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

Poor adherence to continuous positive airway pressure (CPAP) treatment in patients with obstructive sleep apnoea (OSA) limits its therapeutic effectiveness and has a major impact on clinical outcomes. Effective education programme is important to enhance CPAP use. However, existing education programmes are either manpower or resource demanding and may not be feasible in clinical practice. Moreover, the Self-Efficacy Measure for Sleep Apnoea (SEMSA) has been widely adopted for assessing adherence-related cognitions on CPAP therapy in OSA patients, but it was not available for Chinese. The aims of this thesis are: (i) to perform linguistic and psychometric evaluation of a Chinese version of SEMSA (SEMSA-C); (ii) to examine the efficacy of brief motivational enhancement education programme in addition to standard care versus standard care only on improving adherence to CPAP treatment in patients with OSA. The SEMSA-C was obtained after the standard forward-backward translation process. A randomised controlled trial was then conducted on newly diagnosed OSA patients. Patients in the control group received standard care (SC) comprising advice on the importance of CPAP therapy and its care while those in the intervention group received SC plus motivational enhancement education programme (ME). ME focused to enhance subjects’ knowledge, motivation and self-efficacy to use CPAP, comprising one 45-minute session on the day after CPAP titration and one 10-minute telephone follow-up shortly after commencing CPAP treatment. Epworth Sleepiness Scale (ESS), SEMSA-C, and quality of life were assessed. CPAP usage data were downloaded at the completion of this 3-month study. The primary outcome was the CPAP adherence. Furthermore, 21 patients were randomly sampled at baseline and completed the SEMSA-C at one week. 100 patients (Men : Women, 84 : 16) with OSA indicated for CPAP treatment were recruited, with an average age of 52±10 years, and apnoea hypopnoea index (AHI) of 36.2±22 events/hour. Factor analysis of SEMSA-C identified three factors: risk perception, outcome expectancies and treatment self-efficacy. Their corresponding internal consistency was high with Cronbach’s alpha >0.88, which were larger than all correlations between subscales (Range: 0.14 to 0.58). The correlations between items and their hypothesized subscale (Range: 0.58 to 0.85) were generally higher than the correlations between items and their competing subscales (Range: -0.10 to 0.58). One-week test-retest intra-class correlation ranged from 0.70 to 0.82. CPAP adherence was associated with outcome expectancies and treatment self-efficacy at 3-month assessment. Furthermore, SEMSA-C demonstrated an improvement in self-efficacy (standardised response mean = 0.33, p = .044) but no significant changes were observed in the other two factors, after CPAP use. The 100 patients were followed for 3 months. The interventional effects maintained during the 3-month study period. There were a better CPAP use [higher daily CPAP usage of 2 hours/day (Cohen d = 1.33, p < .001), four-fold the number of subjects using CPAP for ≥ 70% of days with ≥ 4 hours per day (p < 0.001)], and greater improvements in ESS by 2.2 (p = 0.001) and treatment self-efficacy by 0.2 (p = 0.012) in the intervention group, relative to the control group. The traditional Chinese SEMSA-C possesses satisfactory psychometric properties. It is a reliable and responsive instrument to measure perceived risks, outcome expectancies and treatment self-efficacy in Chinese patients with OSA. Moreover, the newly developed brief motivational enhancement education programme in addition to standard care is effective in improving adherence to CPAP treatment, treatment self-efficacy and daytime sleepiness. / published_or_final_version / Nursing Studies / Doctoral / Doctor of Nursing

published_or_final_version / Nursing Studies / Master / Master of Nursing

published_or_final_version / Dentistry / Master / Master of Orthodontics

Obstructive Sleep Apnea (OSA) is becoming an increasingly prevalent health problem, affecting 4% of men and 2% of women in North America. OSA is associated with many debilitating side-effects and co-morbidities; the most common being excessive daytime sleepiness (EDS), which effects the majority of OSA sufferers. EDS is negatively associated with physical activity (PA) and exercise. As a result, EDS may decrease the levels of PA performed by OSA patients. Previous research has revealed that the OSA population engages in less physical activity than the average healthy population. Studies show that CPAP treatment positively impacts EDS, and therefore; may impact PA. The primary purpose of this study was to objectively measure OSA patients' PA levels prior to CPAP treatment and 8 weeks after treatment initiation to assess whether CPAP treatment' impacts PA levels.Actigraph GT 1 M measures PA was assessed at baseline (prior to CPAP) and 8-weeks after. initiation of CPAP treatment. At each time frame, cardiovascular., blood data, body composition, and maximal cycle ergometer exercise measures were obtained. Also, subjective questionnaires, 1 reflective of sleep apnea and 1 regarding PA, were completed by the subjects.Six male subjects with severe OSA (AHI = 41.2 ± 28.4 events/hr) started and completed the study. No significant changes occurred in PA, represented as steps/day nor mean activity counts/day, throughout the 8 weeks of CPAP treatment. Significant changes were found in diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, and Epworth sleepiness scale scores. No significant changes occurred in any other body composition, heart rate, systolic blood pressure, triglycerides, and blood glucose. Exercise parameters, total test time, peak Watts, and V02max trended toward an increase and maximal heart rate and blood pressure toward a decrease, but none changed significantly.In conclusion, these results demonstrated that 8 weeks of CPAP treatment was not successful in increasing PA levels of severe OSA patients. The OSA subjects were categorized as sedentary according to their steps/day. Compliance to CPAP could have been an issue with subjects' average nightly usage ranging from 1.85 – 6.6hours/night. Consequently, more research regarding OSA patients PA habits and CPAP treatments effects on PA should be investigated. / School of Physical Education, Sport, and Exercise Science

Background. Obstructive Sleep Apnoea (OSA) is associated with an increase in nocturnal gastro-oesophageal reflux (nocturnalGOR) events and symptoms, however the mechanism for this remains undefined. Treatment of OSA with continuous positive airway pressure (CPAP) has been shown to reduce nocturnalGOR in individuals with OSA however the reasons for this reduction are not clear. The combination of OSA and nocturnalGOR could be particularly problematic for individuals who have had a lung transplant in whom Bronchiolitis Obliterans Syndrome (BOS) limits survival. It is thought that GOR plays a role in the development of BOS in these individuals. Methods and Results. Five interrelated studies were undertaken. The first two studies sought to determine and compare the prevalence and risk factors of nocturnalGOR in OSA patients with the general population. To do this, a GOR questionnaire was completed by 2,042 members of the general community as part of the Busselton Health Survey and by 1,116 patients with polysomnography-diagnosed OSA. Risk of OSA in the general population was determined using a standardised sleep questionnaire. 137 of the OSA patients completed the questionnaire before and after treatment with CPAP. The prevalence of nocturnalGOR symptoms reported more than once a week (frequent symptoms) was greater in OSA patients (10.1%) than the general population (5.8%) (p<0.001), in individuals from the general population at high (11.2%) than low risk of OSA (4.5%) (p<0.001) and in patients with severe (14.7%) than mild OSA (5.2%) (p<0.001). Treatment of OSA with CPAP decreased the prevalence of frequent nocturnalGOR from 9.0% to 3.8% (p=0.04). In the general population, high risk of OSA was independently associated with a 2.4-fold increased risk of frequent ABSTRACT vi nocturnalGOR symptoms than low risk. In the OSA group, disease severity was independently associated with nocturnalGOR symptoms, with an adjusted odds ratio of 1.7 for frequent nocturnalGOR symptoms.

阻塞性睡眠呼吸暂停（OSA）是一种常见的睡眠障碍，睡眠过程中反复发作的气道阻塞，导致间歇性低氧血症。OSA 中的間歇性缺氧（IH）一直被视為一個主要致病因素。會影響神經認知功能，包括記憶障礙，遲鈍的反應和其它。以前的研究提示氧化应激产物（ROS）和细胞凋亡是間歇性缺氧引起的认知功能障碍的主要機制之一。然而，确切的机制仍然知之甚少，并没有得到解决。我们基于間隙性缺氧 （IH）的动物模型的实验结果首次发现，即在IH 模型中海馬長時程增強（LTP）的降低，以及腦源性神經營養因子（BDNF）的表达减少。同時我們發現，大脑内注射BDNF 可以有效地恢复LTP 的幅度。因此，我们的研究提供了一种新的可能机制，即在缺乏脑源性神经营养因子可能是阻塞性睡眠呼吸暂停導致的伴有脑功能障碍一个关键因素。 / Ampakine 是一種AMPA 受體調節劑，更重要的是可以增加腦內BDNF 的表達。在这项研究中，我們在不同缺氧時間處理的動物模型中通过腹部注射ampakine 來觀察其效應。我們使用了四组成年雄性小鼠，其中組接受7 天IH处理，另外两组接受14 天缺氧处理。所有四组均分别接受腹腔ampakine 和对照生理盐水注射。 IH 模式仍然是氧含量在90 秒内从21 降到10%，再回复到21%。缺氧时间是每天8 小時周期。从整个IH /正常氧环境的第一天开始，八臂放射迷宮被用来研究参考记忆和工作记忆的表现。然后，我们对脑源性神经营养因子，活性氧和细胞凋亡的分子标记和海马的树突棘形态的表达进行了检查， 海馬突触可塑性的表現，包括E-LTP，L-LTP 也都被檢測。 / Western blot 分析显示，ampakine 注射有效恢复了IH 導致的海马BDNF 水平下降。同时， 我們也發現在ampakine 注射組中ROS 的表达减少，细胞凋亡的减轻，其中包括内质网应激诱导的细胞凋亡。树突棘被認為是海马突触可塑性的结构基础之一。高尔基体染色也表明， ampakine 注射IH 成功回復了7 天IH 導致的較大的，成熟树突棘的減少。 / 此外，八臂放射迷宮的结果表明，无论是参考记忆和工作记忆在7 天IH和14 天IH 均有受損表現。但是，ampkine 的使用同樣挽救了IH 引起的這些记忆障碍。 / 最後，通過研究AMPA 受體調節劑（ampakines）對IH-誘導的神經認知功能障礙及長時程增強障礙影響，我們發現進一步的闡明BDNF 在OSA 所起的重要作用。這些結果也將探索新的藥物治療的OSA 了新的思路。 / 阿爾茨海默病（AD），也叫老年癡呆癥，在65 歲的人的失憶症中，是最常見的原因，也是最常見的神經退行性疾病。 AD 的原因並不清楚，其起病也並不明顯。它的特點是逐漸喪失記憶，語言障礙及其他認知功能障礙，這些症狀可能會變得明顯。在AD 中，兩種蛋白質聚集體的參與和特點的AD 病理澱粉樣斑塊，由澱粉樣蛋白-β 肽，並導致細胞外病變和tau 蛋白纏結，這是由過度磷酸化的絲微管相關蛋白tau，並導致細胞內的病變。 / 鐵是最豐富的微量金屬，在大腦中參與範圍廣泛的細胞過程的運作。然而，鐵臭名昭著的另一方面是其強大的氧化催化性能。事實上，失調的鐵已被發現與細胞老化和各種各樣的神經退行性疾病有牽連。鐵在突觸功能的重要性是對突觸的影響，例如其可以順行軸突運輸突觸功能區域，這也是阿爾茨海默病中的澱粉樣蛋白斑的沉積的起始部位。然而，到現在，鐵的積累是如何影響突觸功能以及更普及的大腦功能很少被研究。 / 為了調查是否高鐵食有任何正常或阿爾茨海默氏病的影響，我們在實驗中引入了APPswe/ps1 轉基因小鼠，這是一個經典的老年癡呆症的疾病的動物模型。研究中，我們使用四組動物模型，即野生型（WT）和APPswe/ps1 小鼠（TG），每組給予至少10 個月正常（ctrl）的食和高鐵（HI）食。 / 海馬LTP 記錄表明，野生小鼠與正常食（WT-HI）的海馬長時程增強下降。 Tg-ctrl 組也相比wt-ctrl 組顯示LTP 水準下降，包括E-LTP 和L-LTP。引人注目的是，高鐵食下的APPswe/ps1 下顯示了被提高和恢復的海馬長時程突觸可塑性。 / 八臂放射迷宮的結果還表明，與高鐵食的野生型以及正常食的APPswe/ps1，無論是在參考記憶體或工作記憶，比野生型與正常食組有較差的記憶水準。同樣，我們驚訝地發現，和APPswe/ps1 正常食的小鼠相比，給予高鐵食的APPswe/ps1 組的迷宮成績要好得多,几乎回复到和野生型对照组一样的水平。 / 這些結果表明，鐵在阿爾茨海默病的功能是非常複雜的，可能會對其神經可塑性顯示雙相調節作用特性。詳細機制有待進一步探討。 / Obstructive sleep apnea (OSA) is a common sleep disorder, characterized by repeated episodes of airway obstruction during sleep resulting in intermittent hypoxemia. Previous studies proposed that reactive oxygen species (ROS) and apoptosis caused by intermittent hypoxia (IH) contributed to cognitive deficits. However, the exact mechanism is still poorly understood and not settled. Our recent studies, for the first time, showed that there is decreased expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and impairment in long-term potentiation (LTP). Intra-brain injection of BDNF can effectively restore the magnitude of LTP. Thus, our study provides a novel mechanism and insight in the etiology of OSA-induced brain dysfunction in that lacking BDNF could be a critical factor. / In this study, ampakine application was used as “BDNF raiser“ during 7-day IH and 14-day IH treatment by intraperitoneal (i.p.) injection. Four groups of adult male mice were used, two of them exposed to 7-day IH and two of them exposed to 14-day IH, each received either vehicle or ampakine i.p. injection. The paradigm of IH consisted of cycles of oxygen levels between 10% and 21% every 90s during the daytime for 8 hrs. Radial arm maze was used to investigate the performance of reference memory and working memory during the whole IH/ normoxia treatment from the first day. After that, expression of BDNF, ROS and molecular markers of apoptosis and morphology of hippocampal dendritic spines were examined, together with the investigation of both hippocamal synaptic plasticity, including early phase LTP (E-LTP) and late phase L-LTP (L-LTP). / Ampakine treatment restored the decreased level of hippocampal BDNF in the IH-treated group, as revealed by Western blot. Meanwhile, decreased ROS expression and alleviated cell death, including ER stress induced-apoptosis are all found in those ampakine injected groups. Golgi staining also showed that ampakine injection IH treatment rescued the decrease of mature dendritc spines, which is the structural basis of hippocampal synaptic plasticity, under 7-day IH treatment. Hippocampal long-term synaptic plasticity, which underlies the proposed mechanism of memory, was also found reversed in those ampakine injected groups, compared with groups under IH treatment. / Furthermore, results of radial arm maze showed that both the reference memory and working memory are impaired by 7-day IH treatment or 14-day IH treatment. However, the application of ampakine rescued IH-induced memory deficits. / Finally, by studying the effects of the ampakines on IH-induced neurocognitive dysfunction and LTP impairment, the role played by BDNF in OSA was further elucidated. These results were shed new lights on the exploration of novel pharmacological treatments in the OSA. / Alzheimer’s disease is the most common cause of dementia among aged people. The causes of AD are not clear and onset of the disease is also not obvious. Iron is the most abundant trace metal in the brain and dysregulation of iron has been implicated in cell aging and a wide variety of neurodegenerative diseases including Alzheimer disease. However, up to now, very little is known about how iron accumulation is involved in Alzheimer disease. / To investigate whether high iron diet has any effects on normal or Alzheimer’s disease, we introduced APPswe/ps1 transgenic mice, an Alzheimer’s disease animal model, and used four groups in our study, namely wild type (wt) and APPswe/ps1 mice (tg), each with normal (ctrl) diets and high iron (HI) diet for at least 10 months. / Hippocampal LTP recording showed that wild type with high iron diet (wt-HI) decreased than that of wt-ctrl group. Tg-ctrl group also displayed decreased LTP level, including E-LTP and L-LTP, than that of wt-ctrl group. Strikingly, that of APPswe/ps1 under HI diets rescued the impaired hippocampal long-term synaptic plasticity than that of APPswe/ps1 mice under normal diets. / Results from radial arm maze also showed that both APPswe/ps1 with normal diet and wild type with HI diet had worse performance, either in reference memory or working memory, than those of wild type with normal diets. Again, it is surprised to find that performances of tg-HI group were much better than APPswe/ps1 mice under normal diet. / These results showed that the function of iron are very complicated, may have different effects on neural function of normal and AD objects. The detailed mechanisms needs to be further explored. / 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. / 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. / Xie, Hui. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 200-225). / Abstracts also in Chinese. / Declaration --- p.II / ABSTRACT OF THESIS ENTITLED --- p.III / 中文摘要 --- p.VII / Acknowledgements --- p.XI / List of abbreviations --- p.XIII / List of publications --- p.XVI / Chapter CHAPTER 1 --- INTRODUCTION --- p.4 / Chapter 1.1 --- Overview of the study --- p.4 / Chapter 1.2 --- Obstructive sleep apnea --- p.7 / Chapter 1.2.1 --- Epidemiology --- p.8 / Chapter 1.2.2 --- Pathogenesis --- p.10 / Chapter 1.2.3 --- Pathophysiologic Consequences --- p.11 / Chapter 1.2.4 --- Diagnosis --- p.14 / Chapter 1.2.5 --- Treatment --- p.15 / Chapter 1.3 --- Memory and long-term potentiation --- p.17 / Chapter 1.3.1 --- Memory --- p.17 / Chapter 1.3.2 --- Hippocampal Synaptic plasticity --- p.19 / Chapter 1.3.3 --- Dendritic Spines --- p.23 / Chapter 1.4 --- Brain-derived neurotrophic factor --- p.35 / Chapter 1.4.1 --- Introduction of BDNF --- p.35 / Chapter 1.4.2 --- BDNF and synaptic plasticity --- p.36 / Chapter 1.5 --- Intermittent hypoxia impaired memory and neuroplasticity --- p.38 / Chapter 1.5.1 --- Clinical and basic studies on IH-induced neurological dysfunction --- p.38 / Chapter 1.5.2 --- Current mechanisms of IH-induced neurological dysfunction --- p.39 / Chapter 1.5.3 --- ROS generation and intermittent hypoxia --- p.41 / Chapter 1.5.4 --- Critical role of decreased BDNF expression in chronic intermittent hypoxia --- p..46 / Chapter 1.6 --- Ampakine --- p.48 / Chapter 1.6.1 --- Effects of ampakine on receptor activities --- p.49 / Chapter 1.6.2 --- Effects of ampakine on synaptic transmission --- p.50 / Chapter 1.6.3 --- Effects of ampakine on long-term potentiation --- p.52 / Chapter 1.6.4 --- Ampakine, BDNF and neurological disease --- p.53 / Chapter CHAPTER 2 --- METHODS --- p.61 / Chapter 2.1 --- Experimental procedure --- p.61 / Chapter 2.1 --- Animal model of Obstructive Sleep Apnea --- p.62 / Chapter 2.1.1 --- Chronic Intermittent Hypoxia --- p.62 / Chapter 2.1.2 --- Oxygen saturation measurement under normoxia and intermittent hypoxia --- p.64 / Chapter 2.1.3 --- Body weight during hypoxia treatment --- p.64 / Chapter 2.2 --- Western Blot Analysis --- p.65 / Chapter 2.3 --- ROS measurement --- p.67 / Chapter 2.4 --- Golgi staining --- p.67 / Chapter 2.4.1 --- Analysis of spine density --- p.68 / Chapter 2.4.2 --- Measurement of dendritic spines --- p.68 / Chapter 2.5 --- Electrophysiological Experiments --- p.69 / Chapter 2.5.1 --- Brain Slice Preparation --- p.69 / Chapter 2.5.2 --- Multi-electrode Recording Setup (MED64) --- p.70 / Chapter 2.5.3 --- Slice Superfusion --- p.72 / Chapter 2.5.4 --- Field Potential Recordings --- p.73 / Chapter 2.5.5 --- LTP Induction Protocol --- p.74 / Chapter 2.6 --- Radial arm maze --- p.76 / Chapter CHAPTER 3 --- RESULTS --- p.91 / Chapter 3.1 --- Molecular detection under IH treatment and ampakine injection --- p.91 / Chapter 3.1.1 --- BDNF expression under IH treatment and ampakine injection --- p.91 / Chapter 3.1.2 --- ROS measurement under IH treatment and ampakine injection --- p.92 / Chapter 3.1.3 --- Involvement of ER stress during IH treatment --- p.93 / Chapter 3.2 --- Changes of dendritic spines under IH treatment and ampakine injection --- p.100 / Chapter 3.2.1 --- Changes of total dendritic spine density under IH treatment and ampakine injection --- p.100 / Chapter 3.2.2 --- Changes of different dendritic spine density under IH treatment and ampakine injection --- p.101 / Chapter 3.2.3 --- Changes of dendritic spine morphology under IH treatment and ampakine injection --- p.103 / Chapter 3.3 --- IH-induced impairment in hippocampal synaptic plasticity --- p.110 / Chapter 3.3.1 --- E-LTP measurement of 7-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.110 / Chapter 3.3.2 --- L-LTP measurement of 7-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.111 / Chapter 3.3.3 --- E-LTP measurement of 14-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.112 / Chapter 3.3.4 --- L-LTP measurement of 14-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.113 / Chapter 3.4 --- Behavioral studies under IH treatment and ampakine injection --- p.119 / Chapter 3.4.1 --- Reference memory test under IH treatment and ampakine injection --- p.119 / Chapter 3.4.2 --- Working memory measurement under IH treatment and ampakine injection --- p..122 / Chapter CHAPTER 4 --- DISCUSSION --- p.140 / Chapter 4.1 --- Molecular changes under IH treatment and ampakine application --- p.140 / Chapter 4.1.1 --- Intermittent hypoxia down regulate BDNF expression in hippocampus while ampakine injection rescued IH-induced decreased BDNF level --- p.140 / Chapter 4.1.2 --- Ampakine injection against ROS and apoptosis --- p.143 / Chapter 4.1.3 --- Involvement of ER stress-induced apoptosis during IH treatment --- p.145 / Chapter 4.2 --- Changes of spine morphology and density under IH treatment and ampakine injection --- p.146 / Chapter 4.3 --- Ampakine rescued hippocampal synaptic plasticity --- p.152 / Chapter 4.4 --- IH impaired reference memory and working memory --- p.156 / Chapter 4.5 --- Summary --- p.160 / Chapter Chapter 5 --- Effects of High-iron diet in Alzheimer’s Disease --- p..164 / Chapter 5.1 --- Overview of the study --- p.164 / Chapter 5.2 --- Introduction --- p.166 / Chapter 5.2.1 --- Alzheimer's disease --- p.166 / Chapter 5.2.2 --- Function of iron in brain --- p.167 / Chapter 5.2.3 --- Involvement of iron in oxidative damage --- p.168 / Chapter 5.2.4 --- Role of iron in neurodegeneration diseases --- p.168 / Chapter 5.2.5 --- Role of iron in Alzheimer's disease --- p.169 / Chapter 5.2.6 --- Deleterious effects of iron in memory function --- p.171 / Chapter 5.3 --- Methods --- p.172 / Chapter 5.3.1 --- Experimental design --- p.172 / Chapter 5.3.2 --- T-maze --- p.172 / Chapter 5.4 --- Results --- p.174 / Chapter 5.4.1 --- Validation of animal model of Alzheimer's disease --- p.174 / Chapter 5.4.2 --- Examination of normal and high iron diet on body weight --- p.174 / Chapter 5.4.3 --- Effects of Aβ accumulation and high-iron diet on hippocampal synaptic plasticity --- p.175 / Chapter 5.4.4 --- Effects of Aβ accumulation and high-iron diet on spatial memory measured by T-maze --- p.177 / Chapter 5.4.5 --- Effects of Aβ accumulation and high-iron diet on reference memory and working memory measured by radial arm maze --- p.178 / Chapter 5.5 --- Discussion --- p.180 / Chapter Chapter 6 --- General discussion --- p.195 / Reference --- p.200

In the early 1990s claims were made that in all areas of health care, “30-40% of patients do not receive treatments of proven effectiveness”, and, “20-25% of patients have treatments that are unnecessary or potentially harmful”. Many such practices were diffused prior to the acceptance of modern evidence-based standards of clinical- and cost-effectiveness. I define disinvestment in the context of health care as the processes of withdrawing (partially or completely) resources from any existing health care practices, procedures, technologies or pharmaceuticals that are deemed to deliver little or no health gain relative to their cost, and thus are not efficient health resource allocations. Arguably disinvestment has been central to Evidence-Based Medicine(EBM) for well over a decade yet despite general advances in EBM, this topic remains relatively unexplored. This thesis examines the ongoing challenges that exist within the Australian context relating to effective disinvestment. Upper airway surgical procedures for the treatment of adult Obstructive Sleep Apnoea Syndrome (OSA) are used as a case study to contextualise these challenges. This thesis has six sections: 1. A review of the literature outlines developments in EBM broadly and provides a detailed background to OSA, including the numerous treatment options for the condition. This review examines evidence that highlights the importance of ‘highly effective treatment’ over ‘subtherapeutic treatment’ as a necessity to confer improved health outcomes in OSA. It is argued that claims of surgical success inherent in most published results of surgery effectiveness fail to assimilate contemporary evidence for clinically significant indicators of success. 2. Section two comprises the first reported meta-analysis in this area. It presents the pooled success rates of surgery according to various definitions. Specifically, when the traditional ‘surgical’ definition of success is applied the pooled success rate for Phase I (i.e. soft palate) surgical procedures is 55% (that is 45% fail). However, using a more stringent definition (endorsed by the peak international sleep medicine body), success is reduced to 13% (that is 87% fail). Similarly for Phase II (i.e. hard palate) procedures success rates decrease from 86% to 43% respectively when moving from a surgical to a medical definition of success. That various medical specialties differentially define treatment success, I argue, creates uncertainty for observers and non-clinical participants in this debate (eg policy stakeholders and patients). This represents a barrier to disinvestment decisions. 3. Results are presented from a clinical audit of surgical cases conducted as a component of this thesis. Both clinical effectiveness and procedural variability of surgery are reported. A unique methodology was utilised to capture data from multiple centres. It is the first time such a methodology has been reported to measure procedural variability alongside clinical effectiveness (inclusive of a comparative treatment arm). The observed cohort (n=94) received 41 varying combinations of surgery in an attempt to treat OSA. Results on effectiveness demonstrate an overall physiological success rate of 13% (according to the most stringent definition; phases I and II combined). This demonstration of procedural variability combined with limited effectiveness highlights clinical uncertainty in the application of surgical procedures. 4. Section four outlines how a qualitative phase of enquiry, directed at exploring the perspectives and experiences of surgery recipients, was approved by three independent research ethics review boards but was not supported by a small group of surgeons, resulting in the project being canceled. Potential consequences of this for impeding health services research (HSR) are discussed. 5. Two sets of results are reported from a qualitative phase of enquiry (semi-structured interviews) involving senior Australian health policy stakeholders. The first results are of policy stakeholders’ perspectives on the surgical meta-analysis and clinical audit studies in 2 and 3 above. The second results are from an extended series of questions relating to challenges and direction for effecting disinvestment mechanisms in Australia. Stakeholder responses highlight that Australia currently has limited formal systems in place to support disinvestment. Themes include how defining and proving inferiority of health care practices is not only conceptually difficult but also is limited by data availability and interpretation. Also, as with any policy endeavour there is the ever-present need to balance multiple interests. Stakeholders pointed to a need, and a role, for health services and policy research to build methodological capacity and decision support tools to underpin disinvestment. 6. A final discussion piece is presented that builds on all previous sections and summarises the specific challenges that exist for disinvestment, including those methodological in nature. The thesis concludes with potential solutions to address these challenges within the Australian and international context. Systematic policy approaches to disinvestment represent one measure to further improve equity, efficiency, quality of care, as well as sustainability of resource allocation. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1297655 / Thesis (Ph.D.) -- University of Adelaide, School of Population Health and Clinical Practice, 2007

published_or_final_version / Medicine / Master / Master of Philosophy

In the early 1990s claims were made that in all areas of health care, “30-40% of patients do not receive treatments of proven effectiveness”, and, “20-25% of patients have treatments that are unnecessary or potentially harmful”. Many such practices were diffused prior to the acceptance of modern evidence-based standards of clinical- and cost-effectiveness. I define disinvestment in the context of health care as the processes of withdrawing (partially or completely) resources from any existing health care practices, procedures, technologies or pharmaceuticals that are deemed to deliver little or no health gain relative to their cost, and thus are not efficient health resource allocations. Arguably disinvestment has been central to Evidence-Based Medicine(EBM) for well over a decade yet despite general advances in EBM, this topic remains relatively unexplored. This thesis examines the ongoing challenges that exist within the Australian context relating to effective disinvestment. Upper airway surgical procedures for the treatment of adult Obstructive Sleep Apnoea Syndrome (OSA) are used as a case study to contextualise these challenges. This thesis has six sections: 1. A review of the literature outlines developments in EBM broadly and provides a detailed background to OSA, including the numerous treatment options for the condition. This review examines evidence that highlights the importance of ‘highly effective treatment’ over ‘subtherapeutic treatment’ as a necessity to confer improved health outcomes in OSA. It is argued that claims of surgical success inherent in most published results of surgery effectiveness fail to assimilate contemporary evidence for clinically significant indicators of success. 2. Section two comprises the first reported meta-analysis in this area. It presents the pooled success rates of surgery according to various definitions. Specifically, when the traditional ‘surgical’ definition of success is applied the pooled success rate for Phase I (i.e. soft palate) surgical procedures is 55% (that is 45% fail). However, using a more stringent definition (endorsed by the peak international sleep medicine body), success is reduced to 13% (that is 87% fail). Similarly for Phase II (i.e. hard palate) procedures success rates decrease from 86% to 43% respectively when moving from a surgical to a medical definition of success. That various medical specialties differentially define treatment success, I argue, creates uncertainty for observers and non-clinical participants in this debate (eg policy stakeholders and patients). This represents a barrier to disinvestment decisions. 3. Results are presented from a clinical audit of surgical cases conducted as a component of this thesis. Both clinical effectiveness and procedural variability of surgery are reported. A unique methodology was utilised to capture data from multiple centres. It is the first time such a methodology has been reported to measure procedural variability alongside clinical effectiveness (inclusive of a comparative treatment arm). The observed cohort (n=94) received 41 varying combinations of surgery in an attempt to treat OSA. Results on effectiveness demonstrate an overall physiological success rate of 13% (according to the most stringent definition; phases I and II combined). This demonstration of procedural variability combined with limited effectiveness highlights clinical uncertainty in the application of surgical procedures. 4. Section four outlines how a qualitative phase of enquiry, directed at exploring the perspectives and experiences of surgery recipients, was approved by three independent research ethics review boards but was not supported by a small group of surgeons, resulting in the project being canceled. Potential consequences of this for impeding health services research (HSR) are discussed. 5. Two sets of results are reported from a qualitative phase of enquiry (semi-structured interviews) involving senior Australian health policy stakeholders. The first results are of policy stakeholders’ perspectives on the surgical meta-analysis and clinical audit studies in 2 and 3 above. The second results are from an extended series of questions relating to challenges and direction for effecting disinvestment mechanisms in Australia. Stakeholder responses highlight that Australia currently has limited formal systems in place to support disinvestment. Themes include how defining and proving inferiority of health care practices is not only conceptually difficult but also is limited by data availability and interpretation. Also, as with any policy endeavour there is the ever-present need to balance multiple interests. Stakeholders pointed to a need, and a role, for health services and policy research to build methodological capacity and decision support tools to underpin disinvestment. 6. A final discussion piece is presented that builds on all previous sections and summarises the specific challenges that exist for disinvestment, including those methodological in nature. The thesis concludes with potential solutions to address these challenges within the Australian and international context. Systematic policy approaches to disinvestment represent one measure to further improve equity, efficiency, quality of care, as well as sustainability of resource allocation. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1297655 / Thesis (Ph.D.) -- University of Adelaide, School of Population Health and Clinical Practice, 2007