本研究主要探討生技產業公開說明書之風險因子揭露以及首次公開發行(IPO, initial public offering)前之策略聯盟關係對首次公開發行折價所產生之影響。本研究以美國生技產業首次公開發行公司為研究對象，樣本期間為1997年至2012年。 許多文獻指出當初級市場認購人間資訊不對稱程度越大時，IPO價值之事前不確定性(ex ante uncertainty)越高，因此以事前不確定性的概念來衡量資訊不對稱程度，並透過公開說明書中資訊之揭露作為事前不確定性的代理變數以探討其與IPO折價現象之關聯。本研究即利用公開說明書之風險因子揭露作為事前不確定性的代理變數，並預期揭露的數量多寡與內容描述將影響IPO折價。另外，由於文獻指出策略聯盟所傳達的正面訊號，可能有助於生技公司減少因產業特性所造成的不確定性，因此本研究預期生技公司於IPO前擁有策略聯盟關係將影響IPO折價。 本研究參考過去文獻，建立資訊揭露的四級指標加上風險因子所揭露的項目多寡，系統性地衡量生技公司公開說明書之風險因子，並以多元迴歸分析檢測假說。實證結果顯示：風險因子的內容描述越具量化或越具體，IPO折價越大，並且發現大公司之風險因子揭露數量與IPO折價具正向關係，而生技公司於IPO前擁有策略聯盟關係對IPO折價幅度具有顯著負向關係。研究結果顯示公開說明書之風險因子揭露及策略聯盟與事前不確定性所產生之IPO折價現象之關聯性。 / This study investigates whether disclosure of risk factors in the prospectus and the effect of strategic alliances before IPO date will influence underpricing of the biotech firms. Data is collected for biotech companies of U.S IPOs issued from 1997 to 2012 as the research sample. Much literature indicates that the greater is the information asymmetry between different investors, the higher is the ex ante uncertainty about an initial public offering’s value. Hence, the ex ante uncertainty is measured as the degree of asymmetric information. And there are a number of studies that use different measurement as a proxy for ex-ante uncertainty including disclosures in the prospectus to examine its relation to underpricing. This study uses risk factors in the prospectus as a proxy for ex-ante uncertainty and expects that the quantity of risk factors and the content or description of risk factors will influence underpricing. Furthermore, since previous studies consider that strategy alliances convey a positive signal to investors which would reduce the uncertainty from the industrial characteristics of the biotech industry and would mitigate investors’ concern, this study expects that a biotech IPO with strategic alliances before IPO date will affect underpricing. Referring to past literature, this study builds four-class index for disclosure score and uses the number of risk factors to systematically measure risk factors in the prospectus. The empirical results show that a biotech IPO with more quantitative information or some specific information of risk factors will experience higher underpricing. In addition, in larger firms the greater are risk factors disclosed no matter the quantity or the content and its description, the higher is underpricing. And there is a significantly negative relation between strategic alliances before IPO date and underpricing. In conclusion, disclosure of risk factors in the prospectus and the effect of strategic alliances are related to underpricing as expected.

Os tumores carcinóides típicos broncopulmonares são proliferações de células neuroendócrinas. Foram consideradas como adenomas e acreditava-se que não tinham potencial para disseminação hematogênica e linfática. Porém, a ocorrência de metástase linfática e hematogênica acontece em um quinto dos indivíduos acometidos por essa patologia. A variação no comportamento clínico dos carcinóides broncopulmonares torna imperativa a realização de pesquisas que visem à melhor compreensão dessa doença. É fundamental determinar a agressividade e o risco individual da ocorrência de metástase linfática e hematogênica para que se possa oferecer um tratamento individualizado para cada binômio doente-doença. A classificação atual divide os tumores carcinóides, conforme o grau histológico de malignidade em típico e atípico, agrupando as neoplasias de acordo com o índice mitótico, relação volumétrica núcleo/citoplasma, presença ou ausência de necrose, pleomorfismo nuclear e invasão vascular. Esta análise, porém, é realizada em espécimes histológicos corados pela hematoxilina-eosina, técnica tradicional consagrada, mas que não permite avaliar processos biomoleculares relacionados ao potencial maligno das células que já podem estar presentes e não serem detectados pelo método. Em tumores carcinóides vários estudos já foram realizados na tentativa de identificar o potencial proliferativo de células que ainda não apresentam figuras de mitose, como PCNA, p53, Ki-67, o processo apoptótico (Bcl-2, Bax e Bak), fibras do sistema colágeno e elástico e angiogênese. Entretanto, a linfangiogênese nunca foi estudada. Na última década várias moléculas funcionais e constitucionais que são expressas especificamente nas células do endotélio ou nos podócitos dos vasos linfáticos foram identificadas, como o VEGF-C, VEGFR-3 e o LYVE-1, possibilitando a melhor compreensão da linfangiogênese. Estudamos a imunomarcação dessas estruturas no carcinóide típico. Pela primeira vez no Brasil, a quantificação de vasos linfáticos foi realizada usando o LYVE1 como marcador. Apesar do uso de vários bloqueios de sítios inespecíficos não foi possível quantificar a expressão do VEGF-C e VEGFR-3 em carcinóides típicos, pois não encontramos controle interno negativo. Houve diferença significante entre as médias da idade em relação ao gênero. Não houve diferença significante entre as médias do diâmetro e número de linfonodos acometidos em relação ao gênero. Em relação ao grupo com e sem metástase encontramos difenca significante em relação ao diâmetro e ao comprometimento da margem. Não houve diferença da mediana do número de vasos linfáticos corados por mil células entre os grupos sem e com metástase linfática. Por regressão logística identificamos o diâmetro do tumor primário como uma variável independente preditiva do risco de metástase hematogênica e o diâmetro do tumor primário e a localização central ou periférica como variáveis independentes preditivas do risco de qualquer metástase (linfática ou hematogênica). O número de vasos linfáticos corados por mil células não foi identificado pelo modelo de regressão logistica como uma variável independente preditiva do risco individual de metástase linfática. Conclui-se que há correlação do diâmetro do tumor com o potencial de metástase hematogênica e há correlação entre diâmetro e localização do tumor primário e a ocorrência de metástase linfática ou hematogênica. A quantificação da imunoexpressão do LYVE-1 não demonstrou correlação. Outras técnicas devem ser estudadas e empregadas para identificar a importância da linfangiogênese no carcinóide típico. / Typical pulmonary carcinoids are neuroendocrine cells proliferations and they were former considered lung adenomas with no hematogenic or lymphatic metastatic potential. However, it is known that up to 20% of patients develop metastatic disease. It is mandatory that new studies be developed due to the variation in clinical presentation of these patients. It is also required that the individual risk of lymphatic and hematogenic metastasis be determined in order to individualize the patients treatment. Pulmonary carcinoids are classified according to hystologic grade. The current classification includes hystologic grade, presence or absence of necrosis, nuclear pleomorphism, and vascular invasion. This classification is based on Hematoxylin and Eosin stain and this technique can not assess biomolecular processes related to malignant potential. Trying to identify the malignant potential of the carcinoid tumors some studies have already been designed to identify some proteins as PCNA, p53, Ki-67, apoptosis proteins (Bcl-2, Bax and Bak), collagen and elastic fibers as well as angiogenic process. However, the lymphangiogenic mechanism has never been evaluated in typical pulmonary carcinoid tumors. Recently some molecules (VEGF-C, VEGFR-3 and LYVE-1) that are specifically expressed in the endothelium of the lymphatic vessels have been identified. These findings have improved the lymphangiogenic mechanism comprehension. This study used the immunohistochemical technique to identify VEGF-C, VEGFR-3 and LYVE-1 in 182 patients submitted to surgical procedures to treat Typical pulmonary carcinoid tumors. Lymphatic metastasis were diagnosed in 23 of 182 patients and 17 of 182 patients were identified with hematogenic metastasis. Futhermore, this study was the first reported one which has tried to quantify the lymphatic vessels using the LYVE-1 as an immunohistochemical marker. This study could not assess VEGF-C and VEGFR-e expression in Typical pulmonary carcinoids since an internal negative control could not be determined. There was a statistical difference between the median age and gender. There was no statistical difference between the median diameter and the number of positive lymph nodes related to the gender. This study demonstrated a statistical difference between the diameter and positive margins related to the group of patients that have developed metastatic disease and the group of patients with no metatastatic disease. There was no difference between the group of patients that have developed metastatic disease and the group of patients with no metatastatic disease according to the median number of lymphatic vessels stained. Based on logistic regression this study demonstrated that there is a predictive risk of developing hematogenic metastasis related to the diameter of the tumor. The predictive risk of the lymphatic metastasis was not improved by the number of the immunohistochemical stained lymphatic vessels, according to the logistic regression model. The immunohistochemical expression of LYVE-1 has not demonstrated statistical correlation between the parameters studied. Other than immnuhistochemical techniques are required to improve the comprehension of the lymphangiogenic mechanism involved in the Typical pulmonary carcinoid tumor

Background: ST-elevation acute myocardial infarction (STEMI) represents one of the leading causes of death. The time of STEMI onset has a circadian rhythm with a peak during diurnal hours, and the occurrence of STEMI follows a seasonal pattern with a salient peak of cases in the winter months and a marked reduction of cases in the summer months. Scholars investigated the reason behind the winter peak, suggesting that environmental and climatic factors concur in STEMI pathogenesis, but no studies have investigated whether the circadian rhythm is modified with the seasonal pattern, in particular during the summer reduction in STEMI occurrence. Methods and Results: Here, we provide a multiethnic and multination epidemiological study (from both hemispheres at different latitudes, n=2270 cases) that investigates whether the circadian variation of STEMI onset is altered in the summer season. The main finding is that the difference between numbers of diurnal (6:00 to 18:00) and nocturnal (18:00 to 6:00) STEMI is markedly decreased in the summer season, and this is a prodrome of a complex mechanism according to which the circadian rhythm of STEMI time onset seems season dependent. Conclusions: The “summer shift” of STEMI to the nocturnal interval is consistent across different populations, and the sunshine duration (a measure related to cloudiness and solar irradiance) underpins this season-dependent circadian perturbation. Vitamin D, which in our results seems correlated with this summer shift, is also primarily regulated by the sunshine duration, and future studies should investigate their joint role in the mechanisms of STEMI etiogenesis.

This thesis focuses on considering of the investor economic risk during the preparation of the investment project including the financial plan, its evaluation and suggestions of proposals for risk reduction. Correct decisions on implementation or rejection of the project are based on the realistic financial plan. However, expenses and revenues are only implied and are burdened with some variability that leads to the risk of failure to achieve the planned values. To assess the acceptability of certain risks for the investor, an analysis of risk factors was conducted. The factors are first identified for their significance and potential negative impact, then the most risk factors are evaluated and determined whether it is necessary to further tracking or the risk to the investor is acceptable.

Background. Previous research suggests that individuals experiencing DSM-IV panic attacks (PA) are at increased risk for various forms of psychopathology, including anxiety, depressive and substance use disorders. However, little is known regarding whether the sole occurrence of fearful spells (FS-only; distressing spells of anxiety with less than four panic symptoms and/or lacking crescendo in symptom onset) similarly elevates the risk for subsequent psychopathology and could therefore be promising to identify high-risk groups for targeted preventive interventions. Thus, the current dissertation thesis aims to examine (a) whether FS-only predict incident mental disorders in addition to full-blown PA and whether their associations with subsequent psychopathology differ from those obtained for PA, (b) whether FS-only, PA, and panic disorder (PD) share similar etiologies, (c) which characteristics of initial FS/PA and other risk factors predict a progression to more severe panic pathology and other mental disorders, and (d) whether help-seeking/potential treatment in individuals with panic alters the risk for subsequent psychopathology. Methods. A representative community sample of adolescents and young adults (N=3021, aged 14-24 at baseline) was prospectively followed up in up to three assessment waves over a time period of up to 10 years. FS-only, PA, PD, and other mental disorders were assessed at each assessment wave using the DSM-IV-M-CIDI. Additional modules/questionnaires were used to assess characteristics of initial FS/PA (T1/T2), potential risk factors, and help-seeking/potential treatment. Logistic regressions were applied to test associations (Odds Ratios, OR) of FS-only and PA at baseline with incident mental disorders at follow-up as well as respective interactive effects with help-seeking at baseline. Associations (Hazard Ratios, HR) of putative risk factors with the onset of panic pathology (FS-only, PA, and PD) or the onset of subsequent anxiety/depressive vs. substance use disorders in those with panic pathology (aggregated data across assessment waves) were estimated with Cox regressions. Multinomial logistic regressions were used to test associations of initial FS/PA characteristics (aggregated from T1 and T2) with PA and PD (lifetime incidences aggregated across assessment waves). Results. FS-only at baseline predicted incident anxiety and depressive disorders at follow-up (OR 1.59-4.36), while PA at baseline predicted incident anxiety, depressive, and substance use disorders at follow-up (OR 2.08-8.75; reference group: No FS/PA). Merely any anxiety disorder (OR=3.26) and alcohol abuse/dependence (OR=2.26) were significantly more strongly associated with PA than with FS-only. Female sex, parental anxiety disorders, parental depressive disorders, behavioral inhibition, harm avoidance, lower coping efficacy, and parental rejection predicted FS-only, PA, and PD (HR 1.2-3.0), whereas the associations with other risk factors partially differed for FS-only, PA, and PD and tended to be more pronounced for PA and PD than for FS-only. Alcohol consumption, use of drugs/medication, and physical illness as perceived reasons for the initial FS/PA were associated with the occurrence of full-blown PA (without PD, OR 2.46-5.44), while feelings of anxiety/depression and having always been anxious/nervous as perceived reasons for the initial FS/PA, appraising the initial FS/PA as terrible and long-term irritating/burdensome, subsequent feelings of depression, avoidance of situations/places, and consumption of medication, alcohol, or drugs were associated with the development of PD (OR 2.64-4.15). A longer duration until “feeling okay again” was associated with both PA and PD (OR 1.29-1.63 per category). Moreover, partially different risk constellations in subjects with panic pathology (FS/PA/PD) predicted the onset of subsequent anxiety/depressive vs. substance use disorders. Panic pathology (FS/PA) and help-seeking/potential treatment at baseline interacted on predicting incident PD (OR=0.09) and depression (OR=0.22) at follow-up in a way that panic pathology only predicted these disorders in individuals not seeking help at baseline. Conclusions. Findings suggest that individuals with FS-only are at similar risk of developing subsequent psychopathology compared to individuals with full-blown PA. Specific initial FS/PA characteristics and additional risk factors may be used to identify sub-groups of individuals with panic pathology, which are at particular risk of progressing to more severe panic pathology or other mental disorders and might therefore profit from supplemental outcome-related preventive interventions in addition to panic-specific treatment. Future research may replicate the current findings and test the efficacy of targeted preventive interventions in panickers at elevated risk for PD and other forms of psychopathology.:CONTENT 0 Synopsis 10 1 Introduction 13 1.1 Current challenges in clinical psychology 13 1.2 Psychological models of mental disorders 13 1.3 Diagnostic approaches to psychopathology 15 1.4 Methodological issues 16 1.5 Preventive and early treatment interventions 17 2 Panic pathology 18 2.1 Definitions 18 2.2 Epidemiology 19 2.3 Etiology 20 2.4 Physiological, neurobiological, and genetic findings 21 2.5 Unresolved issues 22 3 Aims 24 4 Methods 26 5 Study I: Associations of fearful spells and panic attacks with incident anxiety, depressive, and substance use disorders: A 10-year prospective-longitudinal community study of adolescents and young adults 27 5.1 Abstract 27 5.2 Introduction 27 5.3 Materials and methods 28 5.4 Results 30 5.5 Discussion 35 6 Study II: Characteristics of initial fearful spells and their associations with DSM-IV panic attacks and panic disorder in adolescents and young adults from the community 37 6.1 Abstract 37 6.2 Introduction 37 6.3 Materials and methods 38 6.4 Results 41 6.5 Discussion 43 7 Study III: Risk factors for fearful spells and panic: A 10-year prospective-longitudinal study among adolescents and young adults 47 7.1 Abstract 47 7.2 Introduction 47 7.3 Materials and methods 49 7.4 Results 52 7.5 Discussion 60 8 Study IV: Does help-seeking alter the risk for incident psychopathology in adolescents and young adults with and without fearful spells or panic attacks? Findings from a 10-year prospective-longitudinal community study 63 8.1 Abstract 63 8.2 Introduction 63 8.3 Materials and methods 64 8.4 Results 66 8.5 Discussion 70 9 General discussion 73 9.1 Summary and discussion of main findings 73 9.2 Preventive interventions among individuals with panic pathology 75 9.3 Research implications 77 10 Conclusions 78 11 References 79 12 Appendix 94 12.1 Acknowledgements 94 12.2 Erklärung zu den Eigenanteilen an einzelnen Publikationen 95 12.3 Eigenständigkeitserklärung 96 / Theoretischer Hintergrund. Auf Grundlage früherer Forschungsbefunde ist anzunehmen, dass Personen mit DSM-IV-Panikattacken (PA) ein erhöhtes Risiko für zahlreiche psychische Störungen, einschließlich Angst-, depressiver und Substanzstörungen, aufweisen. Unklar ist jedoch, ob das alleinige Auftreten von Fearful Spells (FS-only, Angstanfälle mit weniger als vier Paniksymptomen und/oder fehlendem Crescendo in der Symptomentwicklung) das Risiko für Psychopathologie in ähnlicher Weise erhöht und hilfreich sein könnte, um Hochrisikogruppen für Präventivinterventionen zu identifizieren. Innerhalb der vorliegenden Dissertation wird daher untersucht, (a) ob FS-only zusätzlich zu PA inzidente psychische Störungen vorhersagen und ob sich Unterschiede in den Assoziationen von FS-only vs. PA mit nachfolgender Psychopathologie ergeben, (b) ob FS-only, PA und Panikstörung (PS) ähnliche Ätiologien teilen, (c) welche Merkmale initialer FS/PA und welche anderen Risikofaktoren die Entwicklung schwerer Panikpathologie und weiterer psychischer Störungen vorhersagen und (d) ob Hilfesuchverhalten/potenzielle Behandlung bei Personen mit Panik das Risiko für nachfolgende Psychopathologie verändert. Methodik. Eine repräsentative Bevölkerungsstichprobe Jugendlicher und junger Erwachsener (N=3021, 14-24 Jahre zur Baseline-Erhebung) wurde in bis zu drei Erhebungswellen über einen Zeitraum von bis zu 10 Jahren untersucht. FS-only, PA, PS und andere psychische Störungen wurden zu jeder Erhebungswelle mithilfe des DSM-IV-M-CIDI erfasst. Merkmale initialer FS/PA (T1/T2), mögliche Risikofaktoren sowie Hilfesuchverhalten/potenzielle Behandlung wurden mit weiteren Modulen und Fragebögen erhoben. Mithilfe logistischer Regressionen wurden Assoziationen (Odds Ratios, OR) von FS-only und PA zu Baseline mit inzidenten psychischen Störungen zum Follow-Up sowie diesbezügliche Interaktionen mit Hilfesuchverhalten zu Baseline getestet. Zusammenhänge zwischen möglichen Risikofaktoren und dem Auftreten von Panikpathologie (FS-only, PA und PS) bzw. nachfolgender Angst-/depressiver und Substanzstörungen bei Personen mit Panikpathologie (Verwendung von über die Erhebungswellen hinweg aggregierter Daten) wurden mithilfe von Cox-Regressionen geschätzt. Multinomiale logistische Regressionen wurden genutzt, um Assoziationen von Merkmalen initialer FS/PA (aggregiert über T1 und T2) mit PA und PS (über die Erhebungswellen hinweg aggregierte Lebenszeitinzidenzen) zu erfassen. Ergebnisse. FS-only zu Baseline sagten inzidente Angst- und depressive Störungen zum Follow-Up vorher (OR 1.59-4.36), wohingegen PA zu Baseline inzidente Angst-, depressive und Substanzstörungen zum Follow-Up vorhersagten (OR 2.08-8.75; Referenzkategorie: Keine FS/PA). Lediglich irgendeine Angststörung (OR=3.26) und Alkoholmissbrauch/-abhängigkeit (OR=2.26) waren signifikant stärker mit PA als mit FS-only assoziiert. Weibliches Geschlecht, elterliche Angst- und depressive Störungen, Verhaltenshemmung, Schadensvermeidung, geringere Coping-Erwartung und elterliche Zurückweisung sagten FS-only, PA und PS vorher (HR 1.2-3.0), während sich teils unterschiedliche Assoziationen anderer Risikofaktoren mit FS-only, PA und PS ergaben, die tendenziell stärker für PA und PS als für FS-only waren. Alkoholkonsum, Drogen-/Medikamentengebrauch und körperliche Erkrankungen als wahrgenommene Gründe für die initiale FS/PA waren mit dem Auftreten vollständiger PA assoziiert (ohne PS; OR 2.46-5.44), während Gefühle von Angst/Depression und die Einschätzung schon immer ängstlich/nervös gewesen zu sein als wahrgenommene Gründe für die initiale FS/PA, die Bewertung der initialen FS/PA als schrecklich und langfristig verunsichernd/belastend, nachfolgende Gefühle von Niedergeschlagenheit, Vermeidung von Situationen/Orten und Konsum von Medikamenten, Alkohol oder Drogen mit der Entwicklung von PS assoziiert waren (OR 2.64-4.15). Eine längere Dauer bis sich die betroffene Person wieder vollständig in Ordnung fühlte war sowohl mit PA als auch mit PS assoziiert (OR 1.29-1.63 pro Kategorie). Weiterhin sagten teils unterschiedliche Risikokonstellationen bei Personen mit Panikpathologie (FS/PA/PS) die nachfolgende Entstehung von Angst-/depressiven und Substanzstörungen vorher. Panikpathologie (FS/PA) und Hilfesuchverhalten/potenzielle Behandlung zu Baseline interagierten bei der Vorhersage von inzidenter PS (OR=0.09) und Depression (OR=0.22) zum Follow-Up; d.h. das Vorhandensein von Panikpathologie sagte diese Störungen nur bei Personen ohne, nicht aber bei Personen mit Hilfesuchverhalten zu Baseline vorher. Schlussfolgerungen. Die vorliegenden Ergebnisse implizieren, dass Personen mit FS-only im Vergleich zu Personen mit vollständigen PA ein ähnliches Risiko für die Entwicklung nachfolgender Psychopathologie aufweisen. Spezifische Merkmale initialer FS/PA und zusätzliche Risikofaktoren könnten zur Identifikation von Sub-Gruppen von Personen mit Panik genutzt werden, die sich durch ein besonderes Risiko für schwergradige Panikpathologie und andere psychische Störungen auszeichnen und demzufolge von Outcome-bezogenen Präventionen (ergänzend zu Panik-spezifischer Intervention) profitieren könnten. Zukünftige Studien sollten die vorliegenden Befunde replizieren und die Effektivität gezielter Präventivinterventionen bei Personen mit erhöhtem Risiko für PS und andere psychische Störungen testen.:CONTENT 0 Synopsis 10 1 Introduction 13 1.1 Current challenges in clinical psychology 13 1.2 Psychological models of mental disorders 13 1.3 Diagnostic approaches to psychopathology 15 1.4 Methodological issues 16 1.5 Preventive and early treatment interventions 17 2 Panic pathology 18 2.1 Definitions 18 2.2 Epidemiology 19 2.3 Etiology 20 2.4 Physiological, neurobiological, and genetic findings 21 2.5 Unresolved issues 22 3 Aims 24 4 Methods 26 5 Study I: Associations of fearful spells and panic attacks with incident anxiety, depressive, and substance use disorders: A 10-year prospective-longitudinal community study of adolescents and young adults 27 5.1 Abstract 27 5.2 Introduction 27 5.3 Materials and methods 28 5.4 Results 30 5.5 Discussion 35 6 Study II: Characteristics of initial fearful spells and their associations with DSM-IV panic attacks and panic disorder in adolescents and young adults from the community 37 6.1 Abstract 37 6.2 Introduction 37 6.3 Materials and methods 38 6.4 Results 41 6.5 Discussion 43 7 Study III: Risk factors for fearful spells and panic: A 10-year prospective-longitudinal study among adolescents and young adults 47 7.1 Abstract 47 7.2 Introduction 47 7.3 Materials and methods 49 7.4 Results 52 7.5 Discussion 60 8 Study IV: Does help-seeking alter the risk for incident psychopathology in adolescents and young adults with and without fearful spells or panic attacks? Findings from a 10-year prospective-longitudinal community study 63 8.1 Abstract 63 8.2 Introduction 63 8.3 Materials and methods 64 8.4 Results 66 8.5 Discussion 70 9 General discussion 73 9.1 Summary and discussion of main findings 73 9.2 Preventive interventions among individuals with panic pathology 75 9.3 Research implications 77 10 Conclusions 78 11 References 79 12 Appendix 94 12.1 Acknowledgements 94 12.2 Erklärung zu den Eigenanteilen an einzelnen Publikationen 95 12.3 Eigenständigkeitserklärung 96

This quantitative, descriptive study investigated risk factors for MDR-TB in Addis Ababa, Ethiopia. A total of 439 medical records belonging to MDR-TB and non MDR-TB patients managed in public health centres from January 2008 to December 2011 were analysed. Data were transcribed from each TB patient‟s medical records using a specifically designed checklist. The findings revealed that male gender, previous history of TB treatment, poor treatment adherence, an outcome of failure after TB re-treatment, previous category of failure, pulmonary involvement of TB infection and HIV infection were associated with MDR-TB. The findings illustrate that efforts should be made to prioritise the development and implementation of effective MDR TB screening and treatment protocols for these high risk groups to improve treatment outcome and minimize the emergence of XDR TB. / Health Studies / M.A. (Public Health)

中文摘要 在本文中，我們依據模擬的風險因子變動，包括死亡率風險，利率風險，解約率風險以及模型的參數風險，來估計第一個保單年度的期末責任準備金之涉險值 (Value at Risk)。本文中，雖僅計算生死合險保單的準備金之涉險值，但是本文所提供的方法以及計算過程可以很容易的應用到其它險種，甚至配合資產面的考量來計算保險公司盈餘(Surplus)的涉險值，進而作為清償能力的監測系統。 本文的特點包括下列幾項：第一，本文提供了一個不同於傳統短期間(Short Horizon)的涉險值計算方式，來估計壽險商品的保單責任準備金(Policy Reserve)的涉險值。第二，本文利用生命表來估計死亡率風險所造成的涉險值。第三，我們利用隨機利率模型來捕捉隨機利率對於責任準備金涉險值的影響。第四，我們考慮解約率對於責任準備金涉險值的影響，值得注意的是，在我們的解約率模型中，引入的利率對於解約率的影響。第五，本文亦考慮風險因子模型當中的參數風險對於涉險值的影響。最後，我們利用無母數方法計算出涉險值的信賴區間，而信賴區間的估計在模擬過程當中尤其重要，因為它可以用來決定模擬次數的多寡。 本文包含六節：第一節為導論。第二節為計算死亡率風險的責任準備金涉險值。第三節是計算加上利率風險後責任準備金涉險值的變化。第四節則為加上解約率後對涉險值的影響。第五節為計算涉險值的信賴區間。第六節是我們的結論以及後續研究的方向探討。 本文包含六節：第一節為導論。第二節為計算死亡率風險的責任準備金涉險值。第三節是計算加上利率風險後責任準備金涉險值的變化。第四節則為加上解約率後對涉險值的影響。第五節為計算涉險值的信賴區間。第六節是我們的結論以及後續研究的方向探討。 / ABSTRACT In this paper, we estimate the VAR of life insurer's terminal reserve of the first policy year by the simulated risk factors, including mortality risk, interest rate risk, lapse rate risk, and estimation risks, of future twenty years. We found that the difference between the VAR under the mortality risk and the interest rate risk is very large because interest rate is a stochastic process but not mortality rate. Thus, the dispersion of interest rate is more then mortality rate. In addition, the VAR will reduce a lot after adding the impact of lapses because the duration of the reserve reduced. If we neglect the impact of lapses to VAR, we will overestimate the VAR significantly. The features of this paper are as follows. First, we provide an approach to measure the VAR of a life insurer's reserve, and it is rather different from traditional VAR with short horizons. Second, we use mortality table to estimate the VAR of a life insurer's reserve. Third, we use stochastic interest rate model to capture the effect of random interest rate to the VAR of a life insurer's reserve. Fourth, we relate the future cash outflows to interest rate and produce a reasonable estimator of VAR. Fifth, we consider the effect of estimation errors to the VAR of a life insurer's reserve. Last, we calculate the confidence interval of the VAR estimates of the policy reserves. This paper consists of six sections. The first section is an introduction. In the second section, we present the method used to estimate the variance of the mortality rate and then estimate the VAR of reserves from these variances. In the third section, we explore how to use stochastic interest rate model to estimate the reserve's VAR and the VAR associated with the parameter risk of the interest rate model. In the fourth section, we analyze the contribution of the lapse rate risk and the parameter risk of the lapse rate model to the reserve's VAR. We also analyze the relative significance of the interest rate risk, the lapse rate risk, and the mortality rate risk in terms of their marginal contributions to the VAR of an insurer's reserves in this section. In the fifth section, we calculate the confidence intervals of the VAR estimates discussed in the previous sections. The last section is the conclusion section containing our conclusions and discussions about potential future researches.

Research in risk awareness has been relatively neglected in the health informatics literature, which tends largely to examine project managers’ perspectives of risk awareness; very few studies explicitly address the perspectives held by senior executives such as directors. Another limitation evident in the current risk literature is that studies are often based on American data and/or they are restricted to American culture. Both factors highlight the need to examine how senior executives (i.e., directors) who oversee or direct eHealth projects in Canada perceive risk awareness. This research explores and discusses the perspectives of risk awareness (i.e., identification, analysis, and prioritization) held by directors and project managers who implement Canadian eHealth projects. Semi-structured interviews with nine directors and project managers uncovered six key distinctions in these two groups’ awareness of risk. First, all project managers valued transparency over anonymity, whereas directors believed that an anonymous reporting system for communicating risks had merit. Secondly, most directors emphasized the importance of evidence-based planning and decision making when balancing risks and opportunities, an aspect none of the project managers voiced. Thirdly, while project managers noted that the level of risk tolerance may evolve from being risk-averse to risk-neutral, directors believed that risk tolerance evolved toward risk-seeking. Directors also noted the importance of employing risk officers, a view that was not shared by project managers. Directors also believed the risk of too little end-user engagement and change management was the most important risk, whereas project managers ranked it as the least important. Finally, when directors and project managers were asked to identify and define the root cause(s) of eHealth risks, directors identified the complexity of health care industry, while project managers attributed it to political pressure and a lack of resources where eHealth projects are concerned. This research proposes that the varied perspectives of risk awareness held by directors and project managers must be considered and integrated to properly align expectations and build partnerships for successful eHealth project outcomes. Understanding risk awareness offers a means to systematically identify and analyze the complex nature of eHealth projects by embracing uncertainties, thereby enabling forward thinking (i.e., staying one step ahead of risks) and the ability to prevent avoidable risks and seize opportunities. / Graduate / 0723 / 0489 / 0454 / randbpark@gmail.com

The dissertation deals with the analysis of roundabout design elements and their impact on accidents. The analysis objective was to identify the important elements of roundabouts that have impact on accidents. In order to achieve this goal, the multifactorial statistical safety assessment method was used on the basis of a representative sample of data, by developing several safety performance functions, verifying them and interpreting the result. Several design elements, which from the point of view of the traffic accident mechanism belong to the infrastructure factor, have been identified: AADT, average diameter, entrance width, entry angle, direct passage angle, location and many others. The original sample contained about 1200 roundabouts, which were reduced to 200 based on data availability. Accident frequencies were monitored between 2009 and 2016, i.e. for eight years, resulting in total 2674 roundabouts accidents. The result is an accident prediction model, developer based on roundabout approach design elements, and map of critical roundabouts, identified based on empirical Bayes estimate of accident frequency. Following approach parameters were identified: AADT, entry angle, distance between collision points, deviation of angles between approaches, presence of apron, presence of bypass, entry type, presence of pedestrian crossing and surrounding area type.

La dengue circule en Polynésie française sur un mode épidémique depuis plus de 35 ans. Néanmoins, en dépit de la taille relativement faible de la population de Polynésie française, la circulation de la dengue peut persister à de faibles niveaux pendant de nombreuses années. L’objectif de ce travail de thèse est de déterminer si l'épidémiologie de la dengue dans le système insulaire de la Polynésie française répond aux critères d’un contexte de métapopulation. Après avoir constitué une base de données regroupant les cas de dengue répertoriés sur les 35 dernières années, nous avons réalisé des analyses épidémiologiques descriptives et statistiques. Celles-ci ont révélé des disparités spatio-temporelles distinctes pour l’incidence de la dengue des archipels et des îles, mais la structure de l'épidémie globale à l’échelle de la Polynésie française pour un même sérotype ne semble pas être affectée. Les analyses de la métapopulation ont révélé l'incidence asynchrone de la dengue dans un grand nombre d’îles. Celle-ci s’observe plus particulièrement par la différence de dynamique de l’incidence entre les îles plus peuplées et celles ayant une population plus faible. La taille critique de la communauté nécessaire à la persistance de la dengue n’est même pas atteinte par la plus grande île de Polynésie Française, Tahiti. Ce résultat suggère que la dengue peut uniquement persister grâce à sa propagation d’île en île. L'incorporation de la connectivité des îles à travers des modèles de migration humaine dans un modèle mathématique a produit une dynamique de la dengue davantage en adéquation avec les données observées, que les tentatives de modélisation traitant la population dans son ensemble. Le modèle de la métapopulation a été capable de simuler la même dynamique que les cas de dengue observés pour l'épidémie et la transmission endémique qui a suivi pour la période de 2001 à 2008. Des analyses complémentaires sur la différenciation de l'incidence de la maladie et de l'infection seront probablement instructives pour affiner le modèle de métapopulation de l'épidémiologie de la dengue en Polynésie française. / Dengue has been epidemic in French Polynesia for the past 35 years. Despite the relatively small population size in French Polynesia, dengue does not disappear and can persist at low levels for many years. In light of the large number of islands comprising French Polynesia, this thesis addresses the extent to which a metapopulation context may be the most appropriate to describe the epidemiology and persistence of dengue in this case. After compiling a database of dengue cases over the last 35 years, we used a number of descriptive and statistical epidemiological analyses that revealed distinct spatio-temporal disparity in dengue incidence for archipelago and islands. But the global structure of the epidemics of the same serotype were not affected. Metapopulation analyses revealed asynchronous dengue incidence among many of the islands and most notably larger islands lagged behind the smaller islands. The critical community size, which determines dengue persistence, was found to exceed even the largest island of Tahiti, suggesting that dengue can only exist by island-hopping. Incorporation of island connectedness through patterns of human migration into a mathematical model enabled a much better fit to the observed data than treating the population as a whole. The metapopulation model was able to capture to some extent the epidemic and low level transmission dynamics observed for the period of 2001-2008. Further analyses on differentiating incidence of disease and infection will likely prove informative for the metapopulation model of dengue epidemiology in French Polynesia.