RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells.

The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to TH17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of RORγt using cell-transducible form of transcription modulation domain of RORγt (tRORγt-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tRORγt-TMD specifically inhibited TH17-related cytokines induced by RORγt, thereby suppressing the differentiation of naïve T cells into TH17, but not into TH1, TH2, or Treg cells. tRORγt-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4(+) T cells and spinal cord-infiltrating CD4(+) T cells, and suppress the functions of TH17 cells. The clinical severity and incidence of EAE were ameliorated by tRORγt-TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4(+) IL-17(+) T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tRORγt-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking TH1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tRORγt-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with TH17 or TH1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.ope

비가우시안 잡음 영상 복원을 위한 그룹 희소 표현

학위논문(박사)--서울대학교 대학원 :자연과학대학 수리과학부,2020. 2. 강명주.For the image restoration problem, recent variational approaches exploiting nonlocal information of an image have demonstrated significant improvements compared with traditional methods utilizing local features. Hence, we propose two variational models based on the sparse representation of image groups, to recover images with non-Gaussian noise. The proposed models are designed to restore image with Cauchy noise and speckle noise, respectively. To achieve efficient and stable performance, an alternating optimization scheme with a novel initialization technique is used. Experimental results suggest that the proposed methods outperform other methods in terms of both visual perception and numerical indexes.영상 복원 문제에서, 영상의 비국지적인 정보를 활용하는 최근의 다양한 접근 방식은 국지적인 특성을 활용하는 기존 방법과 비교하여 크게 개선되었다. 따라서, 우리는 비가우시안 잡음 영상을 복원하기 위해 영상 그룹 희소 표현에 기반한 두 가지 변분법적 모델을 제안한다. 제안된 모델은 각각 코시 잡음과 스펙클 잡음 영상을 복원하도록 설계되었다. 효율적이고 안정적인 성능을 달성하기 위해, 교대 방향 승수법과 새로운 초기화 기술이 사용된다. 실험 결과는 제안된 방법이 시각적인 인식과 수치적인 지표 모두에서 다른 방법보다 우수함을 나타낸다.1 Introduction 1 2 Preliminaries 5 2.1 Cauchy Noise 5 2.1.1 Introduction 6 2.1.2 Literature Review 7 2.2 Speckle Noise 9 2.2.1 Introduction 10 2.2.2 Literature Review 13 2.3 GSR 15 2.3.1 Group Construction 15 2.3.2 GSR Modeling 16 2.4 ADMM 17 3 Proposed Models 19 3.1 Proposed Model 1: GSRC 19 3.1.1 GSRC Modeling via MAP Estimator 20 3.1.2 Patch Distance for Cauchy Noise 22 3.1.3 The ADMM Algorithm for Solving (3.7) 22 3.1.4 Numerical Experiments 28 3.1.5 Discussion 45 3.2 Proposed Model 2: GSRS 48 3.2.1 GSRS Modeling via MAP Estimator 50 3.2.2 Patch Distance for Speckle Noise 52 3.2.3 The ADMM Algorithm for Solving (3.42) 53 3.2.4 Numerical Experiments 56 3.2.5 Discussion 69 4 Conclusion 74 Abstract (in Korean) 84Docto

Multivariable index for assessing the activity and predicting all-cause mortality in antineutrophil cytoplasmic antibody-associated vasculitis

BACKGROUND: So far, there has been no tool to estimate activity at diagnosis and predict all-cause mortality in patients with ANCA-associated vasculitis (AAV). Hence, we determined the initial predictors of them in patients with AAV. METHODS: We retrospectively reviewed the medical records of 182 patients with AAV. Severe AAV was defined as Birmingham Vasculitis Activity Score (BVAS) ≥ 16. The cutoffs were extrapolated by the receiver operator characteristic (ROC) curve. The odds ratio (OR) and the relative risk (RR) were assessed using the multivariable logistic regression analysis and the chi-square test, respectively. RESULTS: In the comparison analysis, patients with severe AAV exhibited the higher neutrophil and platelet counts, creatinine, erythrocyte sedimentation rate and C-reactive protein, and the lower lymphocyte count, hemoglobin, and serum albumin than those without. In the multivariable logistic regression analysis, creatinine ≥ 0.9 mg/dL (OR 2.264), lymphocyte count ≤ 1430.0/mm3 (OR 1.856), and hemoglobin ≤ 10.8 g/dL (OR 2.085) were associated with severe AAV. We developed a new equation of a multivariable index for AAV (MVIA) = 0.6 × (Lymphocyte count ≤ 1430.0/mm3 ) + 0.7 × (Hemoglobin ≤ 10.8 g/dL) + 0.8 × (Creatinine ≥ 0.9 mg/dL). The optimal cutoff of MVIA for severe AAV was set as 1.35. Severe AAV was identified more frequently in patients with MVIA at diagnosis ≥1.35 than those without (RR 4.432). Patients with MVIA at diagnosis ≥1.35 exhibited the lower cumulative patient survival rate than those without. CONCLUSION: Multivariable index for AAV could assess the cross-sectional activity and predict all-cause mortality in patients with AAV.ope

A case of extranodal natural killer/T-cell lymphoma mimicking refractory Behçet's disease

ope

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in Korea: A Narrative Review

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a group of systemic necrotising vasculitides, which often involve small vessels, and which lead to few or no immune deposits in affected organs. According to clinical manifestations and pathological features, AAV is classified into three variants: microscopic polyangiitis, granulomatosis with polyangiitis (GPA), and eosinophilic GPA. The American College of Rheumatology 1990 criteria contributed to the classification of AAV, although currently the algorithm suggested by the European Medicines Agency in 2007 and the Chapel Hill Consensus Conference Nomenclature of Vasculitides proposed in 2012 have encouraged physicians to classify AAV patients properly. So far, there have been noticeable advancements in studies on the pathophysiology of AAV and the classification criteria for AAV in Western countries. However, studies analysing clinical features of Korean patients with AAV have only been conducted and reported since 2000. One year-, 5 year-, and 10 year-cumulative patient survival rates are reported as 96.1, 94.8, and 92.8%. Furthermore, initial vasculitis activity, prognostic factor score, age and specific organ-involvement have been found to be associated with either all-cause mortality or poor disease course. The rate of serious infection is 28.6%, and 1 year-, 5 year- and 10 year-cumulative hospitalised infection free survival rates range from 85.1% to 72.7%. The overall standardised incidence ratio of cancer in AAV patients was deemed 1.43 compared to the general Korean population.ope

Controlling Nutritional Status Score is Associated with All-Cause Mortality in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

PURPOSE: The controlling nutritional status (CONUT) score was developed to detect undernutrition in patients. Here, we investigated whether the CONUT score estimated at diagnosis could help predict poor outcomes [all-cause mortality, relapse, and end-stage renal disease (ESRD)] of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). MATERIALS AND METHODS: We retrospectively reviewed and collated data, including baseline characteristics, clinical manifestations (to calculate AAV-specific indices), and laboratory results, from 196 newly diagnosed AAV patients. Serum albumin, peripheral lymphocyte, and total cholesterol levels (at diagnosis) were used to calculate CONUT scores. RESULTS: In total, 111 patients had high CONUT scores (≥3), which showed higher frequency of myeloperoxidase-ANCA and ANCA positivity, and demonstrated higher AAV-specific indices. The optimal cut-offs of CONUT score (at diagnosis) for predicting all-cause mortality and ESRD were ≥3.5 and ≥2.5, respectively. Patients with CONUT scores higher than the cut-off at diagnosis exhibited lower cumulative and ESRD-free survival rates compared to those with lower scores than the cut-off. In multivariable analyses, diabetes mellitus [hazard ratio (HR): 4.394], five-factor score (HR: 3.051), and CONUT score ≥3.5 (HR: 4.307) at diagnosis were independent predictors of all-cause mortality, while only serum creatinine (HR: 1.714) was an independent predictor of ESRD occurrence.ope

Rituximab Biosimilar Prevents Poor Outcomes of Microscopic Polyangiitis and Granulomatosis with Polyangiitis as Effectively as Rituximab Originator

Purpose: There has been no extensive study to compare the efficacy between rituximab originator (Mabthera®) and its biosimilar (Truxima®) for microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Here, we investigated the clinical effects of rituximab on poor outcomes of MPA and GPA in Korean patients, and compared those between Mabthera® and Truxima®. Materials and methods: We retrospectively reviewed the medical records of a total of 139 patients, including 97 MPA patients and 42 GPA patients. At diagnosis, antineutrophil cytoplasmic antibody positivity and comorbidities were assessed. During follow-up, all-cause mortality, relapse, end-stage renal disease, cerebrovascular accident and acute coronary syndrome were evaluated as poor outcomes. In this study, rituximab was used as either Mabthera® or Truxima®. Results: The median age at diagnosis was 60.1 years and 46 patients were men (97 MPA and 42 GPA patients). Among poor outcomes, patients receiving rituximab exhibited a significantly lower cumulative relapse-free survival rate compared to those not receiving rituximab (p=0.002). Nevertheless, rituximab use did not make any difference in other poor outcomes of MPA and GPA except for relapse, which might be a rebuttal to the fact that rituximab use after relapse eventually led to better prognosis. There were no significant differences in variables at diagnosis and during follow-up between patients receiving Mabthera® and those receiving Truxima®. Patients receiving Truxima® exhibited a similar pattern of the cumulative survival rates of each poor outcome to those receiving Mabthera®. Conclusion: Truxima® prevents poor outcomes of MPA and GPA as effectively as does Mabthera®.ope

Total Haemolytic Complement Activity at Diagnosis as an Indicator of the Baseline Activity of Antineutrophil Cytoplasmic Antibody-associated Vasculitis

Objective. The total haemolytic complement activity (CH50) assay evaluates the functioning of the complement system. Accumulating evidence indicates that the activation of the complement system plays a critical role in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Therefore, this study aimed to investigate whether CH50 levels at diagnosis could reflect the baseline activity of AAV. Methods. This retrospective study included 101 immunosuppressive drug-naïve patients with AAV. At diagnosis, all patients underwent clinical assessments for disease activity, including measurement of the Birmingham Vasculitis Activity Score (BVAS) and Five Factor Score (FFS), and laboratory evaluations, such as tests for CH50, C3, and C4 levels. The association between CH50 levels and disease activity was determined. Results. The median BVAS and FFS at diagnosis were 12.0 and 1.0, respectively, whereas the median CH50 level was 60.4 U/mL. There was a negative correlation between the CH50 level and BVAS (r=−0.241; p=0.015). A CH50 cut-off value of 62.1 U/mL was used to classify the patients into two groups: patients with CH50 levels ＜62.1 U/mL (low-CH50 group) and those with CH50 levels ≥ 62.1 U/mL (high-CH50 group). The low-CH50 group had a higher proportion of patients with high disease activity, based on the BVAS, than the high-CH50 group (52.5% vs. 23.8%, p=0.004). Additionally, the low-CH50 group exhibited a lower relapse- free survival rate than the high-CH50 group; however, this difference was not statistically significant (p=0.082). Conclusion. Low CH50 levels at diagnosis may reflect high baseline activity of AAV.ope

Novel mortality-predicting index at diagnosis can effectively predict all-cause mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis

Background: This study investigated whether the inflammation prognostic index (IPI) and the mortality predicting index (MPI) at diagnosis could predict all-cause mortality in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: We included 223 AAV patients and reviewed their medical records. Clinical and laboratory data and AAV-specific indices at diagnosis were assessed. The IPI was calculated as neutrophil-to-lymphocyte ratio (NLR) × C-reactive protein to albumin ratio (CAR). Here, we newly developed an MPI (NLR × CAR × monocyte counts). Results: The mean age of 223 patients (122 MPA, 57 GPA and 44 EGPA patients) was 59 years. The rate of mortality was 11.2%. Using the receiver operator characteristic curve for all-cause mortality, the cut-offs were calculated as NLR: 3.22, CAR: 3.25, IPI: 18.53 and MPI: 8367.82. In the univariable Cox hazard analysis, age, gender, smoking history, BVAS, FFS and over the cut-off of each index showed statistical significance. As the indices share at least two mutual variables, the multivariable analysis was conducted four times based on each index. An IPI ≥18.53 (HR 3.162) and MPI ≥8367.82 (HR 3.356) were significantly associated with all-cause mortality. Conclusions: This study developed a novel indicator, MPI, that uses the existing NLR and CAR indices and proved that it could predict all-cause mortality in AAV patients.ope

A Study on the Measured Data Analysis of Berthing Velocity for Safe Berthing

When designing mooring facilities for harbor and dock facilities, the port facility manager should consider the berthing energy of the approaching ship. However, it is difficult to directly estimate the ship’s berthing velocity, which has the greatest effect on the berthing energy. Therefore, it is analyzed statistically based on the measured data. The ‘Brolsma curve’, which is widely referred to worldwide as the data on the berthing velocity, is the data collected in the 1970s. However, it does not correspond to the current situation because it is not reflected in the enlargement of the ship and the development of the mooring ability in the port facility. Therefore, it is necessary to determine the criteria of the new design berthing velocity by analyzing the actually measured ship berthing velocity recently. In this study, I try to derive a new criterion by analyzing the berthing velocity data observed from a tanker terminal in Korea. The comparison and analysis of the domestic and international reference data related to the berthing velocity complements the ‘Port and Fishing Design Standards (2014)’and the improvement plan is prepared. The purpose of this study is to produce basic data that can be referenced in the design of mooring facilities by numerical analysis of the actual data analysis results. The actual data of the berthing velocity used in this study is measured at a tanker terminal operated by three jetties located in Korea for about 17 months and the total number of data is 207. As a result of analyzing the actual data by jetty and ship size, it was confirmed that most of the data are within the design berthing velocity of each jetty. In order to apply the actual data of berthing velocity to the probability distribution function, the frequency of berthing velocity was converted into histogram and compared with the three probability distributions of normal distribution, lognormal distribution and Weibull distribution. To find the most suitable probability distribution function, I conduct the goodness of fit test such as K-S test, A-D test and Q-Q plot. As a result, lognormal distribution was most suitable for the ship which was in laden condition and Weibull ditribution was most suitable in the case of ballast condition. Based on the results, I developed a method to calculate and use the predicted value of berthing velocity derived from the concept of probability of exceedance. The relationship curve between the berthing velocity and the DWT was derived by using the relation between the ship’s specification and ship size. Using the linear regression analysis, the relational expressions corresponding to the confidence intervals of 50, 75, 90, 95, 98, and 99% were derived and rearranged into graphs. This study suggests a method to estimate the proper berthing velocity according to ship size through analysis of actual data. It is necessary to revise old reference paper for berthing velocity that do not correspond to the reality such as the data of 'Harbor and Fishing Design Standards'. However, since the actual data used in this study is limited to domestic tanker terminal, further studies are needed to collect and analyze the data collected from various types of vessels and ports. The ultimate goal is to develop the new relationship curve between the vessel size and the berthing velocity that can replace Brolsma curve.|현재 항만 및 부두 시설을 설계함에 있어 항구에 접근하는 선박의 접안에너지를 고려하고 있다. 하지만 이 접안에너지에 가장 큰 영향을 미치는 선박 접안속도를 직접 추정하기는 어려우므로 실측한 데이터에 근거하여 통계적으로 분석하고 있는 실정이다. 접안속도에 대한 자료로 전 세계적으로 많이 참조하고 있는 ‘Brolsma curve’는 데이터 자체가 1970년대에 수집된 자료로써 선박의 대형화 및 계류시설의 발전에 대한 반영이 되어있지 않기 때문에 현재의 실정에 맞지 않는 상황이다. 따라서 최근에 실제로 측정된 선박 접안속도를 분석하여 새로운 설계 접안속도의 기준을 정하는 것이 필요하다. 본 연구에서는 국내의 탱커부두에서 실측된 접안속도 데이터를 분석하여 접안속도에 대한 새로운 기준을 도출하고자 한다. 접안속도와 관련한 국내외 참고문헌을 비교, 분석하여 현재 국내의 항만 및 어항 설계기준(2014)에 대한 보완점을 도출하고 개선방안을 마련하고자 하며, 실측 데이터 분석 결과를 수치화 하여 계류 시설의 설계에 참고할 수 있는 기초 자료를 제작하는 데 목적을 둔다. 본 연구에서 활용한 접안속도의 실측데이터는 3개의 Jetty로 구분되어 운영되는 국내의 한 탱커부두에서 약 17개월간 측정한 것으로써 총 데이터 수는 207개이다. 이 실측데이터를 Jetty별, 선박 규모별로 구분하여 분석해 본 결과, 대부분의 데이터가 각 Jetty의 설계접안속도 범주 안에 있는 것을 확인하였다. 하지만 실측데이터의 최댓값은 설계접안속도의 약 2배를 초과하는 것을 확인하였다. 이렇게 실측 접안속도가 설계접안속도를 초과하는 경우, 접안에너지가 과도하게 산출되어 부두가 손상되는 등의 사고로 이어질 수 있기 때문에 그에 대한 대책마련이 필요하다. 또한, 접안속도 실측데이터를 확률분포함수에 적용시키기 위해 접안속도의 빈도수를 Histogram화 하였으며, 이를 정규분포, 대수정규분포, Weibull 분포 세 가지 확률분포도와 비교하였다. 가장 적합한 확률분포함수를 찾기 위해 K-S 검정, A-D 검정, Q-Q Plot 등의 적합도 검정을 시행하였다. 그 결과 만재상태로 접안하였던 선박은 대수정규분포, 경하상태의 경우에는 Weibull 분포가 가장 적합한 것으로 나타났다. 그 결과를 바탕으로 초과확률 개념에서 도출된 접안속도 예측치를 계산하여 활용할 수 있는 방법에 대해 연구하였다. 또한, 선박의 제원과 선박 규모 간의 관계식을 활용하여 접안속도와 선박 규모와의 관계식을 도출하였다. 선형회귀분석을 활용하여 50, 75, 90, 95, 98, 99 %의 신뢰구간에 해당되는 관계식을 도출하고 이를 그래프로 재정리 하였다. 본 연구에서는 실측 데이터 분석을 통한 선박 규모에 따른 적정 접안속도 값을 산정하는 방법을 제시하여 현재 국내에서 참고 중인‘항만 및 어항설계 기준’의 접안속도 관련 데이터와 같이 현실과 맞지 않는 내용을 개정할 필요가 있음을 확인하였다. 하지만 본 연구에서 사용한 실측 데이터가 국내의 탱커선 부두에 한정되어 있으므로, 다양한 선종 및 부두에서 취합한 데이터를 취합, 분석하는 추가 연구가 필요하며 이를 통해 Brolsma curve를 대체할 수 있는 새로운 선박규모와 접안속도의 관계식을 개발하고자 한다.제 1 장 서 론 1.1 연구의 배경 및 목적 1 1.2 연구의 내용 및 방법 3 제 2 장 선박 접안에너지와 접안속도 2.1 국내외 접안속도 관련 연구 및 기준 검토 6 2.1.1 국제 접안속도 관련 연구 및 기준 6 2.1.2 국내 접안속도 관련 연구 및 기준 13 2.2 선박 접안 에너지의 산정 18 2.2.1 이론적인 방법의 접안 에너지 산정 18 2.2.2 통계적인 방법의 접안 에너지 산정 24 2.2.3 접안 에너지와 방충재 25 2.3 DAS(Dock mounted docking aid systems) 32 제 3 장 실측 접안속도에 대한 확률분포함수의 적용 3.1 접안속도 실측 데이터 분석의 개요 35 3.1.1 실측 데이터의 개요 35 3.1.2 실측 접안속도의 특성 분석 38 3.2 확률분포함수의 종류 49 3.3 확률분포함수의 적용 51 3.3.1 실측 접안속도 빈도수와 확률분포도 51 3.3.2 확률분포도 적합도 검정 55 3.3.3 적합도 검정 결과 요약 65 3.4 초과확률 개념에서의 적용 67 제 4 장 신뢰수준별 접안속도와 선박규모 관계 4.1 선박의 규모와 선박 주요 데이터의 관계 74 4.2 선형회귀분석 75 4.3 선박규모와 접안속도의 관계식 76 4.3.1 신뢰수준별 접안속도와 선박규모의 관계식 도출 방법 76 4.3.2 접안속도와 선박규모의 관계식 도출 결과 80 제 5 장 결론 및 제언 5.1 결 론 88 5.2 제 언 90 참고문헌 92Maste