제2형 당뇨병을 가진 한국인에서 DNA 메틸레이션 시계 분석 및 비교

학위논문(석사) -- 서울대학교대학원 : 보건대학원 보건학과, 2023. 2. 성주헌.Background: Diabetes mellitus, a chronic disease whose prevalence is increasing worldwide, is important to manage because it causes systemic and complex complications. It is also known that the prevalence of diabetes tends to increase with age, and age-related diseases appear earlier in diabetic patients. Among them, type 2 diabetes is an important type of diabetes, accounting for 90% of all diabetes patients. On the other hand, DNA methylation is an emerging tool for studying the epigenetic aging mechanism. It is known to play an essential role in developing various diseases because it reflects the effects of the individual's environment and lifestyle and causes changes in gene expression. In addition, it can function as a clinically and epidemiologically important biomarker because it is stable, has low invasiveness, and is reversible. Estimating age according to DNA methylated loci is called DNA methylation age (mAge), also called epigenetic biomarker of aging. The basic principle is to select hypermethylated or hypomethylated CpGs based on various health risks related to aging, such as cancer, obesity, and cardiovascular disease, and measure aging linearly through this. The modeling calculating the methylation age is called a DNA methylation clock, or a methylation clock. Meanwhile, DNA methylation clock tends to be underestimated in those aged 60-65 years and older. Furthermore, it lacks ethnic diversity, especially in Asians, so the tendency to underestimate the methylation age in the Korean diabetic cohort or the relationship between diabetes-related factors and methylation age was not confirmed yet. Therefore, in order to find out the relationship between Koreans with type 2 diabetes and aging through the correlation between methylation age and the Korean diabetic cohort, this study investigated a relationship among nine DNA methylation clocks (Horvath, Hannum, PhenoAge, GrimAge, AAHorvath, AAHannum, AAPheno, AAGrim, and DunedinPACE), and part of the Seoul National University Hospital T2D cohort (SNUH), and part of the Ansan/Anseong Community-based Cohort (AS) of the Korean Genome and Epidemiology Study (KoGES). Methods: The SNUH cohort consisted of 429 patients (232 patients with type 2 diabetes and 197 patients in the control group), and the AS cohort consisted of 400 patients (200 patients with type 2 diabetes and 200 patients in the control group). After receiving the raw DNA methylation data of the two groups, the methylation density was calculated as a beta value, from which the methylation age and acceleration were obtained. In addition, according to diabetes status, duration of diabetes, and stage of CKD, groups were divided as follows: diabetes group/control group, long duration group (more than 10 years)/short duration group (less than 10 years)/non-diabetic group, and CKD stage 5/CKD stage 4/CKD stage 3 or less with type 2 diabetes groups. Each groups methylation age and acceleration were plotted according to age, and the mean and variance were compared. By applying a multiple linear regression equation, it was confirmed that the clock significantly reflects fasting glucose, an index reflecting the results of diabetes and the primary criterion for diagnosing diabetes. In addition, the AICs of the multiple linear regression models for each clock in the entire cohort were compared. Through a Bland-Altman plot, it was confirmed that the Korean diabetic cohort also shows underestimation tendency of DNA methylation clocks. In addition, it was confirmed whether CpGs known to be related to type 2 diabetes were included in the clocks used in this study. Among those CpGs, CpGs that showed significant differences between groups in this study were summarized. Results: As a result of applying nine epigenetic clocks in the Korean diabetic cohort and examining them in various ways, the clocks in which diabetes status and progression of CKD stage in diabetic patients were reflected in aging were Horvath mAge/EAA, Hannum mAge/EAA, and DunedinPACE. In addition, in the group with more patients with accelerated aging due to aggravated progression of T2D, the glucose variable in the multiple linear regression model appeared significantly, and the underestimation tendency was prominent. The above indicated an association between the Korean diabetic cohort and mAge/EAA. Therefore, this study provides a basis for using mAge/EAA to study aging and complications in Korean diabetic patients. On the other hand, it was found that T2D-related CpGs with significant differences between the subgroups in the Korean diabetic cohort were not included more than 10 in the clocks. Therefore, to study aging and complications in Korean with T2D, we propose to create a next-generation clock that includes them. However, since the two cohorts differ in the composition of diabetes severity and the whole sample size is small, follow-up studies are needed to support this result. If a large sample size is obtained, it is proposed to conduct a study to see the difference in absolute values as well as the difference in slope in the plot of mAges/EAAs by fixing the age of the diabetic group and the control group equally.세계적으로 유병률이 증가하고 있는 만성질환인 당뇨병은 전신적이고 복합적인 합병증을 유발하므로 관리가 중요한 질환이다. 또 당뇨병은 나이가 들수록 유병률이 증가하는 경향성이 있고, 당뇨병 환자에서는 연령 관련 질환들이 일찍 나타나는 것으로 알려져 있다. 그중에서도 제2형 당뇨병은 전체 당뇨병 환자의 90%를 차지할 만큼 중요한 당뇨병 유형이다. 한편 후생유전학적 노화의 메커니즘을 연구하는 데에 있어 DNA 메틸레이션은 떠오르는 도구로, 개체의 환경 및 생활습관의 영향이 반영되고 유전자 발현에 변화를 일으키기 때문에 다양한 질환의 발병에 중요한 역할을 하는 것으로 알려져 있다. 또 안정적이고 침습성이 낮으며 가역적이라는 특성이 있어 임상적, 역학적으로 중요한 바이오마커로 기능할 수 있다. DNA 메틸화가 된 CpG의 위치와 정도에 따라 연령을 추산하는 것을 DNA 메틸레이션 연령이라고 부르고, 이것은 후성유전학적 노화 바이오마커라고도 부른다. 기본 원리는 암, 비만, 심혈관 질환 등 노화와 관련된 다양한 건강 위험들을 기준으로 과메틸화 또는 과소메틸화된 CpG를 선정하고 이를 통해 선형적으로 노화를 측정하는 것이며, 이렇게 메틸레이션 연령을 산출하는 모델링을 메틸레이션 시계라고 부른다. 한편 메틸레이션 시계는 60-65세 이상에서 과소평가되는 경향성이 있고, 특히 아시아인에서 민족 다양성이 부족하여, 한국인 당뇨병 코호트에서 메틸레이션 연령의 과소평가 경향성이나 당뇨 관련 요인들과 메틸레이션 연령의 관련성은 확인되지 않았다. 따라서 메틸레이션 연령과 한국인 당뇨병 코호트와의 상관관계를 통해 제2형 당뇨병을 가진 한국인과 노화의 관계를 알아보기 위해, 본 연구는 메틸레이션 연령 및 가속도를 계산하는 메틸레이션 시계 9가지(Horvath, Hannum, PhenoAge, GrimAge, AAHorvath, AAHannum, AAPheno, AAGrim, and DunedinPACE)와 서울대학교병원 인체자원은행 당뇨병 클리닉 코호트의 일부(SNUH), 질병관리청 한국인유전체역학조사사업 KoGES의 안산/안성 지역사회 기반 코호트의 일부(AS)의 관계를 살펴보았다. SNUH 코호트는 제2형 당뇨병 환자 232명, 대조군 197명 총 429명으로 구성되었으며, AS 코호트는 제2형 당뇨병 환자 200명, 대조군 200명 총 400명으로 구성되었다. 두 그룹의 DNA 메틸레이션 원시 데이터를 받아 메틸레이션 밀도를 베타 값으로 계산하고, 이로부터 메틸레이션 연령과 가속도를 구했다. 또 두 그룹의 당뇨 여부, 당뇨 유병 기간, CKD 기수에 따라 각각 당뇨군/대조군, 유병 기간 긴 군(10년 초과)/짧은 군(10년 이하)/비당뇨군, CKD 5기/CKD 4기/CKD 3기 이하의 당뇨군으로 하위군을 나누어 각 군의 메틸레이션 연령과 가속도를 연령에 따라 그래프를 그리고, 평균과 분산을 비교했다. 또 다중선형회귀식을 적용해 당뇨병의 결과가 반영되는 지표이자 당뇨병 진단의 1차적 기준이 되는 공복 혈당을 유의하게 반영하는 시계를 확인했다. 또 전체 코호트에서 각 시계별 다중선형회귀식 모델의 AIC를 비교하였다. 메틸레이션 연령이 고령자에서는 과소평가되는 경향성이 알려져 있는데, 이것이 한국인 당뇨병 코호트에서도 나타나는지를 블랜드-알트만 플랏을 통해 확인했다. 마지막으로 제2형 당뇨병과 유관한 것으로 알려진 CpG들이 본 연구에 사용된 시계들에도 포함되어 있는지 확인하고, 또 해당 CpG들 중 본 연구에서 그룹 간 차이를 유의하게 나타낸 CpG들을 정리했다. 한국인 당뇨병 코호트에서 9가지 후생유전학 시계들을 적용시키고 위와 같은 다양한 방법으로 살펴본 결과 당뇨병 여부와 당뇨병 환자의 CKD 단계의 심화가 노화에 반영되는 시계는 Horvath, Hannum, AAHorvath, AAHannum, DunedinPACE였다. 또 제2형 당뇨병의 진행 상태가 심화되어 노화가 가속화된 환자가 많은 군일수록 다중선형회귀모델 중 공복 혈당 변수가 유의미하게 나타나고, 과소평가 경향성이 두드러지게 나타났다. 이상에서 제2형 당뇨병을 가진 한국인 코호트와 mAge/EAA는 연관성이 있었다. 따라서 본 연구는 한국인 당뇨병 환자의 노화 및 합병증 연구에 mAge/EAA를 사용할 수 있는 근거가 된다. 한편 한국인 당뇨병 코호트에서 하위군 간 유의한 차이를 갖는 T2D 관련 CpG들은 시계에 많이 포함되지 않은 것으로 나타났다. 따라서 T2D를 가진 한국인 코호트에서 노화 및 합병증을 연구하기 위해 이 CpG들을 포함하는 차세대 시계를 만들 것을 제안한다. 다만 두 코호트에는 당뇨병 중증도의 구성에 있어 차이가 있고 표본 크기가 작기 때문에 본 연구의 결과를 뒷받침할 후속 연구가 필요하다. 큰 샘플 사이즈가 확보된다면, 당뇨군과 컨트롤군의 나이를 동일하게 고정하여 mAge의 플랏에서의 기울기의 차이뿐만 아니라 절대적인 값의 차이를 보는 연구를 해볼 것을 제안한다.I. Introduction 1 1. Background 1 1.1. Type 2 diabetes and aging 1 1.2. Epigenetics and DNA methylation 3 1.3. DNA Methylation age as the new biomarker in aging and age- related diseases 4 2. Objective 8 II. Methods 10 1. Study population 10 2. Data collection 10 3. DNA methylation clocks used in study 12 4. DNA methylation profiling and calculation of mAge 16 5. Statistical analysis 21 III. Results 23 1. Descriptive analysis 23 2. Comparison of the clocks by the subgroups 30 3. Multiple linear regression 46 4. Bland-Altman plot 54 5. T2D-related CpGs in the clocks and the cohorts 56 IV. Discussion 67 V. Conclusion 74 VI. Acknowledgement 75 VII. Reference 76 VIII. Abstract in Korean (국문 초록) 84석

Hospital Characteristics Associated with Patients’ Experience of Care in Korean Hospitals

Objectives: This cross-sectional correlational study aimed to examine the hospital characteristics associated with patients’ experiences of care reported by healthcare consumers in South Korea. Methods: This study used data from the second Korean Patient Experience Survey conducted by the Health Insurance Review and Assessment (HIRA). Additional hospital characteristics were obtained from the HIRA and Korea Institute for Healthcare Association websites. Results: In total, 149 hospitals were included. We found that high-technology hospitals had a significant relationship with the scores on all patient experience dimensions. Hospital nurse staffing levels, location, and high technology status were significantly associated with the nurse service dimension. Conclusions: Patient experience-of-care scores varied according to hospital characteristics. The findings of this study provide preliminary evidence for future research. Further research should examine patient and hospital characteristics that could affect patient experience of care scores in Korean hospitals.ope

인간 뇌 오가노이드를 이용한 알츠하이머 및 니만-피크병 질환 모델링 연구

학위논문(박사) -- 서울대학교대학원 : 수의과대학 수의학과, 2022. 8. 강경선.알츠하이머와 니만-피크 C1형 질환은 신경 퇴행성 뇌 질환으로 많은 연구가 진행됨에도 불구하고 정확한 메커니즘과 효과적인 치료제가 불명확하다. 많은 제약사가 치료제 개발에 앞장서고 있음에도 불구하고, 현재까지 치료제들은 증상을 완화하고 진행 속도를 늦춰주는 효과만 있을 뿐 증상 자체의 치료 효과는 없다. 이와 같은 실패 원인 중 하나는 인체 생리 현상과 질병의 병리 생태를 모방한 실험적 모델의 부재 때문이다. 그러므로 현재 질환 원인 분석 및 치료제 개발이 직면하고 있는 문제점을 극복하기 위해, 실제 인체 생리 현상 모방이 가능한 새로운 모델을 개발해야 한다. 이를 위해 최근 환자 체세포로부터 유래된 이차원 유도 신경줄기세포 모델을 이용해 연구와 신약 개발을 위한 스크리닝 플랫폼으로 적용되고 있다. 또한 줄기세포의 자가 조직화 능력을 활용하여 인간 실제 뇌를 구조적, 기능적으로 모사할 수 있는 삼차원 구조의 미니 뇌 오가노이드가 개발됨에 따라 질환 모델링과 약물 스크리닝이 활발하게 진행 중이다. 따라서 본 연구는 질환의 병리적 특징과 원인 및 약물 효능 검증을 위해 이차원 유도 신경줄기세포부터 삼차원 뇌 오가노이드까지 질환 연구 플랫폼으로 제시하고자 한다. 본 연구의 첫 번째 장에서는 가족성 알츠하이머 환자 섬유아세포 유래 유도 신경줄기세포를 이용해 알츠하이머 초기 병리에 기여하는 미토콘드리아 기능 저하 표현형 연구를 진행했다. 아밀로이드 전구체 단백질(APP)의 아밀로이드 생성경로에서 생기는 C-terminal fragments (APP-CTFs)의 축적이 미토콘드리아 항상성 저해 및 미토파지 장애와 관련 있음을 확인했다. 또한 APP-CTFs의 축적은 γ-secretase 차단에 의한 것이며 PSEN 결핍 세포에서 발생하기 때문에 정상 유도 신경줄기세포에서 유전자 편집 기술을 통해 PSEN 넉아웃 세포를 제작했다. 결과적으로 PSEN1과 PSEN2가 넉아웃된 유도 신경줄기세포는 미토콘드리아 기능 저하와 미토파지 억제를 초래했으며 이차원 신경세포와 삼차원 오가노이드에서 신경세포의 분화 저하를 보였다. 본 연구의 두 번째 장에서는 니만-피크 C1형 환자 유래 삼차원 뇌 오가노이드를 확립하여 질환 특이적 형질을 재현하고 약물 스크리닝에 적합한 질환 모델임을 확인했다. 니만-피크 C1형 오가노이드는 정상 오가노이드에 비해 크기, 세포 증식, 신경 분화에서 감소하지만 세포 사멸은 증가되어 있었다. 또한 니만-피크 C1형 오가노이드 내부의 리소좀에 축적된 콜레스테롤은 자가포식과정의 기능 저하와 관련이 높음을 확인했다. 제작된 니만-피크 C1형 오가노이드가 약물 테스트에 적합한 모델임을 증명하기 위해 콜레스테롤 감소에 효과적인 것으로 알려진 하이드록시프로필 베타 사이클로덱신 (HPβCD)과 더불어 히스톤 탈아세틸화 억제제 중 하나인 발프로 산 (valproic acid) 처리로 질환의 회복을 확인했다. 따라서 본 연구에서는 니만-피크 C1형 질환 환자 유래 삼차원 뇌 오가노이드를 확립하여 질환의 치료 기술을 개발하는데 유용성을 제시한다. 뇌 오가노이드는 질환 모델링뿐만이 아니라 바이러스 감염을 통해 병원성 기전 및 감염경로에 대한 연구에 적용할 수 있다. 이를 위해 본 연구의 세 번째 장에서는 뇌 오가노이드에 지카 바이러스를 감염시켜 알츠하이머 질환 표현형이 증가함을 확인했다. 이는 지카 바이러스가 감염된 뇌 오가노이드에서 지속적인 ER stress가 관찰되었고, 결과적으로 BACE와 GSK3β를 촉진해 아밀로이드 베타와 과인산화된 타우 단백질이 증가함을 확인했다. 바이러스 감염은 알츠하이머의 위험 요인 중 하나이며, 지카 바이러스 감염이 알츠하이머 병리학적 특징을 촉발할 수 있음을 뇌 오가노이드 모델을 통해 입증했다. 본 연구에서는 알츠하이머 및 니만-피크 C1형의 연구 플랫폼으로서 환자 유래 유도 신경줄기세포 및 뇌 오가노이드를 제시했다. 이 모델을 통해 알츠하이머의 초기병리와 관련한 미토콘드리아 기능 저하를 확인하고 바이러스 감염에 의해 알츠하이머 병리적 특징이 증가하는 현상을 구현하였다. 또한 니만-피크 C1형 뇌 오가노이드 제작을 통해 리소좀 축적 질환 관련 특징과 약물 효능을 확인했다. 이로써 알츠하이머 및 니만-피크 C1형의 이차원 유도 신경줄기세포부터 삼차원 뇌 오가노이드까지 모델 확립을 통해 메커니즘 스터디 및 신약 스크리닝 플랫폼을 제시한다.Alzheimer’s disease (AD) and Niemann-Pick type C disease (NPC) are progressive neurodegenerative diseases, and although many studies have been conducted, the mechanism or effective treatment for the cause of the diseases have not been elucidated. Despite multiple attempts on developing treatments by several pharmaceutical companies, current treatments do not target the disease directly but only show the effects of relieving symptoms. One of the reasons for this failure is the lack of experimental models that mimics human physiology and the biological changes that occur during the onset and progression of diseases in a human brain. Therefore, it is necessary to develop a new model capable of mimicking actual human brain physiology. Recently, two-dimensional (2D) induced neural stem cell models derived from patient somatic cells are used as a screening platform for disease research and drug development. In addition, as mini-brain organoids with a three-dimensional (3D) structure that can structurally and functionally mimic the human brain by utilizing the self-organizing ability of stem cells have been developed, disease modeling and drug screening are actively progressing. Therefore, these studies intend to present a therapeutic platform for AD and NPC disease ranging from 2D cell models to 3D organoids to verify pathological characteristics, causes, and drug effects of cells of pathological phenomena. In the first chapter of this study, familial AD patient’s fibroblast-derived induced neural stem cells (iNSCs) were used to study mitochondrial dysfunction phenotypes contributing to the early pathology of AD. I represented that the accumulation of C-terminal fragments (APP-CTFs) generated in the amyloidogenic pathway of amyloid precursor protein (APP) was associated with mitochondrial homeostasis inhibition and mitophagy dysfunction. In addition, since the accumulation of APP-CTF is due to the γ-secretase blockade and occurs in PSEN-deficient cells, PSEN knockout cells were generated from normal induced neural stem cells through gene editing technology. As a result, PSEN1 and PSEN2 knockout-induced neural stem cells showed not only decreased mitochondrial function and mitophagy inhibition, but also decreased neuronal differentiation in 2D neuron and 3D organoids. In the second chapter of this study, 3D brain organoids derived from the patient's iNSCs were established to represent disease-specific traits and apply for drug screening. I confirmed that size, cell proliferation, and neuronal differentiation were downregulated in NPC organoids compared to wild-type organoids, while the cell death increased. I also represented that the lysosomal cholesterol accumulation in NPC organoids was highly related to the impairment of autophagy. These pathological phenotypes observed in NPC organoids were rescued by treatment with 2-hydroxypropyl-β-cyclodextrin (HPBCD) and Valproic acid (VPA), which are known to be effective candidates for NPC disease. Therefore, in this study, NPC brain organoids were established for the first time to verify various phenotypes and drug efficacy of the disease treatments. Organoids are applicable not only to disease modeling, but also to the study of pathogenic mechanisms and transmission routes of virus infection. In the third chapter of this study, I represented that zika virus infection increase AD phenotype. I confirmed that continuous ER stress was observed in brain organoids with zika virus, and as a result, the level of amyloid beta (Aβ) and phosphorylated tau protein was increased by BACE and GSK3β. Virus infection can be one of the risk factors for AD, and it has been proven that zika virus infection can trigger AD pathological features in brain organoids. Through the results of these studies, I generated AD and NPC patient-derived induced neural stem cells and brain organoids as the disease research platform. In these models, I confirmed the mitochondrial dysfunction related to the early pathology of the disease and the increased AD pathological characteristics by zika virus infection. In addition, lysosomal storage disease-related characteristics and drug efficacy were confirmed in NPC brain organoids. Taken together, I present the mechanism study and drug screening platform by establishing models from 2D induced neural stem cells to 3D brain organoids of AD and NPC diseases.CHAPTER I 1.1 INTRODUCTION 35 1.2 MATERIALS AND METHODS 39 1.2.1 iNSCs culture 39 1.2.2 2D neuron differentiation 39 1.2.3 Generation of WT and AD fibroblasts derived iNSCs 39 1.2.4 Generation of PSEN double knock-out iNSCs 39 1.2.5 Western blotting 39 1.2.6 Quantitative reverse transcription PCR (RT-qPCR) 41 1.2.7 Immunocytochemistry 41 1.2.8 MitoTracker & ER-Tracker 42 1.2.9 ATP production assay 42 1.2.10 Statistical analysis 42 1.3 RESULTS 44 1.3.1 Characterization of AD patient iNSCs 45 1.3.2 Altered localization and dysfunction of mitochondria in AD patient iNSCs 47 1.3.3 APP-CTFs accumulation in AD-patient iNSCs altered mitochondrial function 49 1.3.4 Mitophagy failure in AD-patient iNSCs is related to APP-CTFs accumulation 52 1.3.5 Generation of PSEN KO-iNSCs and characterization 57 1.3.6 APP-CTFs accumulation is associated with mitophagy failure in PSEN KO-iNSCs 61 1.3.7 Neuronal differentiation was downregulated in PSEN KO-iNSCs 66 1.4 DISCUSSION 68 CHAPTER II 2.1 INTRODUCTION 72 2.2 MATERIALS AND METHODS 75 2.2.1 iNSCs culture 75 2.2.2 Organoid culture 75 2.2.3 Quantitative reverse transcription PCR (RT-qPCR) 76 2.2.4 Western blot analysis 76 2.2.5 Histology and Immunofluorescence 76 2.2.6 Clearing for 3D fluorescence images 77 2.2.7 Cholesterol assay 78 2.2.8 Quantitative mRNA-sequencing analysis 78 2.2.9 Statistical analysis 79 2.3 RESULTS 80 2.3.1 Generation of brain organoids from iNSCs 80 2.3.2 Characterization of NPC brain organoids 82 2.3.3 Limited expansion ability of NPC brain organoids 87 2.3.4 Cholesterol accumulation in NPC brain organoids 89 2.3.5 Gene expression analysis of WT and NPC organoids 92 2.3.6 VPA treatment increases the number of neuronal-positive cells in NPC organoids 94 2.3.7 VPA rescues NPC organoids via activation of autophagic signaling 99 2.4 DISCUSSION 103 CHAPTER III 3.1 INTRODUCTION 107 3.2 MATERIALS AND METHODS 110 3.2.1 Zika virus production and titration 110 3.2.2 Maintenance of human iPSCs 110 3.2.3 Generation of brain organoids 110 3.2.4 Infection of the brain organoids 112 3.2.5 Inhibitor treatment 112 3.2.6 RNA extraction and quantitative reverse transcription PCR (RT-qPCR) 112 3.2.7 Immunostaining and imaging 113 3.2.8 Western blotting 114 3.2.9 ELISA 114 3.2.10 Statistical analysis 114 3.3 RESULTS 116 3.3.1 The characterization of brain organoids generated from AD patient-derived iPSCs 116 3.3.2 Brain organoids from AD patient-derived iPSCs recapitulate AD pathology 120 3.3.3 ZIKV infection induces Aβ accumulation through increasing BACE abundance 122 3.3.4 ZIKV infection enhances p-TAU levels in AD organoids through GSK3α/β 128 3.3.5 PERK-eIF2α activation is associated with AD phenotypes in ZIKV-infected organoids 130 3.3.6 PERK inhibition attenuated AD phenotypes including Aβ and p-Tau 135 3.4 DISCUSSION 139박

Assessment of Patient Safety and Cultural Competencies among Senior Baccalaureate Nursing Students

This descriptive, correlational, cross-sectional study examined nursing students' educational experiences on self-reported perceptions of patient safety and cultural competence in terms of curriculum content and learning venues. We performed descriptive analyses and a one-way analysis of variance with a sample of senior-year nursing students (N = 249) attending three state universities in the United States. We used the Nurse of the Future Nursing Core Competency Model, the Patient Safety Competency Self-Evaluation Tool for Nursing Students, and The Cultural Competence Assessment Instrument. Overall, participants reported that patient safety and cultural competencies were addressed in their curricula primarily through classroom activities as opposed to laboratory/simulation or clinical settings. Among the required patient safety knowledge topics, elements of highly reliable organizations were covered the least. For patient safety competency, participants reported higher scores for attitude and lower scores for skill and knowledge. For cultural competency, participants scored much higher for cultural awareness and sensitivity than behavior. There was no statistically significant difference between scores for patient safety and cultural competencies by nursing school. The results support the need for curriculum development to include all important aspects of patient safety and cultural competencies in various teaching/learning venues.ope

Mediating roles of patient safety knowledge and motivation in the relationship between safety climate and nurses' patient safety behaviors: a structural equation modeling analysis

Background: Few studies have examined the relationship between patient safety climate and two forms of patient safety behavior (i.e., safety compliance and safety participation) among nurses. Better understanding of factors contributing to nurses' safety behaviors could enhance patient safety. Therefore, this study aimed to examine the effect of patient safety climate on nurses' patient safety behavior and to explore whether patient safety knowledge and motivation mediate this relationship. Methods: This correlational, cross-sectional study used survey data from 1,053 staff nurses working at a general hospital located in a metropolitan area of South Korea. Structural equation modeling was employed to test a hypothesized multiple mediation model that was guided by Griffin and Neal's model of safety performance. Results: The results indicated that patient safety climate was directly related to both patient safety compliance behavior (β = 0.27, p < 0.001) and patient safety participation behavior (β = 0.25, p < 0.001). Concerning indirect effects, patient safety climate was associated with patient safety compliance behavior through both patient safety knowledge (β = 0.26, p < 0.001) and patient safety motivation (β = 0.04, p = 0.038), whereas patient safety climate was related to patient safety participation behavior only through patient safety knowledge (β = 0.27, p < 0.001) and not through patient safety motivation (β = 0.00, p = 0.985). Conclusion: Based on this study's findings, building an organizational climate focused on patient safety is vital for improving nurses' patient safety behavior. Improving an organization's patient safety climate could promote both safety knowledge and motivation in nurses and thereby potentially enhance their patient safety behavior. Hence, healthcare organizations should implement practical interventions to improve their patient safety climate. Also, nursing management interventions designed to transfer patient safety knowledge to nurses would be particularly effective in improving their safety behavior.ope

Exploring Nurses’ Experience and Grievance: Network Analysis and Topic Modeling using a Social Networking Service

Purpose To describe clinical nurses' experience and grievance in an online community using a co-occurrence network and topic modeling. Methods We analyzed posts from Nurscape, which is the largest online community for nurses in Korea. After extracting posts using web scrapping, text preprocessing was done to detect nouns. In a visualization phase, co-occurrence network analysis and latent dirichlet allocation-based topic modeling were applied. Results A total of 13,200 posts were analyzed. The co-occurrence network's core keywords were newly graduate nurse, general ward, career, turnover, and grievance. The topic modeling showed four topics: (1) ‘Clinical practice-related difficulties’ described clinical hardships, such as the heavy workload of nurses; (2) ‘Concerns about resignation’ incorporated keywords asking for advice on resignation; (3) ‘Searching for information on employment/reemployment’ focused on the working conditions or working climate of a specific hospital; and (4) ‘Organizational action call’ captured the voices urging organized actions to improve nurses' work environment. Conclusion Clinical nurses share experiences through the online community and seek advice or information and urge organizational action. Professional nursing organizations should identify and deal with problems that nurses are currently facing. The results of this study can contribute to establishing the policy direction of nursing organizations.ope

Associations among leadership, resources, and nurses' work engagement: findings from the fifth korean Working Conditions Survey

Background: Nurses' work engagement has received extensive attention due to its positive impacts on individual and organizational outcomes, including patient safety and quality care in healthcare organizations. Although nurse managers' leadership and a variety of resources have been identified as important factors of nurses' work engagement, these relationships have not been well understood in Korean nursing contexts. The purpose of this study was to examine the associations among nurse managers' leadership, resources, and work engagement among Korean nurses after controlling for nurses' demographic and work-related characteristics. Methods: This is a cross-sectional study using data from the fifth Korean Working Conditions Survey. Using a sample of 477 registered nurses, we employed hierarchical linear regression analyses. Nurse managers' leadership, job resources (organizational justice and support from peers), professional resources (employee involvement), and personal resources (meaning of work) were examined as potential predictors of nurses' work engagement. Results: We found that nurse managers' leadership (β = 0.26, 95% confidence interval [CI] = 0.17-0.41) was the strongest predictor of nurses' work engagement, followed by meaning of work (β = 0.20, 95% CI = 0.07-0.18), organizational justice (β = 0.19, 95% CI = 0.10-0.32), and support from peers (β = 0.14, 95% CI = 0.04-0.23). Employee involvement was not a statistically significant predictor of nurses' work engagement (β = -0.07, 95% CI = -0.11-0.01). Conclusions: Our findings suggest that comprehensive approaches are required to promote nurses' work engagement. Considering that nurse managers' leadership was the strongest predictor of nurses' work engagement, nurse managers should demonstrate supportive leadership behaviors such as acknowledging and praising their unit nurses' work performance. Furthermore, both individual- and organizational-level strategies are necessary for nurses to be engaged at work.ope

Patient safety educational interventions: A systematic review with recommendations for nurse educators

Aim: This study identified and evaluated tested patient safety educational interventions. This study also described the content, curricular structures and teaching strategies of the educational interventions and determined the methods used for evaluating patient safety learning outcomes. Design: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines directed this review. Methods: Searches for articles describing and evaluating patient safety educational interventions were conducted using four scholarly databases. Study quality was assessed using the McMaster Critical Review Form. Results: Seven studies met the inclusion criteria. Educational interventions were either presented as stand-alone courses or as lessons embedded in an existing course. All studies employed a mixture of various teaching modalities and several evaluation methods and outcomes. Mixed results were observed in terms of the effects of educational interventions. Future researchers should continue to develop patient safety curricula and examine their effect on student competencies with stronger methodological rigour.ope

신규 프로피오닐 프락토올리고당이 장내 균 성장에 미치는 영향

학위논문 (석사)-- 서울대학교 대학원 : 식품영양학과, 2017. 2. 지근억.Numerous studies reported that ingestion of fructooligosaccharides (FOS) can promote the growth of Bifidobacterium in large intestine. Therefore, FOS is currently used as prebiotics. Propionic acid (PA) has an inhibitory effect on the growth of pathogenic molds and bacteria. Propionates such as sodium propionate and calcium propionate are used as preservatives for food. In this study, the effect of novel propionyl-fructooligosaccharides (P-FOS) on the growth of various intestinal bacteria was assessed. According to the structural analyses using FT-IR, MALDI-TOF MS, LC-ESI-MS, and LC-ESI-MS/MS, the major components of P-FOS used in this study contained FOS with 1-3 propionyl groups attached. P-FOS promoted the growth of the most experimental Bifidobacterium and some of the other lactic acid bacteria. In contrast to FOS, P-FOS showed no growth promotion or slight suppression against most of the non-probiotic bacteria. The novel P-FOS is expected to be useful for the improvement of human intestinal microflora.1. Introduction 1 2. Materials and methods 4 2.1. Materials 4 2.1.1. Source of P-FOS 4 2.1.2. The bacterial strains and culture condition 4 2.1.3. Chemicals and reagents 7 2.1.4. The media and carbohydrate sources for bacterial growth test 7 2.2. Purification and preparation of P-FOS 7 2.3. Structural analysis of P-FOS 8 2.3.1. Determination of the linkages in P-FOS by FT-IR 8 2.3.2. Mass analysis by MALDI-TOF MS and LC-ESI-MS 8 2.4. Effect of glucose, FOS, and P-FOS on growth of intestinal bacteria 9 3. Results and Discussion 11 3.1. Structural analysis of P-FOS 11 3.1.1. Investigation of linkages in P-FOS using FT-IR 11 3.1.2. Mass spectra analysis of FOS by MALDI-TOF MS and LC-ESI-MS 14 3.1.3. Mass spectra analysis of P-FOS by MALDI-TOF MS, LC-ESI-MS, and LC-ESI-MS/MS 16 3.2. Growth of various bacteria in the presence of P-FOS, FOS, and glucose 20 4. Conclusion 28 References 29 Abstract in Korean 34Maste

The Yield Curve and Monetary Policy in a Small Open Economy

학위논문 (석사)-- 서울대학교 대학원 : 사회과학대학 경제학부, 2018. 8. 박웅용.This paper analyzes co-movements among the yield curves of small open countries, and the efficiency of each countrys monetary policy. First, I estimate a dynamic factor model to find common movements among the yield curves of six small open countries: Australia, Canada, Denmark, Norway, Switzerland, and the United Kingdom. The empirical results show that nominal interest rates of the countries are well-accounted for by their US counterpart, rather than the small open countries policy rates at long maturities. This may imply that the long-term rates decouple from the short-term policy rates in the small open countries, resulting in limited effects of the countries monetary policy. Thus, to examine the effectiveness of monetary policy, I analyze dynamic responses of macro variables to monetary expansions in Canada and Norway. Estimating a vector auto-regression (VAR) model, I conclude that the high yield curve correlations with the United States reduce the impacts of expansionary monetary policy in small open countries. Norway, whose interest rates are the least explained by the US rates, succeeds in boosting its economy by decreasing the policy rate. On the other hand, Canada, which has the highest yield curve correlations with its US counterpart, fails to invigorate economic activities by monetary expansion.1. Introduction 2. Data 3. The Yield Curve Co-movements 3.1. Dynamic Factor Model 3.2. Estimation 4. Efficiency of Monetary Policy 5. Conclusion AppendixMaste