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This study aimed to evaluate the relative risk of malignancy in patients with Takayasu's arteritis compared to that in the general population. This retrospective nationwide cohort study used data from the Korean Health Insurance Review and Assessment Service database. All newly diagnosed patients with Takayasu's arteritis were identified between January 2009 and December 2019. They were observed until the diagnosis of malignancy, death, or end of the observational period, December 2020. The standardized incidence ratios (SIRs) of the overall and site-specific malignancies were estimated and compared with the incidence of cancer in the general population retrieved from the National Cancer Registry. We identified 1449 newly diagnosed patients with Takayasu's arteritis during the observational period (9196 person-years). A total of 74, 66, and 8 patients had overall, solid, and hematologic malignancies, respectively. The risks of overall [SIR, 1.62; 95% confidence interval (CI) 1.27–2.03], solid (SIR, 1.51; 95% CI 1.17–1.92), and hematologic (SIR, 4.05; 95% CI 1.75–7.98) malignancies were increased compared to those in the general population. In solid malignancies, breast (SIR, 2.07; 95% CI 1.16–3.42) and ovarian (SIR, 4.45; 95% CI 1.21–11.39) cancers had an increased risk. In hematologic malignancies, the risk of myelodysplasia increased (SIR, 18.02; 95% CI 3.72–52.66). Immunosuppressive agent use was not associated with malignancy. There was no specific period when cancer more frequently occurred. An increased risk of malignancy was observed in patients with Takayasu's arteritis compared to that in the general population in this large-scale nationwide population study of Korean health insurance data. [ABSTRACT FROM AUTHOR]

Most of previous works and applications of Bayesian factor model have assumed the normal likelihood regardless of its validity. We propose a Bayesian factor model for heavy-tailed high-dimensional data based on multivariate Student-t likelihood to obtain better covariance estimation. We use multiplicative gamma process shrinkage prior and factor number adaptation scheme proposed in Bhattacharya and Dunson [Biometrika 98(2):291–306, 2011]. Since a naive Gibbs sampler for the proposed model suffers from slow mixing, we propose a Markov Chain Monte Carlo algorithm where fast mixing of Hamiltonian Monte Carlo is exploited for some parameters in the proposed model. Simulation results illustrate the gain in performance of covariance estimation for heavy-tailed high-dimensional data. We also provide a theoretical result that the posterior of the proposed model is weakly consistent under reasonable conditions. We conclude the paper with the application of the proposed factor model on breast cancer metastasis prediction given DNA signature data of cancer cells. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical characteristics and radiographic outcomes of vascular Behçet's disease (BD) involving the aorta or its major branches. Methods: This retrospective cohort study was performed in patients with vascular BD involving the aorta or its major branches. All included patients underwent computed tomography angiography (CTA) at least two times with a 2- to 5-year interval. Radiographic progression was defined as newly developed and/or aggravated (> 20%) characteristic features on CTA. Results: The cohort included 22 patients with BD with a median interval of 3.65 years between the initial and follow-up CTA. Five patients (22.7%) showed radiographic progression. Patients with radiographic progression had a longer disease duration at baseline than those without (6.67 vs. 0.26 years, p = 0.028). Of all patients, 21 (95.5%) had vascular aneurysms/pseudoaneurysms and 11 (50.0%) had thrombosis. The most frequently involved artery with aneurysmal change was the abdominal aorta (8/21, 38.1%), followed by the iliac arteries (5/21, 23.8%). In the case of thrombosis, the most frequently involved arteries were the femoral (4/11, 36.4%) and iliac (4/11, 36.4%) arteries. The characteristics and locations of vascular involvement did not significantly differ according to the radiographic outcome. Conclusions: A considerable proportion of patients with BD with arterial involvement showed radiographic progression within 2–5 years. Patients with radiographic progression had a longer disease duration at baseline. The most common form of arterial involvement of BD was aneurysmal change, followed by thrombus formation. Key Points: • This study evaluated for the first time the radiographic outcomes of 22 patients with Behçet's disease involving the aorta or its major branches. • A considerable proportion of patients (5/22, 22.7%) showed radiographic progression. • Patients with radiographic progression had a longer disease duration at baseline than their counterparts; however, no other clinical factors were significantly different. • The most frequent form of vascular involvement was pseudoaneurysm followed by thrombosis. [ABSTRACT FROM AUTHOR]

This paper proposes a topology optimization formulation for the three-dimensional (3-D) design of segmented permanent magnet (PM) arrays. Specifically, the proposed formulation aims to find an optimal 3-D structural topology of PM segments and their discrete magnetization directions. To achieve this, a design variable is defined in the vector form of a Cartesian coordinate system. The magnitude of the design variable vector determines a PM density, and the directional cosines of the vector determine PM magnetization directions. To acquire a segmented PM design with discrete magnetization directions, a PM strength penalization scheme is proposed. In this scheme, a PM strength is controlled using a minimum distance function between a magnetization direction and target discrete directions. Here, the minimum distance function is approximated using the p-norm for sensitivity calculation. To validate the effectiveness of the proposed formulation, three design examples are provided. In the first example, a two-dimensional (2-D) dipole Halbach cylinder is designed to confirm that the proposed formulation can be applied for a 2-D design problem. The second example aims to design 3-D dipole PM arrays with a cuboid cavity. In the third example, a 3-D PM arrays are designed for maximizing the magnetic force acting on a soft ferromagnetic material. [ABSTRACT FROM AUTHOR]

We aim to generate an artificial neural network (ANN) model to predict early TNF inhibitor users in patients with ankylosing spondylitis. The baseline demographic and laboratory data of patients who visited Samsung Medical Center rheumatology clinic from Dec. 2003 to Sep. 2018 were analyzed. Patients were divided into two groups: early-TNF and non-early-TNF users. Machine learning models were formulated to predict the early-TNF users using the baseline data. Feature importance analysis was performed to delineate significant baseline characteristics. The numbers of early-TNF and non-early-TNF users were 90 and 505, respectively. The performance of the ANN model, based on the area under curve (AUC) for a receiver operating characteristic curve (ROC) of 0.783, was superior to logistic regression, support vector machine, random forest, and XGBoost models (for an ROC curve of 0.719, 0.699, 0.761, and 0.713, respectively) in predicting early-TNF users. Feature importance analysis revealed CRP and ESR as the top significant baseline characteristics for predicting early-TNF users. Our model displayed superior performance in predicting early-TNF users compared with logistic regression and other machine learning models. Machine learning can be a vital tool in predicting treatment response in various rheumatologic diseases. [ABSTRACT FROM AUTHOR]

Hyperuricemia and anemia share several comorbidities, but the association between the two conditions remains unclear. The purpose of this study was to investigate the association between hyperuricemia and anemia. Data of 10794 subjects from the Korean National Health and Nutrition Examination Survey conducted in 2016–2017 were analyzed using multivariate logistic regression analyses. An association between anemia and hyperuricemia was not evident in subjects without chronic kidney disease (CKD). In patients with CKD, anemia increased the risk of hyperuricemia by 2-fold. This association remained significant when adjusting for the glomerular filtration rate. In subgroup analyses, the association of anemia with hyperuricemia was significant in subjects aged ≥65 years, and in those with diabetes or hypertension. Subgroup analyses of CKD patients showed similar results. In the current study using data from Korean representative samples, anemia in subjects with CKD was associated with a 2-fold increase in the risk of hyperuricemia, which remained significant even after adjustment for renal function. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical effectiveness of two treatment strategies for active rheumatoid arthritis (RA) refractory to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs): starting TNF inhibitors (TNFIs) or changing csDMARDs. Methods: We used two nationwide Korean RA registries for patient selection. TNFI users were selected from the BIOPSY, which is an inception cohort of RA patients starting biologic DMARDs. As a control group, we selected RA patients with moderate or high disease activity from the KORONA database whose treatment was changed to other csDMARDs. After comparing baseline characteristics between the two groups in either unmatched or propensity score matched cohorts, we compared potential differences in the 1-year remission rate as a primary outcome and changes in HAQ-DI and EQ-5D scores as secondary outcomes. Results: A total of 356 TNFI starters and 586 csDMARD changers were identified from each registry as unmatched cohorts, and 294 patients were included in the propensity score matched cohort. In the intention-to-treat analysis, TNFI starters had higher 1-year remission rates than csDMARD changers in both unmatched (19.1 vs. 18.4%, p < 0.01) and matched cohorts (19.7 vs. 15.0%, p < 0.01). In per protocol analysis, TNFI starters had much higher remission rates in unmatched (37.2 vs. 28.0%, p = 0.04) and matched cohorts (35.4 vs. 19.1%, p = 0.04). However, in matched cohorts, no significant differences were observed between two groups in HAQ-DI and EQ-5D scores. Conclusions: We compared the clinical effectiveness of the two treatment strategies for active RA refractory to csDMARDs. TNFI starters showed higher 1-year remission rates than csDMARD changers. [ABSTRACT FROM AUTHOR]

Despite improved quality of care for rheumatoid arthritis (RA) patients, many still experience treatment failure with a biologic agent and eventually switch to another biologic agent. We investigated patterns of biologic treatment and reasons for switching biologics in patients with RA. Patients with RA who had started on a biologic agent or had switched to another biologic agent were identified from the prospective observational Korean nationwide Biologics (KOBIO) registry. The KOBIO registry contained 1184 patients with RA at the time of initiation or switching of biologic agents. Patients were categorized according to the chronological order of the introduction of biologic agents, and reasons for switching biologics were also evaluated. Of the 1184 patients with RA, 801 started with their first biologic agent, 228 were first-time switchers, and 89 were second-time or more switchers. Second-time or more switchers had lower rheumatoid factor and anti-CCP positivity, and higher disease activity scores at the time of enrollment than the other groups. Among these patients, tocilizumab was the most commonly prescribed biologic agent, followed by adalimumab and etanercept. The most common reason for switching biologics was inefficacy, followed by adverse events, including infusion reactions, infections, and skin eruptions. Furthermore, the proportion of inefficacy, as a reason for switching, was significantly higher with respect to switching between biologics with different mechanisms of action than between biologics with similar mechanisms. In this registry, we showed diverse prescribing patterns and differing baseline profiles based on the chronological order of biologic agents. [ABSTRACT FROM AUTHOR]

Bone marrow hemophagocytosis is a frequently observed but not mandatory finding for the diagnosis of hemophagocytic lymphohistiocytosis (HLH). However, the impact of bone marrow hemophagocytosis on the diagnosis of HLH is still not clear in adult patients. Thus, we retrospectively analyzed adult patients with bone marrow hemophagocytosis between 2000 and 2014 to determine its clinical significance. Among 264 patients with bone marrow hemophagocytosis, malignant disorders were the predominant underlying cause (n = 170, 64 %), especially T/NK-cell (n = 88) and B-cell (n = 45) lymphomas compared to infectious disease (48/264, 18 %). The data for HLH-2004 diagnostic criteria was available in 182 patients, and only 29 % (77/264) of patients with ≥ five positive criteria could be diagnosed with HLH. Among the criteria for the diagnosis of HLH, increased serum ferritin (89 %) was more common than hypofibrinogenemia, hypertriglyceridemia, and bicytopenia (<40 %). The median overall survival was worse in patients with malignancy (9.0 months, 95 % confidence interval [CI] 5.6-12.5) than in those with non-malignant disorders (71.8 months, 95 % CI 56.5-87.1, P < 0.001). In patients with malignancy, the overall survival of patients fulfilling the HLH-2004 criteria was significantly worse than patients who did not (P < 0.001). In conclusion, our results suggest that bone marrow hemophagocytosis might be an important finding in the diagnosis of HLH in adult patients. Considering the high incidence of malignancy as a predisposing disorder for HLH, immediate evaluation should be performed in adult patients with bone marrow hemophagocytosis. [ABSTRACT FROM AUTHOR]

Requirements engineering (RE) offers the means to discover, model, and manage the requirements of the products that comprise a product line, while software product line engineering (SPLE) offers the means of realizing the products' requirements from a common base of software assets. In practice, however, RE and SPLE have proven to be less complementary than they should. While some RE techniques, particularly goal modeling, support the exploration of alternative solutions, the appropriate solution is typically conditional on context and a large product line may have many product-defining contexts. Thus, scalability and traceability through into product line features are key challenges for RE. Feature modeling, by contrast, has been widely accepted as a way of modeling commonality and variability of products of a product line that may be very complex. In this paper, we propose a goal-driven feature modeling approach that separates a feature space in terms of problem space and solution space features, and establish explicit mappings between them. This approach contributes to reducing the inherent complexity of a mixed-view feature model, deriving key engineering drivers for developing core assets of a product line, and facilitating the quality-based product configuration. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the effects of CIP2A (Cancerous inhibitor of protein phosphatase 2A) on the apoptosis of RA FLS. Proliferation and apoptotic activity of RA FLS following treatment with CIP2A siRNA or control siRNA were analyzed using MTT assays and Cell Death Detection kit. RA FLS was treated with CIP2A siRNA or control siRNA in 3-, 6-, and 9-day intervals for a Western blot analysis to determine C-Myc expression. To evaluate the signal transduction pathways engaged in apoptosis, caspase-3 activity, caspase-9 activity, PARP, and phosphorylation of the Akt kinase were analyzed by Western blot. Cell viability of RA FLS was significantly lower in the CIP2A siRNA-treated group compared with the control after 7 days ( p = 0.022). Apoptosis of RA FLS was significantly higher in the CIP2A siRNA-treated group compared with the control when incubated for 3, 6, and 9 days ( p = 0.029, p = 0.021, p = 0.043, respectively). C-Myc expression did not change with the different incubation periods. CIP2A siRNA-treated FLS expressed higher level of activated caspase-3, caspase-9, and PARP ( p = 0.014, p = 0.020, p = 0.021, respectively) and lower level of phosphorylated Akt ( p = 0.001) compared with those treated with the control siRNA. Our data show that CIP2A expression in RA FLS is an important mediator of dysfunctional apoptosis independent of c-Myc stabilization. Expression of CIP2A may contribute to apoptotic resistance of RA FLS through the activation of Akt and deactivation of caspase-3, caspase-9, and PARP. Inhibition of CIP2A may therefore constitute a novel, promising therapeutic target in RA. [ABSTRACT FROM AUTHOR]

The classification system for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis and polyarteritis nodosa had its limitations due to numerous overlapping features of these disease entities. The aim of this study is to investigate the clinical features and outcome of patients diagnosed with microscopic polyangiitis (MPA) according to the newly proposed consensus algorithm of ANCA-associated vasculitides and polyarteritis nodosa. Fifty-five cases of MPA, comprised of 33 men and 22 women, diagnosed according to a new consensus algorithm at a single tertiary hospital were identified for analysis. The main clinical features were constitutional symptoms (78.2%), followed by renal involvement (74.5%), musculoskeletal symptoms (67.3%), skin manifestations (50.9%), neurologic involvement (43.6%), and lung involvement (41.8%). P-ANCA and/or anti-myeloperoxidase antibody were present in 69.1%. Five Factor Score and Birmingham Vasculitis Activity Score (BVAS) at diagnosis were 1.1 ± 0.9 and 10.9 ± 4.9, respectively. Forty-four patients were available for a long-term follow-up, and six patients (13.6%) resulted in death. Mortality was associated with BVAS > 9 at the time of diagnosis, age > 60 years, and presence of cardiomyopathy and interstitial lung disease. The survival rate at 1 and 3 years was 93.9 and 89.2%, respectively. Eight patients (14.5%) required dialysis at the time of diagnosis. This is the first study to demonstrate the clinical features in patients with MPA using a new consensus algorithm. Survival rate was higher than previously reported, and interstitial lung disease was a new risk factor for death in patients with MPA. [ABSTRACT FROM AUTHOR]

Wegener's granulomatosis (WG), Churg-Strauss syndrome, and microscopic polyangiitis (MPA) are closely related small vessel vasculitides characterized by anti-neutrophil cytoplasmic antibodies (ANCA). Although there were some reports of MPA presenting with claudication, there are very few reports on WG presenting with claudication of calf muscles. We report an unusual case of ANCA-associated vasculitis in a 75-year-old man who presented with bilateral calf claudication. Comprehensive evaluations, including electromyography, nerve conduction study, lower extremity magnetic resonance imaging, and Doppler scan, did not reveal any other cause of bilateral calf claudication. P-ANCA and anti-myeloperoxidase antibody was positive, but the anti-proteinase 3 antibody was negative. Chest computed tomography scan showed subpleural honeycombing and reticulation, predominantly in both basal lung areas. Biopsy of the calf muscle showed granulomatous vasculitis. Kidney biopsy was also performed which revealed focal necrotizing glomerulonephritis. Our patient does not exhibit typical clinical features for WG, but histopathologic findings of necrotizing granulomatous vasculitis in calf muscle biopsy is highly suggestive of WG. [ABSTRACT FROM AUTHOR]

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that leads to cellular proliferation in cancer cells. We aim to investigate CIP2A expression in fibroblast-like synoviocytes (FLS) and its association with the histopathological grade of synovitis and the invasive function of FLS in rheumatoid arthritis (RA). CIP2A protein expression was measured in 8 RA FLS and 8 OA FLS using Western blot analysis. CIP2A mRNA expression from 19 RA FLS and 7 OA FLS was measured using real-time PCR. Synovitis score of RA FLS-matched synovial tissues was semiquantitatively measured by two independent pathologists. An in vitro cell invasion assay was performed using RA FLS treated with CIP2A small interfering RNA (siRNA) or with control vector. Western blot analysis showed that CIP2A is more frequently overexpressed in RA FLS compared with OA FLS. CIP2A mRNA expression was higher in RA FLS compared with those in OA FLS, but did not reach statistical significance ( P = 0.076). In RA, total synovitis score was strongly correlated with FLS CIP2A mRNA expression ( rs = 0.849, P = 0.043). TNF-α treatment induced a robust increase in the invasive function of control FLS ( P = 0.0021), but no significant effect was observed in CIP2A siRNA-treated FLS. Our data demonstrate that CIP2A expression is closely associated with the histopathological score of synovitis and invasive function of FLS in RA. These results suggest that CIP2A may play a critical role in the destructive process in RA and warrant further investigation of CIP2A as a therapeutic target. [ABSTRACT FROM AUTHOR]

The outcome of systemic lupus erythematosus (SLE) is largely influenced by the existence of lupus nephritis (LN), and its histologic classification guides the treatment and prognosis of SLE. International Society of Nephrology-Renal Pathology Society (ISN-RPS) announced a revised classification of LN in 2004. The present study investigated the differential outcome of World Health Organization (WHO) class III LN when reclassified according to ISN-RPS classification. Forty-three patients with biopsy-proven WHO class III LN at a single tertiary hospital were included in the study. Baseline characteristics at the time of renal biopsy and clinical data during follow-up were obtained from medical records. Renal response to treatment at one-year follow-up was analyzed in three ways; complete response (CR), partial response (PR), and no response (NR). Of 43 patients with previous WHO class III LN, 12 cases were reclassified into ISN-RPS class IV (9 cases of class IV-S and 3 cases of IV-G). Baseline characteristics at the time of renal biopsy were not different between the reclassified class IV and remaining class III LN group except activity index on renal histology, which was significantly elevated in the reclassified class IV group (4.90 vs. 6.75; P = 0.02). Significantly higher number of patients with remaining class III LN achieved CR to treatment than those with reclassified class IV LN at one-year follow-up since initial biopsy (CR: PR: NR; 16:7:7 vs. 3:1:8; P = 0.032). Our study suggests that the ISN-RPS classification is more advantageous in predicting renal outcome and guiding treatment when evaluating previously classified WHO class III LN. [ABSTRACT FROM AUTHOR]

The aim of this study is to compare the expression of TIM-3 from CD4+ T cells from rheumatoid arthritis (RA) patients and healthy controls and to evaluate the effect of galectin-9 (Gal-9) on apoptosis of CD4+ T cells in these patients. CD4+ T cells from RA patients and healthy controls were isolated from peripheral blood mononuclear cells and were activated. The expression of TIM-3 mRNA in CD4+ T cells was measured using real-time polymerase chain reaction. CD4+ T cells were activated in the presence of graded doses of Gal-9 or control, and Gal-9-induced cytotoxicity and apoptotic activity of CD4+ T cells were analyzed using MTT assays and annexin-V staining, respectively. TIM-3 mRNA expression was significantly lower in CD4+ T cells from RA patients compared with those in healthy controls ( p = 0.028). CD4+ T cell survival as measured by MTT assay when incubated with Gal-9 (15 nM) was significantly higher in RA patients than in healthy controls ( p = 0.002). Apoptotic activity of CD4+ T cells from healthy controls as measured by annexin staining increased with graded doses of Gal-9 (0 nM vs. 30 nM, 0 nM vs. 90 nM, p = 0.016 each). However, apoptotic activity of CD4+ T cells from RA patients did not change despite the stimulation with Gal-9. Gal-9-mediated apoptosis of CD4+ T cells is dysfunctional in RA patients. Blunted Gal-9-mediated apoptosis may be exerted through underexpression of TIM-3 that negatively regulates Th1 response. Our data suggest that TIM-3 and its interaction with Gal-9 may play an important role in the pathogenesis of RA and may represent a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Fibroblast-like synoviocytes (FLS) play an important role in the pathogenesis of rheumatoid arthritis. Raf kinase inhibitor protein (RKIP) negatively regulates the Raf/MEK/ERK and NF-κB pathway. The role of RKIP in rheumatoid FLS is unknown. The purpose of the present study was to investigate the function of RKIP in rheumatoid FLS. Rheumatoid FLS were transfected with either RKIP-expressing plasmids or RKIP small interfering RNA (siRNA). RKIP protein was detected in rheumatoid synovial tissue (ST) and FLS. RKIP overexpression significantly decreased IL-6 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP overexpression also showed a decreased trend in IL-8, MMP-1, and MMP-3 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP silencing resulted in significantly increased MMP-1 and MMP-3 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP silencing also increased IL-6 and IL-8 mRNA expression in TNF-α-stimulated rheumatoid FLS, but this increase did not reach statistical significance. TNF-α-induced ERK and NF-κB activation was suppressed in FLS with RKIP overexpression. RKIP silencing resulted in a significantly higher invasion index in TNF-α-stimulated rheumatoid FLS compared to controls. These results suggest that RKIP might be a potential therapeutic target for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Survivin belongs to the family of inhibitor of apoptosis proteins and plays an important role in the hyperplastic growth of tissues and tumors. In this study, we assessed the expression of survivin in rheumatoid synovial fluids (SF) and synovial tissues (ST) of rheumatoid arthritis (RA) patients in order to investigate the role of extracellular survivin in the pathogenesis of RA. The survivin level from SF was significantly higher in RA patients ( n = 38) than in osteoarthritis patients ( n = 18; 10.68 ± 2.76 vs. 1.0 ± 0.56 pg/ml, p = 0.02). In addition, SF survivin level was higher in erosive RA patients ( n = 23) than in non-erosive RA patients ( n = 15; 15.26 ± 4.26 vs. 4.47 ± 1.12 pg/ml, p = 0.05). SF survivin level in RA was positively correlated with disease activity score 28, but did not reach statistical significance ( r = 0.309, p = 0.07). RA SF survivin level was also positively correlated with peripheral blood leukocyte counts ( r = 0.443, p = 0.005). The immunohistochemical staining and Western blot analysis revealed survivin expression in the ST and fibroblast-like synoviocytes of RA patients, respectively. These findings suggest that extracellular survivin may be produced from rheumatoid FLS and may play an important role in the destructive RA process. [ABSTRACT FROM AUTHOR]

Kirner deformity is characterized by volar and radial incurvature of the distal phalanx of the 5th finger. A proposed causative mechanism includes abnormal distal insertion of the flexor digitorum profundus tendon along the volar surface of the distal phalanx of the 5th finger. A chronic inflammatory process or altered vascularisation of the soft tissues has also been suggested as the underlying causative mechanism based on MRI findings. We present a teenage boy with Kirner deformity, along with supplementary imaging of his father who also has the deformity, to illustrate MRI findings that dispute the above hypotheses. MRI in both son and father show normal insertion of the deep flexor tendon and no signs of inflammation. [ABSTRACT FROM AUTHOR]

The present study aimed at characterizing the phenotype and functions of adherent synovial fluid (SF) cells derived from rheumatoid arthritis (RA), comparing with fibroblast-like synoviocytes (FLS) derived from RA synovial tissue (ST). Adherent SF-derived cells were spindle-shaped from passages 1–6 under light microscopy. The cell surface marker profile in SF-derived cells from passage 1–6 was similar to that of ST-derived FLS. Levels of MMP-1 and MMP-3 were not significantly different between SF-derived cells and ST-derived FLS ( p = 0.20 and p = 0.40, respectively). There was no significant difference in the optical density value between two cell types in the cell invasion assay ( p = 0.10). SF-derived adherent cells have a fibroblast-like phenotype from very early culture passages and have the potential to produce MMPs with the invasive capacity to degrade cartilage, identical to ST-derived FLS. Therefore, these cells could substitute for ST-derived FLS in studying the pathogenesis of RA. [ABSTRACT FROM AUTHOR]

Systematic discovery and exploitation of commonality across related software systems is a fundamental technical requirement for achieving successful software reuse. By examining a class/family of related systems and the commonality underlying those systems, it is possible to obtain a set of reference models, i.e., software architectures and components needed for implementing applications in the class. FORM (Feature-;Oriented Reuse Method) supports development of such reusable architectures and components (through a process called the “domain engineering”) and development of applications using the domain artifacts produced from the domain engineering. FORM starts with an analysis of commonality among applications in a particular domain in terms of services, operating environments, domain technologies, and implementation techniques. The model constructed during the analysis is called a “feature” model, and it captures commonality as an AND/OR graph, where AND nodes indicate mandatory features and OR nodes indicate alternative features selectable for different applications. Then, this model is used to define parameterized reference architectures and appropriate reusable components instantiatable during application development. Architectures are defined from three different viewpoints (subsystem, process, and module) and have intimate association with the features. The subsystem architecture is used to package service features and allocate them to different computers in a distributed environment. Each subsystem is further decomposed into processes considering the operating environment features. Modules are defined based on the features on domain technology and implementation techniques. These architecture models that represent an architecture at different levels of abstraction are derived from the feature hierarchy captured in the feature model. Modules serve as basis for creating reusable components, and their specification defines how they are integrated into the application (e.g., as-;is integration of pre-;coded component, instantiation of parameterized templates, and filling-;in skeletal codes). Our experiences have shown that for the electronic bulletin board and the private branch exchange (PBX) domains, “features” make up for a common domain language and the main communication medium among application users and developers. Thus, the feature model well represents a “decision space” of software development, and is a good starting point for identifying candidate reusable components. [ABSTRACT FROM AUTHOR]

In previous literature regarding development of rheumatoid arthritis (RA), female reproductive factors have been described as protective factors, risk factors, or irrelevant, leading to inconsistent results. The aim of this study was to investigate the effect of female reproductive factors on the incidence of seropositive RA. A large population-based retrospective cohort of the National Health Insurance Service data in South Korea was used. Postmenopausal women who participated in both cardiovascular and breast cancer screening in 2009 were included and followed until date of seropositive RA diagnosis, death, or December 31, 2018. Multivariable-adjusted Cox proportional hazards model was used to assess the association between reproductive factors and incident seropositive RA. Of 1,357,736 postmenopausal women, 6056 women were diagnosed with seropositive RA, and the incidence rate was 54.16 cases/100,000 person-years. Reproductive factors other than hormone replacement therapy (HRT) were not significantly associated with seropositive RA incidence. Postmenopausal women who used HRT ≥ 5 years were associated with a higher aHR of incident seropositive RA than never-users (aHR 1.25; 95% CI 1.09–1.44). Alcohol consumption less than 30 g per day (aHR 0.80; 95% CI 0.74–0.87), regular physical activity (aHR 0.90; 95% CI 0.84–0.97), diabetes mellitus (aHR 0.85; 95% CI 0.78–0.93), and cancer (aHR 0.77; 95% CI 0.64–0.92) were associated with lower risk of seropositive RA. Most female reproductive factors did not significantly affect the development of seropositive RA in postmenopausal women. Only HRT is associated with a small but significant increase in risk of seropositive RA. [ABSTRACT FROM AUTHOR]

We investigated risk factors for immune-related adverse events (irAEs) in patients treated with anti-programmed cell death protein1 antibody pembrolizumab. A retrospective medical record review was performed to identify all patients who received at least one dose of pembrolizumab at Samsung Medical Center, Seoul, Korea between June 2015 and December 2017. Three hundred and ninety-one patients were included in the study. Data were collected on baseline characteristics, treatment details, and adverse events. Univariate and multivariate logistic regression models were used to identify risk factors for irAEs. Sixty-seven (17.1%) patients experienced clinically significant irAEs; most commonly dermatologic disorders, followed by pneumonitis, musculoskeletal disorders, and endocrine disorders. Fourteen patients (3.6%) experienced serious irAEs (grade ≥ 3). Most common serious irAEs were pneumonitis (2.3%). Four deaths were associated with irAEs, all of which were due to pneumonitis. In multivariate regression analysis, a higher body mass index (BMI) and multiple cycles of pembrolizumab were associated with higher risk of irAEs (BMI: odds ratio [OR] 1.08, 95% confidence interval [CI] 1.01–1.16; pembrolizumab cycle: OR 1.15, 95% CI 1.08–1.22). A derived neutrophil-lymphocyte ratio (dNLR) greater than 3 at baseline was correlated with low risk of irAEs (OR 0.37, 95% CI 0.17–0.81). Our study demonstrated that an elevated BMI and higher number of cycles of pembrolizumab were associated with an increased risk of irAEs in patients treated with pembrolizumab. Additionally, increased dNLR at baseline was negatively correlated with the risk of developing irAEs. [ABSTRACT FROM AUTHOR]