacterium indologenes and Ochrobactrum anthropi. The survival curves of P. gladioli, C. indologenes revealed that these bacteria are resistant to metal as consortia.