대규모 유전체 분석을 통한 대장균의 유전체 다양성 및 진화 분석

학위논문 (박사)-- 서울대학교 대학원 : 생명과학부, 2016. 8. 천종식.Bacterial evolution is driven by enormous genomic diversity present in the populations. Genomic diversity of a bacterial population is generated and maintained by the compounded influences of several microevolutionary mechanisms. Uniqueness of bacterial genome evolution originates from the mixture of vertical and horizontal heredity. As a result the dynamics of bacterial genomes within a species exhibits both the characters of clonal and sexual genetics, and impressively, seemingly unlimited genomic repertoire could be achieved by a single species. The course and consequences of genomic diversification within bacterial species have not been fully understood. Because of extensive genomic diversity within a species, understanding of the genomic evolution within bacterial species requires large scale exploratory and descriptive studies as well as explanatory studies based on the working hypothesis on how genomes evolve. A well-known laboratory model organism Escherichia coli has been shown to exploit highly diverse ecological niches in its natural population. Genomic studies of E. coli indeed revealed significant genome dynamism accompanied by ecological diversification. E. coli includes several types of pathogens that have exerted severe global burden of enteric diseases, and by that reason, whole genome surveys have been active for this species. At this point of time more than four thousands of E. coli genome sequences from genetically diverse strains have become available. Therefore E. coli constitutes an ideal model for studies of intra-specific genomic evolution of bacteria. In this thesis, multiple aspects of the genomic diversity of E. coli were explored and described by comparative analysis of 3,945 genome sequences of the strains belonging to the genus Escherichia. In addition the roles played by distinct microevolutionary mechanisms in the shaping of current structure of genomic diversity were assessed. Lastly a broader perspective on the evolution of E. coli genomes was achieved by analyzing the evolutionary history of E. coli and its closest relatives. Exploration of the genomic diversity of E. coli was conducted in 4 aspects, by analyses of pan-genome size, sequence diversity, structural diversity and phylogenetic diversity. Openness of E. coli pan-genome was indicated from the analysis of 3,909 E. coli strains. Comparison between the phylogenetic diversity and the pan-genome size estimated for randomly selected subsets of the strains showed a linear relationship between the two values. Counter-intuitively the relative ratio of pan-genome size growth over the increment of phylogenetic diversity was higher in the phylogenetic groups of E. coli than for the entire species. Seeking for the reason behind this trend comprised a major theoretical motivation of this thesis. Sequence diversity of E. coli core genes had a unimodal distribution with 1.3% as the modal value. The core gene order was unexpectedly well conserved among E. coli genomes and the presence of clonal frame was supported by the linkage analysis, both indicating that the core-genome of E. coli was highly stable. An emerging conclusion from the analysis of genomic diversity was that the paces of gene contents diversification and gene sequence diversification can be uncoupled. Based on whole genome scale phylogenetic analysis the phylogenetic structure was clearly present among the strains of E. coli. The nature of given phylogenetic structuring of E. coli population was another major theoretical motivation of this thesis. Increased inter-SNP linkage within the phylogenetic groups provided a clue that each phylogenetic group has relatively elevated clonality, while recombination rates in the ancestral population of E. coli were higher than the current rates. Assumption of clonality within phylogenetic groups could provide an explanation for the observed higher rate of within-group pan-genome growth rate per phylogenetic diversity expansion. Increased clonality is expected to result in increased efficiency of selective sweep caused by positive selection, thus resulting in the destruction and delay of sequence diversification. Inferences of recombination history in the core-genome of E. coli identified that 0.78% - 4.1% of the DNA segments in the core-genome has been replaced by homologous recombination. Among the extant lineages of E. coli the relative impact of recombination over mutation in the changes introduced to DNA sequences was distributed around 0.6 – 0.8. Relatively recent branches showed lower R/Theta than the ancestral branches, implying historical decline of recombinations influence. This direct observation of temporal decline of recombination supported the hypothesis of E. colis shifting toward clonality. In the pan-genome of E. coli the singleton genes that occurred in just a single strain of E. coli could be originated from recent horizontal gene transfer or recent duplication. About half of the singleton genes could not be matched to any other genes in the current prokaryotic genome database. For about 10% of the E. coli singleton genes, highly similar proteins were found in diverse taxonomic divisions. Most frequently the best hits resided in the close relatives of E. coli in the Enterobacteriaceae family. However, distant taxa in other phyla, especially the Firmicutes, contributed significant amount of best hits, implying that those microbes share the common environmental gene pool with natural E. coli population. Predominant direction of natural selection in E. coli genes were shown to be negative selection, which suppresses the diversification of sequences. Strength of negative selection was stronger in the core-genome in comparison to the genes with lower gene frequency. Despite that negative selection was dominant across all gene frequency spectrum, some genes exhibited dN/dS larger than 1 and seemed to be positively selected. Transposases comprised the largest proportions of positively selected genes. Multiple genes involved in flagellar biosynthesis were detected to be positively selected or have been under relaxed negative selection. Based on the phylogenetic analysis of 21 genera in Enterobacteriaceae using their core-genome, the diversification within Enterobacteriaceae was characterized by the pattern of radiation and extensively conflicting phylogenetic signals at the basal area. Such ambiguity at deep branches were also observed for phylogenetic networks within the genus Escherichia. Temporally fragmented speciation might be supported by the observation. In attempt to resolve the divergence order between the species in Escherichia, Bayesian multi species coalescent analysis was carried out using 3 gene sets each composed of 60 core genes. The reconciled species tree and the collective graph of the coalescences estimated by the gene set re-confirmed that the divergence order between Escherichia spp. are ambiguous in reality. To add the geological time-scale information to the knowledge about E. coli evolution, a time-tree analysis was performed on the core-genome and the previously estimated divergence time of E. coli. By extending the previously known divergence time between E. coli and Salmonella enterica the age of Escherichia was shown to be between 37.9 – 40 MYA. The age of E. coli was estimated to be between 16.6 – 17.7 if the clade I was excluded from E. coli and 25.9 – 26.9 MYA if the clade I was included in E. coli. The obscurity of phylogenetic scenario for the origin of Shigella pathogens within E. coli was tackled by the comparison between multigene phylogeny of Shigella virulence plasmids and the chromosomal phylogeny. At least five independent plasmid acquisition events had to be assumed to explain the incongruence between the two phylogenies. According to the results obtained in this study, population genetics of E. coli went through a transition from relatively sexual global population to relatively clonal sub-populations. Such a transition can provide the basis for the presence of phylogenetic structure, which is not common in bacterial species. Strong clonality was shown to have negative association with the genetic diversity of species, and the slowed sequence diversification due to the reduced recombination might be the reason for increased pan-genome growth rate per phylogenetic diversity in the phylogenetic groups of E. coli. As shown in the example of E. coli, bacterial genome evolution is affected by complex interplay between evolutionary mechanisms, and moreover, can be shifted in the course of intra-specific evolution. Therefore, the nature and concept of species and speciation in bacteria could be variable from species to species, and from time to time.CHAPTER 1. General introduction 1 1.1. Bacterial genome evolution 2 1.2. Escherichia coli 9 1.3. Purposes and organization of this study 13 CHAPTER 2. Analysis of intra-specific genomic diversity of E. coli represented in the genome dataset 15 2.1. Introduction 16 2.2. Materials and methods 20 2.2.1. Newly sequenced E. coli genomes and the genome data obtained from public databases 20 2.2.2. Taxonomic identification, annotation of protein-coding genes and clustering of orthologous proteins 25 2.2.3. Pan-genome statistics 27 2.2.4. Phylogenetic analysis 29 2.2.5. Population structure inference using core single nucleotide polymorphisms 30 2.2.6. Analysis of gene contents variation, gene order conservation and genome-wide linkage between SNP sites 31 2.3. Results 33 2.3.1. Basic characterization of the genomes data 33 2.3.2. Open pan-genome of E. coli 40 2.3.3. Statistical analysis of pan-genome gene frequency distribution 47 2.3.4. Evolutionary rate of pan-genome growth 53 2.3.5. Phylogenetic and population genetic structure inferred from genome data 58 2.3.6. Intra-specific sequence diversity in the pan-genome of E. coli 65 2.3.7. Analysis of gene content variation 69 2.3.8. Conservation of synteny and linkage over long distance 75 2.3.9. Comparison of E. coli pan-genome properties and phylogenetic structure with those of other bacterial species 80 2.4. Discussion 87 CHAPTER 3. Characterization of microevolutionary processes that mediated genomic diversification of E. coli 93 3.1. Introduction 94 3.2. Materials and methods 97 3.2.1. Genome dataset 97 3.2.2. Analysis of homologous recombination events 98 3.2.3. Analysis of gene gain and loss history and tracking the origins of the singleton genes in E. coli pan-genome 100 3.2.4. Analysis of dN/dS ratio 102 3.3. Results 103 3.3.1. Impact of homologous recombination in genomic evolution of E. coli 103 3.3.2. Impact of gene gain and loss in the genomic evolution of E. coli and the origins of recently gained genes 119 3.3.3. Analysis of the signs of natural selection in the pan-genome of E. coli 128 3.4. Discussion 136 CHAPTER 4. Systematics study of E. coli and related taxa 143 4.1. Introduction 144 4.1.1. Timed history of bacterial evolution 144 4.1.2. Obscurities in the systematics of E. coli 147 4.2. Materials and methods 149 4.2.1. Reconstruction of Enterobacteriaceae phylogeny 149 4.2.2. Molecular clock analysis and species tree analysis of Escherichia 151 4.2.3. Reconstruction of Shigella virulence plasmid phylogeny 153 4.2.4. Reconstruction of rut and phn operon phylogenies 155 4.3. Results 156 4.3.1. Phylogenomic analysis of the evolutionary relationships of Enterobacteriaceae species 156 4.3.2. Molecular chronology of E. coli 168 4.3.3. Phylogenetic scenario for Shigella spp 170 4.3.4. Genes that distinguished E. coli from other Escherichia spp 175 4.4. Discussion 181 CHAPTER 5. Conclusions 189 REFERENCES 197 국문 초록 219Docto

『근역서화징』의 기록학적 연구

학위논문(석사)--서울대학교 대학원 :인문대학 협동과정 기록학전공,2019. 8. 정긍식.『槿域書畫徵』은 20세기 초반에 위창 오세창(葦滄 吳世昌, 1864-1953)이 우리나라 서화가의 이름, 행적, 내력 등을 기록하기 위하여 삼국시대부터 근대에 이르기까지 한국의 역대 서화가 총 1,118명의 인적 정보 및 관련 문헌 기록을 모아 정리한 기록자료집이다. 서화가를 주제로 하여 체계적으로 編輯한 첫 기록물이라는 점과 후대에도 참고하여 고증할 수 있도록 출처를 밝혀 객관적으로 자료를 서술하였다는 점에서 높은 자료적 가치를 가진다고 평가받는다. 『槿域書畫徵』은 오세창 개인이 출전에서 선별·평가하여 옮겨 적은 것이므로 문헌 기록들의 파편으로 구성된 책이다. 따라서 인용하는 과정에서 원전 기록과 달라질 수밖에 없다. 이에 본 연구에서는 오세창이 얼마나 원전에 충실하여 기록을 인용하였는지 파악하기 위해 『槿域書畫徵』의 본문과 원전 내용의 비교·대조를 통해 자료 인용 형태를 객관적으로 분석하는 기록학적 접근을 시도하였다. 먼저 『槿域書畫徵』의 전체 구성요소 분석을 통해 기록을 整理하는 기준을 알아보았다. 서화가를 중심으로 편년체로 정리하였고 색인을 만들어 기록을 쉽게 찾아볼 수 있도록 하였다. 서술 내용 분석을 통해 오세창이 기록을 記述한 방식을 알아보았다. 서술 내용은 오세창이 범례에 제시한 편집체제를 기반으로 하였다. 서술 내용을 구체적으로 살펴보면 성명과 인적 정보, 특기할 예술 분야, 그를 뒷받침해주는 실증자료, 작품 또는 제발문, 오세창의 개인 의견으로 이루어져 있다. 다음으로 오세창이 정리·기술한 기록들의 선별기준을 파악하기 위해 『槿域書畫徵』의 인용 형태와 층위를 살펴보았다. 그 대상은 서화가를 정리한 인용서에 언급된 화가들을 중심으로 하였다. 그 이유는 서화가를 정리한 인용서에 화가들에 대한 2·3차 인용 자료들이 다양하게 전하기 때문이다. 실증자료 중에서 전체 인용한 문헌 자료는 주로 화가에 대한 평이 드러나는 경향을 보인다. 부분 발췌하여 인용한 문헌 자료는 주로 화가나 그의 그림과 관련된 일화이다. 혹은 화가에 대한 평이 드러나지 않는 제화시의 경우 오세창은 작품의 제목만 인용하고 시는 생략하기도 하였다. 요약의 경우에도 오세창은 출전 기록에서 그림에 관한 평가나 일화가 드러나는 부분만 인용하였다. 따라서 화가에 대한 평과 그림 관련 일화를 위주로 인용하는 것으로 보아 오세창이 『槿域書畫徵』에 서술할 기록을 선별하는 기준은 그림보다 화가에 맞춰져 있음을 알 수 있다. 마지막으로 오세창이 『槿域書畫徵』에 인용한 자료의 간행 상황을 분석하고 오세창이 인용하지 않은 필사본 및 간행된 자료들과 비교해 보았다. 그 결과 당대 필사본으로 존재하거나 간행되지 않아 오세창이 볼 수 없었던 자료들도 있지만, 당시 볼 수 있었음에도 오세창이 인용하지 않았던 자료가 있다는 점을 확인할 수 있었다. 간행본 중에서도 오세창이 인용하지 않은 서화가 자료들은 서화가의 작업 과정을 생생하고 상세하게 보여주는 중요한 정보들도 있었다. 이러한 조사 결과 『槿域書畫徵』의 저술 목적이 서화가들의 모든 자료를 모으는 것이 아니라 모든 서화가를 정리하는 것이었다는 결론을 도출하였다. 따라서 위와 같이 인용 형태와 인용 자료들을 분석한 결과 오세창이 『槿域書畫徵』에 인용한 자료는 개별 서화가에 대해서 그림 관련 행적과 내력 위주의 한정적인 정보만을 제공할 수밖에 없다는 한계점을 찾아내었다. 하지만 『槿域書畫徵』에는 다른 자료에서 찾아볼 수 없고 『槿域書畫徵』에만 남아있는 서화가 자료들도 있다. 현전 여부를 확인할 수 없는 인용 자료와 오세창의 개인 의견, 참고문헌 표시가 없는 자료들이 그에 해당한다. 현전 여부를 확인할 수 없는 인용 자료는 失傳하는 상태이기 때문에 현재로서는 『槿域書畫徵』에 있는 자료가 원전 대신 문헌적 준거로서의 가치를 가진다. 그리고 『槿域書畫徵』에 있는 출전 정보를 바탕으로 원문을 발견할 만한 여지가 있으므로 현전 여부를 확인할 수 없는 인용 자료 또한 문헌적 증거로서 가치가 있다.Geunyokseohwajing( 『槿域書畫徵』) is a book summarizing 1,118 records of human information and related documents from the period from the Three Kingdoms Period to the modern times in order to record the name, act and history of calligraphers and painters in Korea in the early 20th century. It has been evaluated that it has high data value because it is first book that lists its sources so that it can be referred to later. However, this book is composed of fragments of the documentary records selected and evaluated by Se-chang O(吳世昌). Therefore, it is inevitably different from the original record in the process of quoting. In this study, we attempted a logistic approach to objectively analyzing the citation style of the data through comparing and contrasting the text and original records of this book in order to understand how Se-chang O was faithful to the original records. First, I examined the basics of organizing records through an analysis of the entire component of the book. It was arranged in a chronological order focusing on calligraphers and painters and the author made an index so that records can be easily found. And I analyzed the way in which the authors describes the records related to each calligrapher and painter through analysis of narrative contents. The description was based on the editing system presented by the author in the explanatory notes. The details of the description consist of the name and personal information, the field of art to be distinguished, the supporting evidence for it, the work or the statement, and the personal opinion of the author. In order to understand the standard for selection of the records that the author summarized and described, the citation type and level of the book are as follows. The object was centered on the painters mentioned in the cited book that summarized the painters and calligraphers. The reason for this is that the quotation book that summarizes the paintings is diverse, and the second and third citation data about the painters are various. Among the empirical data, the total quoted literature tends to reveal the level of the painter. The literature data quoted by the excerpt is mainly an anecdote related to the painter or his paintings. In the case of a poem on a painting that does not reveal the painter's name, the author cites only the title of the work and omits the poem. In summary, the author cites only the part of the picture that reveals anecdotes and anecdotes about the picture. Therefore, it can be seen that the criterion that the authors select the records to be described in this book is based on paintings rather than paintings. And finally, I analyzed the publishing situation of the material cited in this book by the author and compared it with manuscripts and published materials that the author did not cite. As a result, there were some materials that were not present or published in the manuscripts of the day and were not available to the author, but there were some materials that were available at that time but not cited by the author. Among the editions that the author did not cite, there were important information that showed the work of the artist in vivid detail. These findings led to the conclusion that the purpose of this book was not to collect all the materials of the calligraphers and painters but to sort out all the calligraphers and painters. Therefore, as a result of analyzing citation type and citation data, it is found that the data quoted by the authors of this book are limited to limited information of individual artist's conduct and history. There are, however, some painters in this book that do not remain elsewhere but remain in this book only. These are cited data that can not be confirmed as a present, individual opinions of the author, and materials without reference. Because the cited data that can not be confirmed as the present is not conveyed, the data in this book has value as a literature standard instead of the original record at present.제 1 장 서론 1 제 1 절 문제제기와 연구목적 1 제 2 절 연구방법 및 범위 5 제 2 장 『槿域書畫徵』의 정리·기술 7 제 1 절 『槿域書畫徵』의 정리·기술 체계 7 제 2 절 『槿域書畫徵』의 기술 내용 10 제 3 장 『槿域書畫徵』의 인용 형태 18 제 1 절 전체 인용 19 제 2 절 부분 발췌 인용 25 제 3 절 요약 인용 33 제 4 절 변형 인용 36 제 4 장 『槿域書畫徵』의 인용 자료 40 제 1 절 인용 자료 전체 분석 40 제 2 절 『槿域書畫徵』 외 현전 서화가 기록 45 제 3 절 『槿域書畫徵』 유일 서화가 기록 56 제 5 장 결론 60 부록 63 참고문헌 94 Abstract 98Maste

Analytical Tools and Databases for Metagenomics in the Next-Generation Sequencing Era

Metagenomics has become one of the indispensable tools in microbial ecology for the last few decades, and a new revolution in metagenomic studies is now about to begin, with the help of recent advances of sequencing techniques. The massive data production and substantial cost reduction in next-generation sequencing have led to the rapid growth of metagenomic research both quantitatively and qualitatively. It is evident that metagenomics will be a standard tool for studying the diversity and function of microbes in the near future, as fingerprinting methods did previously. As the speed of data accumulation is accelerating, bioinformatic tools and associated databases for handling those datasets have become more urgent and necessary. To facilitate the bioinformatics analysis of metagenomic data, we review some recent tools and databases that are used widely in this field and give insights into the current challenges and future of metagenomics from a bioinformatics perspective.

Real-World Effectiveness, Tolerability, and Safety of Dolutegravir/Lamivudine in Korea

Most studies on the real-world effectiveness and safety of dolutegravir/lamivudine (DTG/3TC) have been conducted in Western countries, and Asian reports are lacking. We evaluated the effectiveness and safety of DTG/3TC in Korean adult people living with HIV (PLWH). This retrospective study was conducted from July 2020 to July 2022 at a tertiary hospital in Korea. Those who were followed up for more than 12 months were included. We analyzed the baseline characteristics, effectiveness, resistant profiles, body weights, metabolic parameters, and safety of DTG/3TC treatment in 151 PLWH, dividing them into the treatment-naïve group and the switching group. The median DTG/3TC treatment durations in the treatment-naïve and switching groups were 507.5 and 525.0 days. In the treatment-naïve group, the viral RNA titer was undetectable at 6 and 12 months in 95% of patients. In the switching group, virologic suppression was well-maintained. Meanwhile, the creatinine levels were slightly elevated in both groups compared to baseline. Five participants complained of mild side effects, such as indigestion, constipation, diarrhea, and fatigue. However, no patient stopped treatment during the follow-up period. Since there was no virological failure or serious complications observed in this study, DTG/3TC may be a good treatment option for PLWH in Korea.ope

Clinical characteristics of nontuberculous mycobacterial disease in people living with HIV/AIDS in South Korea: A multi-center, retrospective study

With the introduction of combination antiretroviral therapy (cART), the prevalence of human immunodeficiency virus (HIV)-associated nontuberculous mycobacteria (NTM) disease has declined. However, NTM diseases still occur in people living with HIV/acquired immunodeficiency syndrome (AIDS) (PLWHA). We analysed the clinical and microbiological features of NTM diseases in PLWHA in South Korea. PLWHA who were diagnosed with NTM diseases between January 2000 and March 2021 were retrospectively enrolled from five different hospitals in South Korea. Data on baseline demographics, HIV status, CD4+ T cell counts, viral load, past and current cART regimens, isolated NTM species, results of antimicrobial susceptibility tests, treatment regimens, and outcomes were collected by reviewing medical records. A total of 34 cases of NTM in PLWHA were included. Pulmonary and extrapulmonary NTM diseases accounted for 58.8% (n = 20) and 41.2% (n = 14), respectively. The lymph node was the most common site of extrapulmonary NTM disease (64.3%). The age at the time of NTM disease diagnosis was younger in the extrapulmonary NTM group than in the pulmonary NTM group (37.0 vs. 49.0 years). Mean CD4+ T cell counts at the time of NTM disease diagnosis was 186.6 cells/μL (range: 1-1394). Nine patients (26.5%) had fully suppressed viral loads at the time of NTM disease diagnosis. Mycobacterium avium complex (MAC) was the most common species found, followed by M. intracellulare and M. kansasii. MAC isolates were all susceptible to clarithromycin, but the rates of non-susceptibility to moxifloxacin, linezolid, ethambutol, and rifampin were 75%, 37.5%, 12.5%, and 12.5%, respectively. The average duration of treatment was 17 months and the mortality rate was 8.8%. NTM diseases may occur in PLWHA, even with completely suppressed viral loads. The identified clinical features of NTM diseases are essential for its clinical management in South Korea.ope

Increasing Fusobacterium infections with Fusobacterium varium, an emerging pathogen

Infections caused by Fusobacterium species are rare; however serious infections with complications or mortality may occur occasionally. We conducted a retrospective study to investigate the clinical features of patients with Fusobacterium infections and the differences between infections caused by the species F. necrophorum, F. nucleatum, and F. varium. Additionally, we attempted to identify risk factors for Fusobacterium-associated mortality. This study included all patients at a large tertiary care teaching hospital in South Korea with Fusobacterium infections from January 2006 to April 2021. Demographic, clinical, laboratory, and outcome data were analyzed. Multiple logistic regression analysis was performed to assess the risk factors for in-hospital mortality associated with F. nucleatum and F. varium infections. We identified 272 patients with Fusobacterium infections during the study period. The number of Fusobacterium cases has increased recently, with F. varium infections markedly increasing since 2016 and causing a significant proportion of infections. Patients with F. varium infections were older and had a higher proportion of nosocomial infections than the other groups. The F. nucleatum and F. varium groups showed higher in-hospital mortality than the F. necrophorum group. Through logistic regression analysis, APACHE II score and serum albumin level were considered risk factors for in-hospital mortality. APACHE II score was positively correlated with age, red cell distribution width, and serum blood urea nitrogen, and negatively correlated with serum albumin level. Infections caused by Fusobacterium species are increasing. F. varium causes a significant proportion of severe infections.ope

Impact of Valve Culture Positivity on Prognosis in Patients with Infective Endocarditis Who Underwent Valve Surgery

Introduction: Infective endocarditis (IE) is a severe and fatal infection with high in-hospital and overall mortality rates of approximately up to 30%. Valve culture positivity was associated with in-hospital mortality and postoperative complications; however, few studies have analyzed the relationship between valve cultures and overall mortality over a long observation period. This study aimed to compare the association of valve culture positivity with overall mortality in patients with IE who underwent valve surgery. Methods: A total of 416 IE patients admitted to a tertiary hospital in South Korea from November 2005 to August 2017 were retrospectively reviewed. A total of 202 IE patients who underwent valve surgery and valve culture were enrolled. The primary endpoint was long-term overall mortality. Kaplan-Meier curve and Cox proportional hazards model were used for survival analysis. Results: The median follow-up duration was 63 (interquartile range, 38-104) months. Valve cultures were positive in 22 (10.9%) patients. The overall mortality rate was 15.8% (32/202) and was significantly higher in valve culture-positive patients (36.4%, p = 0.011). Positive valve culture [hazard ratio (HR) 3.921, p = 0.002], Charlson Comorbidity Index (HR 1.181, p = 0.004), Coagulase-negative staphylococci (HR 4.233, p = 0.001), new-onset central nervous system complications (HR 3.689, p < 0.001), and new-onset heart failure (HR 4.331, p = 0.001) were significant risk factors for overall mortality. Conclusions: Valve culture positivity is a significant risk factor for long-term overall mortality in IE patients who underwent valve surgery. The importance of valve culture positivity needs to be re-evaluated, as the valve culture positivity rate increases with increasing early surgical intervention.ope

Clinical and microbiological characteristics of and risk factors for bloodstream infections among patients with extracorporeal membrane oxygenation: a single-center retrospective cohort study

Extracorporeal membrane oxygenation (ECMO) provides hemodynamic and oxygenation support to critically ill patients. Due to multiple catheter cannulations, patients on ECMO are vulnerable to bloodstream infections (BSIs). We aimed to investigate the incidence, clinical characteristics, risk factors, and microorganisms associated with BSIs during ECMO. This single-center retrospective cohort study was conducted between January 2015 and May 2021. Patients aged 18 years or older with an ECMO duration of &gt; 48 h for cardiogenic or respiratory support were included in the study. Patients who developed bacteremia or candidemia from 12 h after ECMO cannulation to 7 days after de-cannulation were included. The clinical factors between non-BSI and BSI were compared, along with an analysis of the risk factors associated with BSI during ECMO. A total of 480 patients underwent ECMO for cardiogenic shock (n = 267, 55.6%) or respiratory failure (n = 213, 44.4%) during the study period. The incidence was 20.0 episodes per 1000 ECMO-days. Approximately 20.2% (97/480) and 5.4% (26/480) of the patients developed bacteremia and candidemia, respectively. The median numbers of days of BSI development were 8.00 days for bacteremia and 11.0 days for candidemia. The most common pathogens were methicillin-resistant coagulase-negative staphylococci (n = 24), followed by vancomycin-resistant Enterococcus (n = 21). Multivariable logistic analysis demonstrated that hemodialysis (odds ratio [OR] 2.647, p &lt; 0.001), veno-arterial-venous mode (OR 1.911, p = 0.030), and total ECMO duration (OR 1.030, p = 0.007) were significant risk factors for bacteremia. The total ECMO duration was the only risk factor associated with candidemia (OR 1.035, p = 0.010). The mortality rate was significantly higher in the bacteremia (57.7%) and candidemia (69.2%) groups than that in the non-BSI group (43.6%). BSI is a common complication of patients receiving ECMO support and is associated with poor clinical outcomes. Determining the type of frequently isolated organisms and the median onset time of BSI would help in the selection of appropriate prophylactic antibiotics or antifungal agents.ope

Duration of culturable SARS-CoV-2 within different specimens among mild and severe COVID-19 patients: A longitudinal study

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비가환 원환면 위의 의미분 작용소 계산법. 타원형 작용소의 역핵과 복소수 거듭제곱

학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 수리과학부, 2018. 8. 라파엘 폰즈.약 40여년 전 알랭 콘은 $C^*$-동역학계 위의 의미분 작용소를 도입했으며, 이는 비가환 원환면 위의 의미분 작용소 또한 포함한다. 그리고 최근 콘-트랫코프의 논문을 기폭제로 활발히 연구되고 있는 비가환 원환면의 미분기하학 연구에 콘이 도입한 의미분 작용소가 매우 널리 쓰이고 있다. 또한 매개변수를 갖는 비가환 원환면 위의 의미분 작용소, 의미분 작용소들의 복소해석적인 모임 그리고 타원형 의미분 작용소의 복소수 거듭제곱과 같은 개념들 역시 비가환 원환면의 미분기하학 연구에 매우 중요한 역할을 한다. 그러나 이 개념들에 대한 자세한 서술이 된 문헌은 비교적 최근까지 없었다. 본 학위논문에서는 이 개념들에 대한 자세한 서술을 함으로서 콘-트랫코프 논문으로부터 촉발된 연구에 도움을 주는 것을 목표로 한다. 우선 처음으로, 비가환 원환면 위의 의미분 작용소에 대한 정확한 설명을 한다. 이를 위해 비가환 원환면에 대한 진동 적분을 정의하는데, 이는 비가환 원환면 위의 의미분 작용소의 기본적인 성질을 다루는 데도 도움이 된다. 두 번째로 우리는 비가환 원환면 위의 매개변수를 갖는 의미분 작용소를 정의하고 공부하며, 타원형 의미분 작용소의 역핵이 실제로 매개변수를 갖는 의미분 작용소가 됨을 증명한다. 본 학위논문의 마지막 목표는 의미분 작용소들의 복소해석적인 모임을 공부하고 타원형 의미분 작용소의 복소수 거듭제곱을 구성하는 것이다. 특히, 타원형 의미분 작용소의 복소수 거듭제곱이 의미분 작용소의 복소해석적인 모임이 되는 것을 보이고자 한다.1 Introduction 1 1.1 Motivation 2 1.2 Oscillating integrals 4 1.3 Pseudodifferential calculus on noncommutative tori 5 1.4 Sobolev mapping properties and Schatten-class properties of ΨDOs 8 1.5 Elliptic operators 9 1.6 ΨDOs with parameters and resolvents 11 1.7 Complex powers of elliptic ΨDOs 11 2 Noncommutative tori 15 2.1 Noncommutative tori 15 2.2 The smooth noncommutative torus Aθ 20 2.3 Distributions on Aθ 28 2.4 Differential operators 30 3 Pseudodifferential calculus on noncommutative tori, I. Oscillating integrals 33 3.1 Classes of symbols on noncommutative tori 33 3.1.1 Standard symbols 34 3.1.2 Homogeneous and classical symbols 37 3.2 Amplitudes and oscillating integrals 41 3.2.1 Spaces of amplitudes 41 3.2.2 Aθ-Valued oscillating integrals 44 3.3 Pseudodifferential operators on noncommutative tori 54 3.3.1 ΨDOs associated with amplitudes 54 3.3.2 ΨDOs associated with symbols 56 3.A Integration in locally convex spaces 62 3.A.1 Riemann integration 62 3.A.2 Lebesgue integration 65 3.B Differentiable maps with values in locally convex spaces 70 3.B.1 Differentiation 70 3.B.2 Differentiation under the integral sign 77 3.B.3 Fourier transform and Schwartzs class 79 4 Pseudodifferential calculus on noncommutative tori, II. Main properties 85 4.1 Composition of ΨDOs. Amplitudes 86 4.2 Composition of ΨDOs. Symbols 95 4.3 Adjoints of ΨDOs. Action on Aθ 103 4.4 Sobolev spaces on noncommutative tori 107 4.5 Boundedness and Sobolev mapping properties 118 4.6 Smoothing operators 121 4.7 Ellipticity and parametrices 127 4.8 Spectral theory of elliptic operators 133 4.8.1 Fredholm properties 133 4.8.2 Spectra of positive order elliptic ΨDOs 136 4.8.3 Partial inverses of elliptic ΨDOs 144 4.9 Trace-class and Schatten-classes properties of ΨDOs 148 4.9.1 Schatten-classes 148 4.9.2 Schatten-classes properties of ΨDOs 152 5 Resolvents of elliptic operators on noncommutative tori 157 5.1 ΨDOs with parameter 157 5.2 The resolvent of an elliptic ΨDO 172 5.A Holomorphic maps with values in locally convex spaces 186 6 Complex powers of elliptic operators on noncommutative tori 191 6.1 Holomorphic families of ΨDOs 191 6.1.1 Holomorphic families of ΨDOs 191 6.1.2 Composition of holomorphic families of ΨDOs 200 6.1.3 Holomorphic gauging 201 6.2 Complex powers of elliptic ΨDOs 202 Bibliography 213 Abstract (in Korean) 221 Acknowledgement (in English) 222 Acknowledgement (in Korean) 223Docto