published_or_final_version / Medicine / Master / Doctor of Medicine

　　　Obstructive sleep apnoea (OSA) is the most common sleep-related breathing disorder and is associated with a range of adverse physical, social and psychological outcomes that affect quality of life (QoL). Two systematic reviews of the literature (part of this thesis work) found there is conflicting evidence of how different mandibular advancement device (MAD) designs features may affect clinical and subjective OSA outcomes in certain patients. Therefore, a randomized cross-over trial was conducted. Firstly, the correlation between clinical OSA indicators and QOL was explored among patients referred for OSA treatment using MADs. In addition, associations of OSA risk factors, dental status and demographic variables with clinical OSA indicators and QoL indices were determined. Secondly, the efficacy of two different MADs in the treatment of adult OSA patients was assessed and compared. Thirdly, the efficacy of the two MADs in the treatment of adult OSA patients from the subjective perspective of their bed partners was determined. 　　　A consecutive sample of 45 adult OSA patients referred from Queen Mary Hospital Sleep Centre to the Prince Philip Dental Hospital for oral appliance therapy was recruited and treated with a monobloc MAD and a twinblock MADs for a period of 3 months per MAD (cross-over randomised trial). Changes in clinical OSA outcomes were assessed by polysomnography (PSG) and changes in subjective outcomes by the disease-specific Sleep Apnoea Quality of Life Index (SAQLI) questionnaire, the Functional Outcome of Sleep Questionnaire (FOSQ) and Epworth Sleepiness Scale (ESS). Patient compliance, side-effects and MAD preference, as well as MAD treatment impact on the patients’ bed partner was also assessed. At baseline, some clinical OSA indicators, subjective QoL and certain OSA risk factors were significantly correlated (p<0.05). There were significant variations in clinical OSA indicators and subjective QoL indices with respect to certain risk factors (p<0.05), demographic variables (p<0.05) and dental status (p<0.01). 　　　There was a significant difference in favour of the monobloc MAD in terms of improving the apnoea-hypopnoea index (AHI) (p<0.05) and oxygen desaturation index (ODI) (p<0.01). Significantly more patients achieved clinical treatment success with the monobloc compared to the twinblock (p<0.05). Both MADs were efficacious in improving patients’ SAQLI score (p<0.01), FOSQ score (p<0.01) and ESS score (p<0.01). Significantly more patients achieved QoL treatment success with the monobloc (p<0.05) compared to the twinblock. More patients were ‘very satisfied’ with the monobloc treatment (p<0.05) and 63% preferred it to the twinblock. 　　　 No significant difference was found between patients’ and bed partners perceptions of symptom improvement post treatment, however, the monobloc resulted in a significant reduction in bed partners’ daytime sleepiness (p<0.01) and allowed significantly more co-sleeping at night (p<0.05). 　　　 　　　This study concluded that the monobloc is superior in improving subjective QoL and clinical OSA indicators. The monobloc was the preferred MAD and patients were more satisfied with it; bed partners rated this MAD as superior in improving their own daytime sleepiness and co-sleeping. / published_or_final_version / Dentistry / Doctoral / Doctor of Philosophy

With the recent advances in the knowledge of hepato-carcinogenesis, there has been encouraging development in the molecular targeted therapy for patients with advanced hepatocellular carcinoma (HCC). Sorafenib, an anti-angiogenic multi-targeted receptor tyrosine kinase inhibitor, has become the standard of treatment in HCC patients with Child-Pugh A cirrhosis. Nevertheless, the benefits and safety profile of sorafenib in the majority of the unselected advanced HCC patients and other patient subgroups are still unclear. More importantly, the survival benefit associated with sorafenib use is generally modest in Asian population. Therefore, an unmet medical need remains for more effective therapeutic agents. This thesis studied the impact of molecular targeted therapy in the treatment of advanced HCC patients and it contains 10 original studies divided into six sections. The first section provides a concise overview of the epidemiology, risk factors, and current treatment options for HCC patients. Also, the molecular biology and opportunity for the use of targeted therapy in advanced HCC were discussed. The second section is about a new prognostic score system that we developed — Advanced Liver Cancer Prognostic System (ALCPS). Our study results showed that ALCPS was able to objectively estimate the 3-month survival probability of advanced HCC patients and thus could enhance patient selection for targeted therapy or clinical trials. The third section is about the use of sorafenib in the treatment of advanced HCC patients. The results of our single centre phase II study showed that sorafenib had good efficacy and acceptable tolerability in treating advanced HCC patients in hepatitis B endemic area. Furthermore, our retrospective study results confirmed that the overall survival benefits and overall treatment-related adverse events of sorafenib were comparable in elderly and young advanced HCC patients. More importantly, our other retrospective analysis showed that Child-Pugh (CP) A and CP B patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CP B patients, most benefits were observed in patients with score 7. Nevertheless, CP B patients were more susceptible to developing cirrhotic complications. Last but not least, our study also demonstrated that drop in serum alpha-fetoprotein level > 20% in the first 6 weeks of sorafenib treatment was a useful early surrogate endpoint for evaluating antitumor response and survival benefits. All these results are instrumental in guiding future rational use of sorafenib in advanced HCC population. The fourth section is about the role of targeted therapies in treating sorafenib-refractory advanced HCC patients. In a single arm phase II study, we showed that bevacizumab and erlotinib combination was not effective in treating advanced HCC patients who had failed prior sorafenib treatment. The fifth section of the thesis comprises results of four early phase novel clinical trials that may potentially improve the therapeutic outcomes in advanced HCC patients. First, our phase I/II study demonstrated that another anti-angiogenic agent — PTK787 had encouraging and possible synergistic activity when combined with intravenous doxorubicin in treating advanced HCC patients. Second, our multi-center phase II study results demonstrated promising activity with good tolerability of a novel combination — sorafenib together with capecitabine and oxaliplatin (SECOX) in the treatment of advanced HCC patients. Third, in a phase I study, we showed that pazopanib, a novel anti-angiogenic agent, had a manageable safety profile and preliminary activity in advanced HCC patients. Moreover, pazopanib reduced tumor vessel leakage, as shown by contrast-enhanced magnetic resonance imaging indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. Lastly, in another phase I study, we evaluated safety, pharmacological parameters, and potential antitumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. Our results illustrated that arginine depletion in humans can be achieved safely with peg-rhAgr1 in a dose-response manner and peg-rhArg1 had manageable safety profile and preliminary evidence of activity in advanced HCC patients. In the last section, the future perspectives about the use of molecular targeted therapy in the treatment of advanced HCC patients were discussed. / published_or_final_version / Medicine / Master / Doctor of Medicine

Ischemic heart disease (IHD) is the most common cause of death around the world. The underlying cause of IHD is myocardial ischemia as a result of progressive narrowing of coronary arteries due to atherosclerosis with potential thrombotic complications mediated by platelets. In addition to the role in hemostasis, platelets are increasingly recognized as an important mediator in this atherothrombotic disease. Basic management of IHD lies on medical therapy and coronary revascularization procedures. Percutaneous coronary intervention (PCI) is a commonly used revascularization procedure in the treatment of IHD especially for relief and reduction of symptoms. On the other hand, antiplatelet therapy is often administrated to patients undergoing PCI in an attempt to prevent major adverse cardiac events (MACE) following the procedures. However not all patients respond to the same degree of the antiplatelet therapy and some still develop MACE or stent thrombosis in the presence of the treatment with antiplatelet drugs. Recently a flow cytometric-based assay has been developed to monitor the effect of the antiplatelet drug, particularly the P2Y12 receptor antagonist, in patients treated with this kind of drug. This assay measures the activity of platelets as platelet reactivity index (PRI) based on the phosphorylation state of an intracellular platelet protein called vasodilator stimulated phosphoprotein (VASP). The measured value of PRI is inversely related to the response of patient to the antiplatelet drug. In this study, the response of patients to the P2Y12 receptor antagonist Clopidogrel was investigated following PCI. The PRI of patients was found to be significantly lower than normal subjects without taking this drug, indicating the therapeutic effect of this drug on the patients. However nearly one-third of patients (17 out of 59) studied were found to be non-responsive to clopidogrel treatment based on a cut-off established in this study for classifying patients into responders or non-responders. Furthermore, significant difference between the two types of stents used in PCI procedure, namely bare metal stent (BMS) and drug eluting stent (DES), was observed in the study. Patients receiving DES had nearly three times higher percentage of being non-responsive to clopidogrel than the BMS counterpart (45% vs. 16%, p<0.028). This study provides evidence that DES may be implicated in the non-responsiveness or drug resistance of clopidogrel in patient undergoing PCI. / published_or_final_version / Pathology / Master / Master of Medical Sciences

According to the World Health Organization, life-threatening infectious diseases, even in remote and vulnerable locations, can be minimised through immunisation. Vaccines interact with the immune system to produce an immune response similar to that produced by natural infection. However, about 10% of the population avoid vaccination and other needle procedures because of “needle fear”. Because of the prevalence of injection pain and more concern about the adequacy of pain management, and with the steadily increasing number of recommended childhood immunisation, we identified a need for evidence-based guidelines on pain management to be developed in our local setting through translational nursing practice. After a critical appraisal of randomised controlled trials and systematic reviews, it is highly recommended that “topical anaesthetics are effective in reducing vaccination pain” (Grade A recommendation, based on level I evidence by SIGN). In order to facilitate practice from evidence, the implementation potential, transferability, feasibility and cost-benefit ratio - has been examined, and an evidence-based guideline has been developed simultaneously for the new practice. With the identification of stakeholders and the development of a communication plan, potential users of the guideline and pilot testing are discussed. Innovation outcomes and their effectiveness are examined and explored. It is expected that, through this translational nursing practice, vaccination induced pain and distress among healthy children can be managed well, according to the best evidence and up-to-date recommendations. / published_or_final_version / Nursing Studies / Master / Master of Nursing

Hypertension is one of the most common chronic medical problems around the world and it is an important public health challenge. Hypertension can lead to cerebrovascular disease, ischemic heart disease, renal failure, myocardial infraction or stroke. According to the statistics from the Census and Statistics Department, it revealed that the ratio of people with known hypertension was about 11.0% in 2011/12. Exposure to stress has been evidenced by different studies as a risk factor for hypertension. Stress included occupational stress, stressful events from the social environment, and low socioeconomic status. Progressive muscle relaxation therapy plays an important role in controlling hypertension apart from the traditional management such as the use of medication or diet control. Objective The objectives of the translational nursing research are to develop an evidence- based guidelines for hypertension patients to maintain an optimal blood pressure level. Methods 5 electronic databases including Medline (Ovid SP) (1950–Aug week 4 2012), Pubmed, ISI web of knowledge (1956- Aug 2012) , The PsycINFO database (1980- Aug 2012) and Cochrane Library (1950- Aug 2012) are used for systematic search of literature. Five suitable are identified while three studies are randomized controlled trials and two are quasi-experimental design. The 5 studies were summarized and a table of evidence is formed. The Scottish Intercollegiate Guidelines Network (SIGN) checklist was used for critical appraisal. The findings indicate that progressive muscle relaxation exercise has significant effects in maintaining optimal blood pressure for hypertension patients. In order to implement the evidence- based protocol, an implementation plan is developed. A pilot test is implemented before the full- scale implementation of innovation. An evaluation plan is developed in order to assess the effectiveness of the program. Conclusion There are all together 8 recommendations are made in this protocol which based on the 5 chosen studies. According to SIGN’s “Grades of Recommendation”, all 8 recommendations in the protocol are graded as “A”. The innovation is proposed to implemented at an outpatient clinic for the hypertension patients. The progressive muscle relaxation exercise would be last for 6 weeks, which is effective in maintaining optimal blood pressure in hypertension patients. In the views of the transferability of the evidences, the feasibility and the cost-effectiveness of the program, the proposed program is considered as rewarding to carry out at the outpatient clinic in Hong Kong. / published_or_final_version / Nursing Studies / Master / Master of Nursing

Hyperprolactinemia (hyperPRL) is a highly prevalent adverse side effect in antipsychotic therapy as most antipsychotic drugs are dopamine D2 receptor antagonists. Peony-Glycyrrhiza Decoction (PGD, 芍藥甘草湯) is a classic Chinese herbal formula initially used to treat muscle pain and spasm. Our pilot clinical studies have confirmed the effectiveness of PGD in alleviating antipsychotic-induced hyperPRL in patients with schizophrenia. In the present study, we further examined the effects of PGD, its individual herbal preparations and major compounds in suppressing prolactin (PRL) hyperactivity in in vitro and in vivo models and underlying mechanisms. PGD treatment significantly suppressed PRL secretion in MMQ cells, an exemplary model of hyperPRL that is derived from pituitary adenoma cells. PGD also suppressed PRL synthesis of MMQ cells in a dose-dependent manner; however, these suppressive effects were completely abolished by pretreatment with 10 μM haloperidol, a dopamine D2 receptor antagonist. PGD did not affect hyperactive PRL in GH3 cells that lack the D2 receptor expression, but PGD significantly increased the expressions of the D2 receptor and dopamine transporters (DAT) in PC12 cells. In the rat model of hyperPRL produced by repeated injection with the dopamine blocker metoclopramide (MCP), PGD (5 - 10 g/kg daily) treatment for 14 days significantly reduced elevated serum PRL and the reduced magnitude was similar to that of 0.6 mg/kg bromocriptine (BMT), a dopamine D2 receptor agonist used for treating hyperPRL. Both PGD and BMT did not alter serum estradiol, but PGD reversed MCP-induced decreased serum progesterone to control level, whereas BMT did not. Similar to BMT, PGD treatment displayed a great effect in reversing the MCP-induced reduction of the expressions of D2 receptor, DAT and tyrosine hydroxylase in both the pituitary and the hypothalamus, in particular the arcuate nucleus, but both had least effects on the expressions of PRL in the pituitary and hypothalamus. The anti-hyperPRL effects of individual herbal preparation and major compounds of PGD were further examined in cultured cells. The three herbal preparations, Paeoniae Radix (PR) alone, Glycyrrhiza Radix (GR) alone and the pooled PR and GR individual preparation (PR+GR), and the three major constituents 18β-glycyrrhetinic acid (GA), liquiritigenin (LQ) and paeoniflorin (PF), were tested. All these preparations and constituents displayed significant effects in suppressing PRL hyperactivity and enhancing the expressions of dopamine mediators. However, PR had the most robust anti-hyperPRL effects compared to PGD and other preparations and constituents. The present study provides experimental evidence confirming the clinical effects of PGD in suppressing antipsychotic-associated hyperPRL. Not only D2 receptor is involved in the anti-hyperPRL effect of PGD, it is also associated with the modulation of other dopamine mediators and sex hormones. The finding that the magnitudes of the anti-hyperPRL effects of PGD and of combined PR and GR are similar suggests that boiling the herbs together or or separately shows the same effects. Additionally, PR preparation appears to be more efficacious in reducing hyperPRL compared to GR preparation which deserves to be further investigated. / published_or_final_version / Chinese Medicine / Doctoral / Doctor of Philosophy

Acute Myeloid Leukaemia (AML) is a disease normally found in elderly patients, with the median age of presentation at about 68 years. At this age, many of the patients are frail and unlikely to respond well to intensive chemotherapy treatments. Conventional chemotherapy eradicates the proliferating leukaemic progenitors while leaving the quiescent leukaemic stem cells undisturbed. These quiescent LSCs are able to then bring about leukaemic relapse. Fumagillin is a natural metabolite from Asperigillus fumigatus that is generally used as an anti-microbial agent but it is also known to bind to intracellular MetAP-II and inhibit endothelial cell growth. Many cancers are found to have an over expression of MetAP-II. In the past, MetAP-II inhibitors have been tested and shown success in angiogenesis inhibition and tumor reduction. The aim of this study is to observe whether methionine aminopeptidase-2 inhibitors can be used in the treatment of acute myeloid leukemia. The investigation included a dose response comparison of various AML cell lines to fumagillin treatment, cell proliferation assay, a colony forming unit assay, and cell cycle analysis of KG-1 cells following three days of fumagillin treatment. I have determined that fumagillin does indeed decrease the cellular proliferation of KG-1 in vivo and at 10μM, prevents colony formation in methylcellulose plating. There is an increase in cells found in the sub-G1 phase with fumagillin treatment, as analyzed by flow cytometry. It is interpolated that fumagillin treatment increases AML cell apoptosis, in addition to hindering its ability to grow in culture. / published_or_final_version / Medicine / Master / Master of Medical Sciences

Objective The consistent emerging of multidrug-resistant tuberculosis (MDR-TB) cases are increasingly becoming a major threat and challenge in global TB control, especially in some resource-limited settings like India, China, South Africa. Currently there is no widely acknowledged treatment strategy for MDR-TB. Effectiveness and of current DOTS-Plus strategy is remaining controversial. This systematic review aims to investigate treatment outcomes for MDR-TB under DOTS-Plus and potential factors associated with poor outcome (death, default and failure). Methodology The literatures were searched in Pubmed, Medline, the Cochrane library, Essential Evidence Plus, EMBASE and CNKI. Some manual search articles were also added and 164 literatures in total were founded related to treatment outcomes for multidrug resistant patients under DOTS-Plus. After basically screening and carefully full-text reading, nine studies meeting the inclusion criteria were included. A total of 3358 participants from 8 high MDR-TB countries were investigated. Result Baseline characters were varied across these nine studies, including HIV prevalence (0-1.6%), MDR-TB prevalence (0-4.7%), previous treatment history (without TB treatment, with TB treatment but not under directly observed therapy, short courses (DOTS) and with TB treatment under DOTS), and male/female ratio (54%-86.5%). All studies reported a successful outcome rate (cure and complete) higher than 60 percent, and three of the studies reported higher than 70 percent, which are comparatively high in MDR-TB treatment. Factors associated with poor outcomes that reported by these studies were including alcohol use/ abuse, homelessness, unemployment, imprisonment, BMI, cavitary and bilateral disease, missing doses, and resistant to some second-line drugs. Conclusion In sum, the overall treatment outcomes from these nine studies under DOTS-Plus were acceptable, and most of them were satisfactory. Nevertheless, in consideration of potential bias arising from these cohort analyses, conclusions should be drawn carefully. Several major challenges restrict low- and middle- income countries from implementing DOTS-Plus, which put high command on TB infrastructure, policy commitment, human resources and financial support. Further effort could be put on systematical review and meta-analysis on cost-effectiveness of DOTS-Plus programs. In China, policy makers should pay attention to arrive at national and provincial guidelines of MDR-TB treatment under DOTS-Plus. / published_or_final_version / Public Health / Master / Master of Public Health

Introduction Geriatric depression is one of the major public health issues around the world. Geriatric depression is often being misinterpreted as a normal aspect of aging process, but it is indeed a complex psychological problem that would result in significant increases in DALYs. With effective treatments, depressive symptoms and signs can be reduced. Nevertheless, pharmacological intervention is often used as the first-line treatment for geriatric depression. In recent years, different types of non-pharmacological intervention have been getting more attention in terms of theirs effectiveness in treating geriatric depression. Objectives Primary objective is to determine whether two categories of non-pharmacological intervention (physical activity and reminiscence therapy) are effective in relieving depression in elderly that are 60 years old or older. The other objectives are to examine enduring effects of physical activity and reminiscence therapy, and compare the effectiveness of reminiscence therapy and physical activity in alleviating depressive symptoms in elderly compared with no intervention and/or other intervention. Methods Relevant studies published between the year of 2000 and 2013 were searched and identified through several electronic databases, including the Cochrane Library, PubMed, Medline, PsycINFO and Google Scholar, with a combination of keywords. All randomized controlled trials that examine physical activity and reminiscence therapy on elderly that are 60 years old or older, being diagnosed or indicated as suffering from depression were included. The methodological quality of each study was assessed. The outcome measure of this review is the depression symptom level. Main Result A total of 12 randomized controlled trials met the inclusion criteria, in which seven were about physical activity and five of them were about reminiscence therapy. Significant immediate reduction in depressive symptoms was found in five out of seven physical activity studies and in four out of five reminiscence studies. Three and two studies respectively on physical activity and reminiscence therapy had assessed the effect at follow-up and looked at the lasting effect. In two physical activity studies that have assessed the short-term effect beyond the completion of intervention, incongruent findings were found. Only one physical activity study has examined the long-term effect and it reported significant positive result. On the other hand, there were two reminiscence therapy studies assessing the short-term effect on depressive symptoms. These two studies reported significant improvement in depressive symptoms. Since there were few studies reporting the medium and long-term effect of physical activity and reminiscence therapy, no conclusion can be made on their enduring effect of reducing depressive symptoms. Conclusions Physical activity and reminiscence therapy appear to be effective non-pharmacological interventions for relieving depressive symptoms in elderly. They may complement pharmacological intervention and/or may offer alternative treatment option for elderly with depression. However, the mode, intensity, duration, type, format of physical activity and reminiscence therapy on depressive symptoms in elderly remain unclear. Further testing is need before these interventions can be routinely used to alleviate depressive symptoms in elderly with depression. / published_or_final_version / Public Health / Master / Master of Public Health