在亞洲人群包括中國人群中，顱內動脈粥樣硬化（ICAS）發病率很高，是缺血性卒中和短暫性腦缺血發作（TIA）的首要病因。然而，目前ICAS 並未被深入研究。因此我們在一系列研究中通過運用傳統及創新的神經影像學方法，來研究ICAS 的臨床及血流動力學特徵，以期促進其全面評價及危險分層。 / 既往研究發現亞洲人群和西方人群在頭頸部動脈粥樣硬化的發生和發展上存在種族差異。爲了進一步驗證這些種族差異，我們開展了一項社區研究，以探索無癥狀性顱內外動脈粥樣硬化在中國社區成年居民中的發病情況，以及二者之間的相互關係。在該研究中，我們分別採用經顱多普勒（TCD）和頸部血管超聲（CD）來評價顱內和顱外動脈的粥樣硬化。在研究納入的537 例研究對象中，我們發現顱內動脈粥樣硬化的發展優先於頸動脈粥樣硬化，而且不同階段的頸動脈粥樣硬化與顱內動脈粥樣硬化並無獨立相關關係。該結果提示，在中國人群的全身系統性粥樣硬化的過程中，顱內動脈粥樣硬化可能是一個比較早期而且相對獨立的過程，這與西方人群的情況不同。本研究結果進一步支持東西方人群在顱內外動脈粥樣硬化進程上存在的種族差異。 / 根據既往研究結果，病因為癥狀性ICAS的缺血性卒中或TIA患者卒中復發的風險很高。目前，癥狀性ICAS患者的危險分層大多基於其動脈管腔的狹窄程度。然而，管腔的解剖學狹窄程度並不一定與其血流動力學的嚴重程度成比例，而後者也可能影響相關患者的卒中復發風險。因此，我們進行了以下的一系列研究， 以評價癥狀性ICAS的血流動力學特徵，同時初步探索其在相關患者危險分層中的應用價值。 / 我們首先進行了三項研究，採用一種基於磁共振血管成像（MRA）的創新方法來評價癥狀性ICAS的血流動力學嚴重程度。基於時間飛躍法（TOF）MRA的信號對比機制，我們提出了一項名為信號強度比值（SIR）的參數來定量地評價癥狀性ICAS 的血流動力學效應；該參數代表TOF MRA 影像上經過背景信號強度校正后的ICAS 病變后和病變前的信號強度比值。在一項初步研究中，我們確定了該參數的評價和計算方法。在26例癥狀性ICAS病變中，我們發現該參數的計算操作簡便，在臨床上可行，且在同一評價者的兩次評價中具有很高的可重複性。在隨後的一項研究中，我們在102例癥狀性ICAS病變中發現該參數在兩位評價者之間具有顯著的可重複性。在第三項研究中，我們在36例具有癥狀性ICAS的缺血性卒中患者中發現SIR與患者的急性梗死灶體積顯著相關，但我們並未發現該參數與患者1年的卒中復發風險相關，可能由於該研究的樣本量過小。以上三項研究證實，SIR作為一種基於TOF MRA的評價癥狀性ICAS血流動力學嚴重程度的方法，具有可重複性及臨床可行性；而其對於相關患者危險分層的價值需要在前瞻性的較大型研究中進一步驗證。 / 在如下的另外兩項研究中，我們採用計算機流體動力學（CFD）技術對癥狀性ICAS患者的計算機斷層掃描血管成像（CTA）影像進行重建，從而評價其ICAS 病變的血流動力學特徵。首先，在一項初步研究中，我們探索了採用臨床常規CTA影像進行CFD模型重建的可行性。在10例癥狀性ICAS病變中，9例病變的CTA原始圖像成功重建為CFD模型。重建的CFD模型可以定量地反映ICAS病變的各種血流動力學特徵。該初步研究證實了基於臨床常規CTA進行CFD建模從而評價ICAS血流動力學特徵的可行性。在隨後的一項研究中，我們探索了CFD 模型反映的癥狀性ICAS 的血流動力學特徵對於相關患者卒中復發的預測價值。在32例具有70-99%管腔狹窄的癥狀性ICAS病例中，我們發現病變前後血流動力學參數的變化（包括壓力，剪切應變率及血流速度）可能預測患者的卒中復發風險。以上兩項研究證實，基於臨床常規CTA進行CFD模型重建從而定量評價癥狀性ICAS的血流動力學特徵具可行性，同時，這些血流動力學特徵可能對相關患者的卒中復發風險具有預測價值。 / 綜上所述，通過以上研究，我們進一步證實了亞洲人群和西方人群在顱內外動脈粥樣硬化的進程上存在的種族差異。更重要的是，我們的研究證實評價癥狀性ICAS病變的血流動力學特徵具有臨床意義。對於相關患者，採用以上研究中的兩種方法評價癥狀性ICAS的血流動力學特徵，可能對患者的危險分層具有潛在的指導意義。在未來的前瞻性大樣本研究中，上述方法對癥狀性ICAS患者卒中復發風險的預測價值需要進一步證實，以期促進相關的臨床決策，從而在長遠目標上降低相關患者的卒中復發風險。 / Intracranial atherosclerosis (ICAS) is of high prevalence in Asia, which is the leading cause for ischemic stroke and transient ischemic attack (TIA) in Asians, including the Chinese. However, it has not been fully appreciated or adequately investigated in relevant studies. In this thesis, we tried to delineate the hemodynamics and clinical implications of ICAS, by using several traditional and novel neuroimaging methods. / Previous studies had suggested differences in atherogenesis of intra- and extracranial arteries between Asians and Caucasians. To find further evidence, we performed a study to investigate asymptomatic ICAS and carotid atherosclerosis and their correlations in community-dwelling Chinese adults, by using transcranial Doppler and carotid duplex ultrasonography, respectively. For the 537 subjects studied, we found more advanced asymptomatic ICAS than carotid atherosclerosis, and there were no independent correlations between different stages of carotid atherosclerosis and presence of ICAS. The results suggested that atherogenesis of intracranial arteries might be a relatively independent course in systemic atherosclerosis in the Chinese population, which is unlike the case in Caucasians. By combing with previous findings, results of this study further supported the existence of racial differences in cervicocerebral atherogenesis between Asians and Caucasians. / According to previous studies, stroke patients with symptomatic ICAS are at high risk of recurrence. Currently, risk stratification of symptomatic ICAS are usually based on the percentage of luminal stenosis. However, the anatomic severity does not always proportionate to its hemodynamic significance, which may also impact on the risk of stroke recurrence in symptomatic ICAS. Therefore, we performed a series of studies as follows to evaluate the hemodynamics of symptomatic ICAS, and to assess its value in risk stratification of those with such lesions. / We first performed three studies based on time-of-flight (TOF) magnetic resonance angiography (MRA), to gauge the hemodynamic significance of symptomatic ICAS. Based on the signal contrast mechanism of TOF MRA, we developed a novel index, signal intensity ratio (SIR), representing changes of signal intensities (SI) across an ICAS on maximum intensity projections of TOF MRA, to quantify its hemodynamic significance: SIR = (mean post-stenotic SI - mean background SI) / (mean pre-stenotic SI - mean background SI). In a pilot study to establish the methodology of this index, we found it easy to perform, and highly reproducible between repetitive measurements by a same observer in 26 symptomatic ICASs. In a subsequent study, we also found this index to be substantially reproducible between measurements from two observers in 102 symptomatic ICAS lesions. In a third study, we tried to investigate the relationships between SIR of ICAS, other imaging features, and 1 year outcomes of patients with symptomatic ICAS. In the 36 patients enrolled, SIR was found to be significantly, linearly and negatively correlated to acute infarct volume on diffusion-weighted MR images. However, we did not establish a definite correlation between SIR and recurrent ischemic stroke, probably due to the small sample size. These studies suggested that SIR as evaluated on MRA was a feasible and reproducible method to gauge the hemodynamic and functional significance of ICAS. The role of this index in predicting further recurrent risks in those with symptomatic ICAS needs to be verified in future studies. / In another two studies, we applied the computational fluid dynamics (CFD) modeling technique in processing computed tomography angiography (CTA) images, to evaluate the hemodynamic characteristics of ICAS. In a pilot study, we tested the feasibility of CFD modeling of ICAS based on CTA images. Among 10 cases of symptomatic ICAS identified on CTA, the CTA source images of 9 were successfully processed to CFD models, which were able to quantitatively delineate the hemodynamic environment across the lesions. This pilot study demonstrated the feasibility of constructing CFD models of ICAS out of routinely obtained CTA source images. Then in a second study, we preliminarily explored the values of hemodynamics of ICAS revealed by such CFD models, in predicting recurrent risks in patients with symptomatic ICAS of 70-99% luminal stenosis. In the 32 cases evaluated, we found that changes of hemodynamic features across an ICAS lesion, including the changes of pressure, shear strain rate, and blood flow velocity, may be able to predict the recurrent risk in this patient subset. Therefore, it was feasible to model hemodynamics of symptomatic ICAS based on CTA images, and future prospective studies with larger sample sizes are warranted to further validate the role of CFD modeling in risk stratification of affected patients. / In conclusion, in this thesis we found further evidence to support the existence of racial differences in atherogenesis of cervicocerebral arteries between Caucasians and Asians. More importantly, we demonstrated that hemodynamics of symptomatic ICAS could be of clinical significance in characterization of such lesions. In patients with symptomatic ICAS, the two methods to evaluate hemodynamic features of ICAS as used in this thesis, may yield potential values in predicting the recurrent risk of these patients. In the near future, prospective studies enrolling more patients are warranted to further validate findings in this thesis, to embrace more reasonable and comprehensive evaluation of symptomatic ICAS, so as to facilitate decision making in clinical scenarios and patient selection in clinical studies, which in the long run may help reduce the risk of stroke recurrence in affected patients. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Leng, Xinyi. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 131-146). / Abstracts also in Chinese.

在世界範圍內，肝細胞癌(HCC)是其中一種惡性程度很高並且預後很差的疾病。和其他的癌症一樣，肝癌是一种基因疾病，基因異常的積累在肝癌的生成中扮演著重要的角色。近年來，第二代測序技術（NGS）的迅速發展顯現了前所未見的能力揭示癌癥基因組中分子的複雜性，這為癌癥的生物學，診斷和药物治療提供了一個嶄新的思路。 / 非酒精脂肪性肝炎（NASH）是一種與代謝有關的疾病，在發達國家地區例如美國，歐洲，日本和加拿大，這是其中一種越來越常見的HCC 的病因。在本論文的第一部份，三個NASH 相關的HCC 以及其配對的血DNA 進行了全基因組測序（WGS）。另外還有一個來源于這三個NASH 相關的HCC其中之一的細胞株也進行了全基因組測序。在全部樣品中，測序深度範圍介乎29.1X 到102.2X，序列覆蓋度均大於99%。結果顯示發現的新的單核苷酸變異（SNVs）數量介乎于6,898 至17,129，平均值是11,133。根據這些找到的SNV，隨機選出56 個體細胞SNV 進行Sanger 測序，其中92.9%可以被確認。基因突變譜顯示有頻繁的A:T>G:C 和C：G>A:T 體細胞突變，而C：G>T:A 則在CpG 位點頻繁出現。在眾多的非同義體細胞突變基因中，我們選擇了CTNNB1，PNLIP 和MLL2 這三個基因進行進一步研究，此三個基因都在多於一個病例中發現有突變。在額外的一組44 對NASH 相關HCC及50 對HBV 相關的HCC 的癌變組織和其臨近非腫瘤組織中，我們進一步對這三個基因和TP53 的編碼區域進行了測序，而TP53 是在HBV 相關HCC中被報導有高頻率突變的。在NASH 相關的HCC 中，這些基因都只在腫瘤組織中發現重複出現的錯義突變，在臨近的非腫瘤肝組織沒有發現有突變。在NASH 相關的HCC 中，CTNNB1 的突變率（36.4%）明顯高於在HBV相關的HCC 中的突變率（12.0%，P=0.007）。PNLIP 和MLL2 的突變只在NASH相關的HCC 中發現，其突變率分別為12.1%和7.1%，而在HBV 相關的HCC中，則沒有發現突變。然而，TP53 的突變率在NASH 相關的HCC 及HBV相關的HCC 中差別不明顯（P>0.1）。在功能性研究的實驗中，我们发现在HKCI-10（有PNLIP 突變D396N）細胞株中，PNILP 的活性比在正常肝細胞L02 細胞株（野生型PNLIP）中要低。在永生性肝細胞L02 細胞株中，CTNNB1的突變引起了TOPFLASH 活性的提高以及增加了細胞群落形成的能力。HKCI-10 是一條我們實驗室建立的NASH 相關的肝細胞癌細胞株，在HKCI-10細胞株中，抑制CTNNB1 表達引起了細胞生長和增殖的減少。另外，在DEN誘導肝癌的有代謝失衡的db/db 轉基因鼠中，發現了一個CTNNB1 的突變T41A。據報導，CTNNB1 發生的致癌突變會引起蛋白的穩定並且因此激活經典的Wnt/β-catenin 信號通路，從而引致特定基因的轉錄。對於CTNNB1中最常見的突變S45P(在發現的CTNNB1 突變中占31.3%)，我們做了ChIP-array 實驗，結果顯示，在HKCI-10（CTNNB1 有S45P 突變）中，CTNNB1比在Hep3B 中（野生型CTNNB1）有著更緊密的啟動子結合能力（P<0.001）。Gene ontology 分析結果表明，被S45P 富集的生物過程涉及有RNA 代謝調節，轉錄因子活性和凋亡。MYC，E2F1 和ZFX 被ChIP-PCR 證實是與CTNNB1突變子S45P 有著更緊密結合能力的轉錄因子。 / 在本論文的第二部份，爲了進一步闡明致癌性的CTNNB1 突變S45P在HCC 中的角色，我們研究了一個此前未在HCC 報導過的基因ZFX。ZFX是一個在脊椎動物中高度保守，屬於Zfy 家族的zinc finger 蛋白。有報導指出ZFX 對於胚胎和造血幹細胞的自我更新有著重要的作用。另外亦有文獻報導ZFX 在一系列人類癌癥病例中有過度表達，例如食道癌，胃癌，前列腺癌和神經膠質瘤，並且顯現出致癌基因的特性。在本研究中，qRT-PCR結果提示ZFX 在HCC 腫瘤中的表達明顯高於正常肝組織。ZFX 的表達在51.8%的HCC 腫瘤中明顯高於其配對的鄰近非腫瘤肝組織。功能性研究表明，在MTT 實驗中，細胞的生存力在ZFX 缺失的穩定克隆中明顯減弱（P<0.0001）。在細胞群落形成實驗中，ZFX 缺失的穩定克隆顯示出明顯減弱的群落生長能力（P<0.0001）。在單細胞克隆生成實驗中，ZFX 缺失的HCC穩定克隆展示出數量更少，體積更小的細胞群落。另外，ZFX 基因抑制或者cisplatin 單獨處理均顯示細胞生存力的抑制，其抑制效率分別是24.0%和30.9%。當ZFX 基因抑制合併cisplatin 處理時，細胞生存力的抑制效率顯著地提高至65.2%，這個結果提示ZFX 基因抑制和cisplatin 處理兩者有協同增效作用（P<0.0001）。ZFX 基因的缺失會引起兩個為人熟知的胚胎幹細胞（ESCs）標誌物SOX-2 和NANOG 表達的明顯降低。 / 綜上所述，通過進行全基因測序，本論文的研究結果為NASH 相關的HCC 分子層面上的異常提供了一個高解析度的視覺角度。在NASH 相關的HCC 中，一些可能對於肝細胞癌變有重要作用並且重複出現突變的基因被確定，例如CTNNB1 和PNLIP。CTNNB1 的突變體S45P 的其中一個下游目標基因ZFX，在HCC 中被證實有幹細胞和腫瘤啟動細胞特性。闡明在HCC發展過程中的分子改變以及機制，對於為肝癌病人探索新的治療手段有著重要意義。 / Hepatocellular Carcinoma (HCC) is one of the most malignant diseases worldwide with poor prognosis. Like other human cancers, HCC is a genetic disease, where accumulation of genetic aberration plays important role in the liver carcinogenesis. The rapid advances in Next Generation Sequencing (NGS) technology in recent years have allowed unprecedented ability to unravel the molecular complexity of the cancer genome, providing new insights into the cancer biology, diagnosis and therapeutic drug development. / Non-alcoholic steatohepatitis (NASH), which is related to metabolic disorder, is an increasing common etiological factor of HCC, especially in developed countries such as United States, Europe, Japan and Canada. In first part of this thesis, Whole Genome Sequencing (WGS) was performed on three NASH-associated HCCs and their matched lymphocytic DNA. A cell line developed from one of the three NASH-associated HCCs was also subjected to WGS. The sequencing depth ranged from 29.1X to 102.2X with the coverage >99% shown in all samples. Novel SNVs identified ranged from 6,898 to 17,129 with an average of 11,133. Based on the SNVs found, the validation rate was 92.9% in 56 randomly selected somatic SNVs by Sanger sequencing. Mutational spectrum showed frequent somatic substitution of A:T>G:C and C:G>A:T while C:G>T:A transition exhibited a predominant somatic mutation rate in CpG sites. Among the non-synonymous somatic mutated genes, we selected CTNNB1, PNLIP and MLL2 which were mutated in more than one tumor for further study. In additional cohort of 44 NASH-associated and 50 HBV-associated HCC tumors and adjacent non-tumoral tissues, further sequencing all the coding regions of these three genes and TP53, which has been reported to be highly mutated in HBV-associated HCCs, were carried out. In NASH-associated HCCs, all genes harboured recurrent missense mutations exclusive in tumor but none in adjacent ,non-tumoral liver. The prevalence of CTNNB1 mutations was significantly higher in NASH-associated HCCs (36.4%) when compared to HBV-associated HCCs (12.0%, P=0.007). Mutations of PNLIP and MLL2 were detected only in NASH-associated HCCs with rates of 12.1% and 7.1%, respectively, but none in HBV-associated HCCs. The mutation rate of TP53, however, did not differ much between NASH-associated and HBV-associated HCCs (P>0.1). In functional study, for PNLIP, a loss-of-function in PNLIP activity was found in HKCI-10 harbouring D396N mutation as compared to normal liver cell, L02 with wild-type PNLIP. We demonstrated that CTNNB1 mutants conferred elevated TOPFLASH activity and enhanced colony growth in an immortalized hepatocyte cell line L02. Knockdown of CTNNB1 in HKCI-10, which is a NASH-associated HCC in-house cell line, resulted in inhibition of cell growth and proliferation. Also, a CTNNB1 mutation (T41A) was found in DEN-induced liver cancer of db/db transgenic mouse with metabolic disorder. Since oncogenic mutations of CTNNB1 were reported to be contributed to the stabilization of the protein and hence activate the canonical Wnt/β-catenin signaling pathway, inducing transcription of specific gene sets. We performed ChIP-array focusing on the most common CTNNB1 S45P mutation (accounted for 31.3% of all detected CTNNB1 mutants) in NASH-associated HCCs, the result showed more intense promoter binding affinities in HKCI-10 with CTNNB1 S45P mutation than Hep3B with wild-type CTNNB1 (P<0.001). Gene ontology analysis revealed that S45P mutant enriched the process including RNA metabolic regulation, transcription factor activities and apoptosis. Furthermore, we found that CTNNB1 S45P mutant showed more profound binding affinity to the promoter regions of transcription factors MYC, E2F1 and ZFX by ChIP-PCR. / In the second part of the thesis, we aimed to further understand the role of oncogenic CTNNB1 S45P mutant in HCC. Zinc finger protein X-linked (ZFX) gene which is previously undescribed in HCC was studied. ZFX is a zinc finger protein of Zfy family that is highly conserved among vertebrates. It has been reported that ZFX is required for self-renewal of embryonic and hematopoietic stem cells. Also, ZFX is suggested to be overexpressed in a number of human cancers such as esophageal carcinoma, gastric cancer, prostate cancer and glioma, conferring oncogenic characteristics. In this study, qRT-PCR analysis showed a significant higher ZFX expression in HCC tumors compared to normal livers. 51.8% of HCC tumors showed significant up-regulations of ZFX when compared to paired adjacent non-tumoral livers. Functional studies showed significant reduction in in-vitro cell proliferation in HCC by MTT assay (P<0.0001) and colony formation ability by colony formation assay (P<0.0001) in ZFX-deficient stable clones. In single-cell clonogenic assay, ZFX-depleted HCC exhibited fewer and smaller colonies. In addition, while ZFX knockdown or cisplatin treatment alone showed an inhibitory effect on cell viability by 24.0% and 30.9%, respectively, the reduction efficiency of cell viability increased dramatically to 65.2% when combine ZFX-knockdown and cisplatin treatment, indicating a synergistic effect between them (P<0.0001). Also, significant reduced expressions of SOX-2 and NANOG, both well-known embryonic stem cells (ESCs) markers, were observed as a result of ZFX depletion. / In summary, findings from this thesis provided high-resolution insight into the molecular aberrations in NASH-associated HCCs by performing WGS. Recurrent mutated genes which may be of great importance in hepatocellular carcinogenesis induced by NASH were identified, such as CTNNB1 and PNLIP. One of the S45P CTNNB1 downstream targets ZFX was demonstrated to confer stemness and tumor-initiating cells (TICs) characteristics in HCC. The understanding of molecular changes and mechanisms underlying HCC development will thus facilitate the exploration of new therapeutic options in patients with this deadly disease. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chen, Jiawei. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 166-190). / Abstracts also in Chinese.

Speech-language pathologists are constantly trying to use the most efficient and effective assessments to obtain information about the phonetic inventory, speech sound errors, and phonological error patterns of children who are suspected of having a speech sound disorder. These assessments may involve a standardized measure of single words and/or sentences and a non standardized measure, such as a spontaneous speech sample. While research has shown both of these types of assessments to give clinicians information about a child's speech production abilities, the use of delayed imitation tasks, either words or sentences, has not been a widely studied topic and has produced conflicting results when researched. The purpose of the present study was to examine speech sound production abilities in children with a speech sound disorder in a single-word task, an imitated sentence task, and spontaneous speech sample to compare their results of speech sound errors, phonological error patterns, and time administration. The study used the Phonological and Articulatory Bilingual Assessment - English version (PABA-E, Gildersleeve-Neumann , 2008), a formal assessment for identifying children who may have a speech sound disorder. Three male children, between the ages of 4;0 and 5;4 (years;months), participated in this study. All participants were being treated by a speech-language pathologist for a diagnosed speech sound disorder and had hearing within normal limits. The results of the study showed that the majority of participants produced the highest number of speech sounds targeted within the imitated sentence task. Participants attempted and produced the least amount of speech sounds on their spontaneous speech sample. The assessment with the highest percentage of accurately produced consonants was the imitated sentence task. The majority of participants produced a higher number of error patterns in their single-word and imitated sentence task. In terms of efficiency and effectiveness, the imitated sentence task took the least amount of time to administer and transcribe.

This study has developed and evaluated two instruments, a questionnaire, the Grief Diagnostic Instrument, and an interview, the Grief Diagnostic Interview to detect and measure the extant state of grief in general practice patients. These instruments investigate grief from past, present and impending death and non-death related losses occurring directly to the patient, as well as caused indirectly through experiencing grief in sympathy with the grief of others. The unique feature of these instruments is that they investigate grief from all losses rather than merely a single loss. The questionnaire was demonstrated to be a concise, valid, reliable and sensitive measure, and acceptable to general practice patients. It is suitable for epidemiological studies to detect a broad range of losses and to investigate the prevalence and severity of grief in general practice patients. It is also suitable for comparing the course and severity of grief between losses and identifying commonalities and differences. The interview was found to be an acceptable and valid instrument for undertaking clinical studies. Suggestions for further evaluation of the instruments, and for their uses in grief research and as clinical tools have been proposed. The findings that 2/3 of the general practice population studied were experiencing loss and that over 1/4 of all subjects were suffering moderate or severe grief, demonstrate grief to be a previously unrecognised significant mental health issue for general practice. The most frequently encountered loss categories were 'quality of life', 'death', 'separation' and 'job'. Non-death related losses accounted for 4/5 of all the losses detected. The lack of recognition of grief by subjects was demonstrated, particularly relating to migration and relocation. The hypothesis that loss and grief are under diagnosed and under treated in general practice is supported. This indicates the need for a new paradigm of loss and grief in general practice and for large-scale studies to investigate grief in general practice patients and the detection rate by general practitioners. / Thesis (M.D.)--Department of General Practice, Department of Public Health, 2003.

<p>As machines are increasingly used to fulfill even more needs of mankind, the dependence upon those machines increase. To prevent catastrophic failure and to facilitate maintenance a diagnostic system can be used. A diagnostic system supervises the system and can alarm the operator when a fault has occurred, and possibly determine what the cause may be. One architecture of a diagnostic system is a number of tests run by an on-board computer checking certain combinations of sensor values and control signals chosen in advance. To design these tests is a difficult task, which leads to the desire to automate the test construction. A part of this task can be performed using structural methods.</p><p>In this thesis model based diagnosis is considered. This means that a formal mathematical model is used. The models typically consist of a number of equations describing the behavior of the system. In structural methods it is only considered if a variable exists in an equation or not. The goal of this master thesis project has been to apply structural methods to RODON models. RODON is a software diagnostics tool brought to market by Sörman Information & Media, which can perform various diagnostic-related tasks based on a single model. This model is defined in an object oriented fashion using a Modelica-like language called Rodelica. A prototype implementation of a structural algorithm plug-in has been developed and integrated into RODON. An additional part of the project has been to investigate further possible uses of structural algorithms in RODON, apart from diagnostic test construction. This has been performed as a series of interviews with Sörman and university employees.</p><p>The work performed in this thesis has shown that it is possible to apply structural methods to RODON models. It has also shown that even a prototype implementation can handle quite large systems. Some problems have been found as well, most notably in extracting a structural model from a RODON model. A consequence is that the developed structural plug-in only works for a subset of RODON models. It might be possible to deal with these problems if more time would be spent on the task. Finally, the interview survey revealed other possible uses of structural methods in RODON, including optimal sensor placement analysis and isolability and detectability analysis.</p>

<p>Diagnosis is the task of finding faults or malfunctioning components in a technical system, e.g a car. When doing diagnosis on cars with combustion engines, a computer program can be used. The computer program, also called diagnosis system, needs information about the car. This information could be data sheets of all the electronic components in the car. It could also be a description of how the engine behaves in a nominal and a non-nominal case. This information is contained in a model of the engine. RODON, a diagnostic tool developed by Sörman Information and Media AB, uses models of systems for conflict detection diagnosis. RODON needs fault models of the components to do diagnosis. The diagnosis system is then used in workshops, factories, or other places where cars need to be surveyed.</p><p>In this thesis, a Simulink model of the nominal behaviour of a combustion engine is given. The problem is how to make use of the model as well as the diagnostic tool RODON for combustion engine diagnosis. To solve this, the Simulink model is translated into a RODON model. Translating a Simulink model into a RODON model requires a new library in RODON. The library developed in this thesis is called AdvancedBlocks library.</p><p>The Simulink model describes the nominal behaviour of a combustion engine but for diagnosis with RODON, fault models are needed as well. Several types of faults that can occur in an engine have been studied and fault models have been implemented in RODON. The conclusion is that diagnosis in RODON with a translated engine model is possible.</p>

Graduation date: 2006

In unmanned aerial systems an autopilot controls the vehicle without human interference. Modern autopilots use an inertial navigation system, GPS, magnetometers and barometers to estimate the orientation, position, and velocity of the aircraft. In order to make correct decisions the autopilot must rely on correct information from the sensors. Fault diagnosis can be used to detect possible faults in the technical system when they occur. One way to perform fault diagnosis is model based diagnosis, where observations of the system are compared with a mathematical model of the system. Model based diagnosis is a common technique in many technical applications since it does not require any additional hardware. Another way to perform fault diagnosis is hardware diagnosis, which can be performed if there exists hardware redundancy, i.e. a set of identical sensors measuring the same quantity in the system. The main contribution of this master thesis is a model based diagnosis system for a fixed wing UAV autopilot. The diagnosis system can detect faults in all sensors on the autopilot and isolate faults in vital sensors as the GPS, magnetometer, and barometers. This thesis also provides a hardware diagnosis system based on the redundancy obtained with three autopilots on a single airframe. The use of several autopilots introduces hardware redundancy in the system, since every autopilot has its own set of sensors. The hardware diagnosis system handles faults in the sensors and actuators on the autopilots with full isolability, but demands additional hardware in the UAV.

This paper proposes a multitier multilevel TSV diagnosis scheme for 3D ICs to achieve interconnect reliability and yield with targets of interconnect faults under stuck-at and open fault models. This scheme takes advantage of previous work of IEEE 1500 compatible interconnect test and diagnosis methods, and further develop a TSV detection and diagnosis method for 3D circuits. An interconnect diagnosis scheme based on the oscillation ring (OR) test methodology for 3D systems-on-chip (SOC) designs with heterogeneous cores is proposed. The large number of test rings in the SOC design, however, significantly complicates the interconnect diagnosis problem. In this paper, the diagnosability of an interconnect structure is first analyzed then a fast diagnosability checking algorithm and an efficient diagnosis ring generation algorithm are proposed. It is shown in this paper that the both vertical and horizontal ring generation algorithm achieves the maximum detectability for any interconnect.

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Supervisor: Supervisor: Diana M. DiNitto. Vita. Includes bibliographical references. Also available from UMI.