This investigation attempted to determine the relationship of the site of contact ulcers and subject’s handedness. Literature concerned with contact ulcers has indicated that cerebral dominance tends to determine the site of the lesion. Four research questions were posed, two questions were presented in the form of the null hypothesis. The questions were: (1) Is the proportion of right-handed subjects with left-sided ulcers equal to the proportion of left-handed subjects with left-sided ulcers? (2) Is the proportion of right-handed subjects with right-sided ulcers equal to the proportion of left-handed subjects with right-sided ulcers? (3) Will the site of contact ulcers be able to be predicted from subject’s handedness? And (4) Is there a significant relationship between the factors of age, sex and occupation of the sample studied and the occurrence of contact ulcers?

Left ventricular diastolic dysfunction (LVDD) is any abnormality in the filling of the left ventricle (LV).  Despite the prevalence of this disease, it remains difficult to diagnose, mainly due to inherent compensatory mechanisms and a limited physical understanding of the filling process.  LV filling can be non-invasively imaged using color m-mode echocardiography which provides a spatio-temporal map of inflow velocity.  These filling patterns, or waves, are conventionally used to qualitatively assess the filling pattern, however, this work aims to physically quantify the filling waves to improve understanding of diastole and develop robust, reliable, and quantitative parameters. This work reveals that LV filling waves in a normal ventricle act as dispersive waves and not only propagate along the length of the LV but also spread and disperse in the direction of the apex.  In certain diseased ventricles, this dispersion is limited due to changes in LV geometry and wall motion.  This improved understanding could aid LVDD diagnostics not only for determining health and disease, but also for distinguishing between progressing disease states. This work also identifies a limitation in a current LVDD parameter, intra ventricular pressure difference (IVPD), and presents a new methodology to address this limitation.  This methodology is also capable of synthesizing velocity information from a series of heartbeats to generating one representative heartbeat, addressing inaccuracies due to beat-to-beat variations.  This single beat gives a comprehensive picture of that specific patient's filling pattern.  Together, these methods improve the clinical utility of IVPD, making it more robust and limiting the chance for a misdiagnosis. / Master of Science

Indiana University-Purdue University Indianapolis (IUPUI) / Observational studies and clinical trials with time-to-event data frequently involve multiple event types, known as competing risks. The cumulative incidence function (CIF) is a particularly useful parameter as it explicitly quantifies clinical prognosis. Common issues in competing risks data analysis on the CIF include interval censoring, missing event types, and left truncation. Interval censoring occurs when the event time is not observed but is only known to lie between two observation times, such as clinic visits. Left truncation, also known as delayed entry, is the phenomenon where certain participants enter the study after the onset of disease under study. These individuals with an event prior to their potential study entry time are not included in the analysis and this can induce selection bias. In order to address unmet needs in appropriate methods and software for competing risks data analysis, this thesis focuses the following development of application and methods. First, we develop a convenient and exible tool, the R package intccr, that performs semiparametric regression analysis on the CIF for interval-censored competing risks data. Second, we adopt the augmented inverse probability weighting method to deal with both interval censoring and missing event types. We show that the resulting estimates are consistent and double robust. We illustrate this method using data from the East-African International Epidemiology Databases to Evaluate AIDS (IeDEA EA) where a significant portion of the event types is missing. Last, we develop an estimation method for semiparametric analysis on the CIF for competing risks data subject to both interval censoring and left truncation. This method is applied to the Indianapolis-Ibadan Dementia Project to identify prognostic factors of dementia in elder adults. Overall, the methods developed here are incorporated in the R package intccr. / 2021-05-06

I. Extensive experimental and clinical data suggest that certain electrical and structural changes develop in the atria of patients with atrial fibrillation (AF). These alterations are commonly referred as atrial remodeling and are considered to play a crucial role in the self-perpetuation of this arrhythmia. a. A hallmark of LA structural remodeling is the LA dilatation which is a predictor for progression to chronic AF and therapeutic failure as well. However, AF is associated not only with LA enlargement but also with asymmetrical changes in the left atrial geometry. b. Furthermore, the electrical remodeling is characterized by slower and asynchronous inter- and intra-atrial conduction that also contributes to the maintenance of AF. Some studies suggested a role of the conduction block in the Bachmann’s bundle, connecting the right and left atrium, in the AF pathophysiology and LA remodeling. II. Echocardiography and especially the tissue Doppler method can provide additional insight into the nature of the LA remodeling, because it allows the characterization of the intrinsic LA velocities. a. Using pulsed-wave tissue Doppler (PW-TDI) is possible to measure the interval from the onset of the surface P wave to the A´ velocity at the lateral mitral annulus as a representation of the total interatrial conduction time (TACT). In number of studies, it was demonstrated that prolonged TACT was associated with new-onset AF, AF after open heart surgery, and AF recurrences after electrical cardioversion and catheter ablation. b. An important limitation of the previous studies is that TACT has never been validated by direct measurements of the true electrical conduction in the LA. Moreover, it was assumed that the activation of the lateral MA must be the latest LA activation site. III. In this study, we sought to evaluate the feasibility of the PW-TDI as a simple and quick method to evaluate the LA asynchrony. For the purpose, we measured the time intervals from the onset of P-wave to the A´ (P-A´) in PW-TDI at 4 different left atrial sites next to mitral annulus (septal, lateral, anterior and inferior) in patients referred for electrophysiological study and catheter ablation because of atrial fibrillation or other arrhythmias. a. The differences between the longest and shortest P-A´ (DLS-PA´), as well as the standard deviation (SD-4PA´) of all 4 values were calculated as indexes for LA asynchrony. Importantly, LA asynchrony in patients with AF was compared with a matched control group of patients without history of AF. b. Moreover, the TACT was validated by comparing it with the actual electrical activation of the left atrium measured directly in the coronary sinus. For this purpose, the intervals between the onset of the P-wave and the local LA activation at the distal electrode pair of a catheter inserted in the coronary sinus were measured. c. Having in mind the ovoid LA shape and asymmetrical changes in LA geometry observed in patients with AF, we hypothesized that the lateral mitral annulus may not always be the latest activation spot. Therefore, we sought to determine the latest LA activation site exhibiting the longest P-A´ interval, as well as to describe the sequence of LA activation in AF patients and non-AF controls. IV. One hundred and thirty patients with AF (AF group) and 70 patients without a history of AF (non-AF control group) were examined prospectively using PW-TDI. a. Both groups were matched for the baseline characteristics, including LA diameter. The P-A´ interval measured with PW-TDI at the lateral LA showed a strong, positive, linear correlation with the P-A activation at the distal poles of the CS catheter at the lateral MA: Pearson r=0.708; P=0.0001. b. Asynchrony in the AF group was more pronounced in comparison to the non-AF control group. Patients in the AF group had longer DLS-PA´ as compared to controls: 37±16 msec. vs. 28±13 msec.; P=0.0001, as well as bigger SD-4PA´: 17±7 msec. vs. 13±5 msec.; P=0.0001. c. Furthermore, distinct patterns of LA activation were observed. Most AF patients (86.5%) showed an upward LA activation with inferior LA breakthrough, whereas the non-AF controls exhibited mostly a downward LA activation (65.5%), spreading from LA roof downwards. d. ROC analysis revealed that P-A´ at anterior LA successfully discriminated patients with AF from the non-AF controls (AUC 0.85, P<0.0001). A cut off value for P-A´ anterior > 55 msec. discriminated between AF patients and controls with 85% sensitivity; 81% specificity; positive predictive value of 0.898, and negative predictive value of 0.707. V. In conclusion, PW-TDI can be reliably used to assess the LA asynchrony. Patients with atrial fibrillation showed greater LA asynchrony in PW-TDI independently from the LA dimensions. For the first time, we described that LA activation showed 3 distinct patterns with the upward LA activation being the most frequently observed in patients with AF. Patients with AF demonstrated a prolonged P-A´ activation time at the anterior left atrium. P-A´ at anterior LA > 55 msec. discriminates between patients with AF and non-AF controls with high sensitivity and specificity. This method can be useful to identity patients at risk for occurrence of new-onset atrial fibrillation, as well as to assess the severity of the LA remodeling in order to improve the selection of patients for catheter ablation.:Table of Contents 1 Background 5 1.1 Mechanisms of initiation and perpetuation of atrial fibrillation 5 1.2 Left atrial remodeling in atrial fibrillation 7 1.3 Echocardiographic assessment of left atrial remodeling 8 1.4 Pathophysiology of interatrial conduction in atrial fibrillation 10 2 Objectives and methods 11 2.1 Study objectives 11 2.2 Methods 11 2.2.1 Echocardiography 13 2.2.2 Electrophysiological study 15 2.2.3 Statistical methods 16 3 Publication 17 4 Discussion 26 5 Limitations 30 6 Conclusion 31 7 Synopsis 32 8 References 36 9 Selbstständigkeitserklärung 47 10 Curriculum vitae and list of publications 48 11 Danksagung /Acknowledgments 56

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18169号 / 医博第3889号 / 新制||医||1003(附属図書館) / 31027 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 大森 治紀, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20803号 / 医博第4303号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 今中 雄一, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13207号 / 論医博第2161号 / 新制||医||1031(附属図書館) / (主査)教授 福原 俊一, 教授 湊谷 謙司, 教授 小池 薫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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This dissertation focuses on the rise and fall of “local-level foreign policy” and the local coalitions of leftists and liberals behind these policies. Relying on extensive archival research and interviews, the project shows that, in the decades following 1968, newly elected left-liberal city officials collaborated with leftist, international solidarity activists to use city resources as a means of offering support to social movements in distant parts of the world. In the process, city officials and grassroots activists both aided international movements and drew public attention to the downturn in public funding for social programs in lieu of an expanding military budget. The study refers to these partnerships as “Urban Internationalist Coalitions.” In the 1970s and 1980s, Urban Internationalist Coalitions around the United States passed ballot measures, created sister-city relationships, and organized city-based international delegations designed to challenge and ameliorate the impacts of, what they understood as, the unjust foreign policies of the U.S. federal government towards North Vietnam, El Salvador, and Nicaragua. These initiatives reshaped local politics as strategically capable of tackling problems beyond the city’s borders. By the 1980s, local politicians and grassroots activists’ collaborative engagement around opposing U.S. foreign policy made local-level foreign policy a prevalent aspect of city politics nationwide. As the influence of Urban Internationalist Coalitions and their political strategies expanded, this left-liberal group of collaborators experienced growing pains. By the late 1980s, dozens of cities had replicated local-level foreign policy projects in opposition to the Reagan Administration’s policies towards revolutionary Nicaragua. However, cities’ projects often correlated more with distinct, local political conditions rather than an over-arching, national strategy. Thus, as local-level foreign policies grew in prevalence, a coordinated national strategy became more difficult. When Urban Internationalist Coalitions’ politics did come to inform a national strategy in the form of Jesse Jackson’s presidential campaigns, the increased scale of a national campaign unearthed leftists and liberals’ strategic differences. Organizing across an expanded, national terrain, Urban Internationalist Coalitions confronted the obstacle that neoliberalism’s political and economic impact posed to their political goals and the longevity of their left-liberal alliance. Urban Internationalist Coalitions ultimately experienced Jackson’s Rainbow Coalition organization as a series of political clashes. The political schisms exposed within the Rainbow Coalition frayed at the edges of leftists and liberals’ working relationships locally. Facing substantial political and economic challenges, Urban Internationalist Coalitions unraveled by the early 1990s. / History