<p> Bisphenol-A (BPA), used in the production of polycarbonate plastics and epoxy resins, has established estrogenic properties. Early pregnancy in mice is highly sensitive to exogenous estrogens, particularly during the period of blastocyst implantation. Accordingly, I assessed pregnancy outcome, implantation, urinary hormone levels and uterine morphology following BPA exposure. Subcutaneous injections of BPA administered on days 1 through 4 of gestation reduced litter size at a dose of 3 mg/animal/day and decreased the proportion of parturient females at 10 mg/animal/day. Hysterectomies performed on day 6 of pregnancy confirmed a significant disruption of implantation occurring at doses as low as 6 mg/animal/day. Urinary progesterone levels were also reduced by 10 mg/animal/day. Uterine luminal area expanded substantially in response to increasing doses of BPA. Luminal epithelial cell height increased following exposure to 10.125 mg/animal, whereas there were no differences in the number of corpora lutea among conditions. The proportion of cells staining positively for estrogen receptors was affected non-monotonically, showing highest levels at 3.375 mg/animal and lowest levels at 10.125 mg/animal. Similarly progesterone receptor expression measured through western blots related non-monotonically to dose, being highest at 3.375 mg/animal and diminishing with increasing dose. Effects of a single administration of BPA on days 0, 1, or 2 of gestation were also investigated. A single dose of 10 mg reduced the number of implantation sites when given on day 0 or 1, and 6 mg did so on day 1, but there was no such effect of any dose administered on day 2. Exposure to low, environmentally-relevant doses of BPA did not result in any clear reproductive or hormonal effects. These studies highlight the detrimental effects BPA exposure induces during early pregnancy and provides further evidence of its weak estrogenic properties in vivo.</p> / Thesis / Doctor of Philosophy (PhD)

Seminal plasma is commonly known to serve as a transport medium for sperm as it moves through the female reproductive tract for fertilization, however, more recent evidence demonstrates seminal plasma induces an expansive inflammatory response in the uterus. Murine models have found this inflammatory response is important for clearing pathogens and poor-quality sperm, eliciting the secretion of cytokines, chemokines, and embryokines that aid in embryo attachment and growth, placental angiogenesis, and blunting maternal immunity to the embryo. However, there is minimal research on the impacts of seminal plasma uterine priming in bovine, and more specifically embryo growth, uterine blood flow, offspring growth and metabolism, and production efficiency. There is significant evidence that malnutrition and environmental stress during gestation alters uterine blood flow resulting in poor placental efficiency and poor fetal growth and development which persists postnatally. Animal production is vital in providing high-quality protein for human consumption but recent challenges of public misconception, consumer preferences, high input costs, and environmental impacts threaten the security of these production systems. Growth efficiency is imperative for improving economic and environmental sustainability, and in turn ensuring the longevity of animal production systems. Knowing the impact of seminal plasma on the uterus, and its potential role in placental efficiency and subsequent offspring growth and metabolic function, and the negative impacts these can have on economic and environmental sustainability drive the need to better understand seminal plasma uterine priming in bovine.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24835号 / 医博第5003号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 浅野, 雅秀, 教授 柳田, 素子, 教授 近藤, 玄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The female reproductive organs are among the few adult tissues in which periodic angiogenesis normally occurs. Pathological angiogenesis can occur in various conditions, such as solid tumors. Vascular endothelial growth factor (VEGF) signaling often represents a critical rate-limiting step in physiological and pathological angiogenesis. This study utilizes development of utero-ovarian vasculature during pregnancy in goats as a model of physiological angiogenesis. Non-pregnant does and does at 4, 7, 10, 13, 16, and 18 weeks of gestation were used. Arteries of the reproductive tract were injected <i>in situ</i> with Microfil®. The tracts were fixed, dehydrated, and rendered transparent to reveal the paths of arteries. The ovarian artery was tortuous and lay in close apposition to the uterine tributary of the ovarian vein in all specimens studied. In non-pregnant does, this arrangement may serve as a local utero-ovarian pathway for the corpus luteum (CL) luteolysis at the end of non-fertile estrous cycle. During pregnancy, this arterio-venous arrangement may transfer luteotropic substances from uterus to ovary, which may serve in maternal recognition of pregnancy and fit the fact that the goat is CL dependent throughout gestation. In some cases of triplets, the size of the uterine branch of the ovarian artery was equal to or even larger than that of its parent artery and/or the ipsilateral uterine artery; and the vaginal artery contributed a connecting branch to the uterine artery. These physiological adaptations of the ovarian and/or vaginal arteries correlate well with the increasing nutrient demands of the growing multiple fetuses. In a second experiment, the vasculature of the uterus and ovaries was injected <i>in situ</i> with a mixture of Batson's No.17® and methyl methacrylate and then processed for observation by SEM. The microvasculature differed between non-pregnant and pregnant does, and with advancing gestation. We concluded that goats possess a <i>multivillous</i> type placenta. Capillary sinusoids and crypts on the fetal surface of the caruncle may compensate for the negative effect of the increased interhemal distance. Intussusceptive angiogenesis should be considered as equally possible and important mechanism as sprouting angiogenesis during placental development. Capillary diameters increased significantly during pregnancy especially after 4 weeks. Capillary density index was 66.8, 68.7, 55.5, 63.5, 70.1, 70.4, 64.5 percent in non-pregnant, 4, 7, 10, 13, 16, and 18 weeks of pregnancy, respectively. In the ovary, coiling of the ovarian branch of the ovarian artery around the ovarian tributary of the ovarian vein was observed. This may represent a local channel required for product transport from ovarian vein to ovarian artery and might have a role in regulating blood pressure to various ovarian structures. Immunolocalization of VEGF was performed as a third experiment. Immunostaining was observed in cyto- trophoblasts, maternal epithelial tissues, and vascular endothelium and smooth muscle, but not in binucleate giant cells or connective tissue. No apparent differences were observed in intensity and pattern of VEGF staining associated with advancing gestation. Luteal and follicular cells, and endothelium and smooth muscles of the ovarian vasculature positively stained. Patterns and intensity of staining of VEGF suggest that the fetus is directing its own survival by producing growth factors affecting fetal and maternal tissues. VEGF may have a role in growth and differentiation of cytotrophoblasts, as well as, development and maintenance of CL. In the fourth experiment, the sequential expression of VEGF and its receptors (fms-like tyrosine kinase, Flt-1 and kinase-insert domain-containing receptor, KDR) was measured using real-time quantitative PCR. Targets were detected in all studied tissues; however, levels of expression differed according to the stage of pregnancy. Expression of VEGF and its receptor mRNAs increased with advancing pregnancy, which correlates with the expansion of vasculature during pregnancy. Differences in the time-courses of the expression of Flt-1 and KDR mRNAs during pregnancy suggest that each receptor plays a different role in the angiogenic process. As an application of our model of angiogenesis, we tested the effect of swainsonine (active compound of locoweed and a potential anti-cancer drug) on the process. Does treated with swainsonine were euthanized at 7 and 18 weeks. No significant differences were found in sinusoidal diameters in treated does at 7 weeks, but a decrease in capillary density index was noted. In the ovary, focal avascular areas were observed in the corpus luteum of swainsonine-treated does at 7 weeks of pregnancy. Swainsonine caused great distortion in the uterine and ovarian vasculature at 18 weeks. A decrease in intensity of the immunoreactivity to VEGF antibody was observed in tissues from swainsonine-treated does at 7 and 18 weeks. There was no substantial effect of swainsonine on the expression of VEGF and its receptors' mRNAs in any of the studied tissues (except in the left ovary, where it had an inhibitory effect) at 7 weeks of pregnancy, but it had an inhibitory effect at 18 weeks. Demonstration of swainsonine's potential to negatively affect vascular development and suppress genes likely involved in angiogenesis at critical stages of blood vessel proliferation lends credibility to its potential as anti-cancer drug. / Ph. D.

Delayed uterine clearance (DUC) is a significant problem contributing to subfertility and infertility in the mare, characterized by an accumulation of fluid and inflammatory debris in the uterine lumen following breeding events, venereal disease or an estral cycle. This syndrome is typically seen in older, multiparous mares and mares with poor reproductive tract conformation. The etiopathogenesis of DUC has not been fully elucidated but suggested causes include poor genital conformation, a cranioventrally tilted uterus, defective myometrial contractions, decreased intrauterine immune activity, inappropriate lymphatic drainage or mucus overproduction. The objective of this research was to evaluate gene expression of selected genes in endometrial tissue samples taken from three categories of mares (young fertile [YF], older clinically normal [ON] and older susceptible [OS]). The genes assayed in this research were oxytocin receptor, PGF2á receptor and progesterone receptor. The expression of each of these genes was normalized using the expression of two housekeeping genes, beta actin and ribosomal 18S RNA. Quantitative real-time polymerase chain reaction (QPCR) was used to evaluate gene expression of the selected genes. Results indicated that there was no statistically significant difference in the expression of any of the three experimental genes among any of the three categories of mares. From this research, the direction of further research regarding the pathogenesis of DUC can be made: myometrial tissues can be assayed for similar genes, the expression of other genes regulating myometrial contraction can be assayed or the expression of uterorelaxants can be studied. / Master of Science

No / Previous studies in this laboratory have suggested that the isolated uterus from non-pregnant mice has a prostaglandin F and a thromboxane receptor population similar to that found in human myometrium. The aim of this study was to investigate any regional variation in myogenic activity ) and the and responsiveness to prostaglandin F(2alpha) (PGF(2alpha) thromboxane mimetic U46619 in the mouse uterus taken during different stages of the oestrous cycle and during pregnancy. Uterine samples from BKW mice were taken from different anatomical segments along the length of each uterine horn and set up for superfusion at 2 ml/min with Krebs solution (containing 1 microM indometacin) at 37 degrees C, and gassed with 95%O(2)/5%CO(2). Responses (area under the curve) are expressed as a percentage of the final contraction induced by hypotonic shock. Data are expressed as the means +/- s.e.m. of n=5-12 and were analysed using Student's paired t-test or two-way ANOVA with a Bonferroni post hoc test. Regional variation in myogenic activity was observed in all tissues studied except those taken during labour. These tissues displayed significantly greater myogenic activity than tissues taken at late gestation and at all stages of the oestrous cycle. Tissues from pregnant animals were generally more responsive to U46619 and PGF(2alpha) than tissues taken from non-pregnant animals. Tissues taken from the upper segment of the uterine horn were more responsive to both agonists during the oestrous cycle. The findings demonstrated that the hormonal milieu and site of excision are important for myogenic activity and responsiveness.

Le développement et la survie de l’embryon dépendent des nutriments fournis par les sécrétions utérines. Les objectifs de cette étude étaient de déterminer l’effet de la surovulation (SOV) sur la bactériologie et cytologie utérine et sur les paramètres biochimiques utérin et sérique et leurs effets sur le nombre d’embryons transférables (ET). Deux groupes de vaches Holstein (groupe I, non lactante, n=7 et groupe II, lactante, n=28) ont été respectivement induites en chaleur ou surovulées et ensuite inséminées. Au jour 7 du cycle œstral (J7) et lors du jour de la récolte (JR), un prélèvement individuel de sang et de liquide de lavage utérin a été fait pour l’analyse du statut bactériologique et cytologique de l’utérus et la mesure de la concentration de plusieurs paramètres biochimiques présélectionnés. Les embryons récoltés ont été évalués selon les critères de l’IETS. La SOV a donnée une moyenne de 7.39 ± 6.22 ovocytes/embryons dont 3.32 ± 4.81 ET. Il n’y avait pas de variation significative de la bactériologie et cytologie utérine des deux groupes entre J7 et JR. La concentration sérique de l’urée (P=0.0001), d’E2 (P=0.006); la concentration utérine du Glu (P=0.002), de Ck (p=0.0007), de LDH (P <0.0001), de PT (P=0.004), de P4 (P=0.008), de PGFM (P<0.0001) du groupe I et la concentration sérique de P4 (P<0.0001), de PGFM (P<0.0001); la concentration utérine de LDH (P=0.002), de PGFM (P<0.0001) du groupe II ont été significativement élevées à JR qu’à J7. La concentration utérine et sérique de l’urée (P<0.0001 et P<0.0001), de LDH (P<0.0001 et P=0.008), la concentration sérique de P4 (P=0.0002) et la concentration utérine de PT (P=0.0003) à JR du groupe II étaient différente du groupe I. Il n’y avait pas d’association entre la bactériologie et cytologie utérine et le nombre d’ET. Cependant, le nombre d’ET a été positivement corrélé avec la concentration sérique d’IGF-1 à J7 (r=0.45; P=0.001) et la concentration sérique de P4 à JR (r=0.43; P<0.05) et négativement corrélé avec la concentration utérine et sérique de PGFM à la fois à J7 (r=-0.54; P<0.005 et r=-0.67; P<0.001) et à JR (r=-0.48; P<0.01 et r=-0.57; P<0.002). Ces résultats suggèrent que la SOV induit des changements au niveau sérique et utérin qui affectent le nombre d’ET récoltés. / The developing embryo is dependent on the nutrients provided by the oviduct and the uterine fluid. The objectives of this study were to determine the effect of SOV on uterine bacteriology and cytology, on serum and uterine biochemical parameters and consequently on the number of TE. Non-lactating (n=7) and lactating (n=28) Holstein cows were synchronized for estrus and superovulated respectively and were inseminated twice. Uterine bacteriology and cytology and various uterine and serum biochemical parameters were measured at day 7 of estrus cycle (D7, starting day of the SOV protocol) and at the designated day of embryo recovery (DER). Harvested embryos were evaluated according to IETS’s criteria. Superovulated cows produced an average of 7.39 ± 6.22 ova/embryos of which 3.32 ± 4.81 were TE. There were no significant variations of uterine bacteriology and cytology between D7 and DER within the two groups. Serum urea (P=0.0001), E2 (P=0.006); uterine Glu (P=0.002), Ck (P=0.0007), LDH (P<0.0001), TP (P=0.004), P4 (P=0.008), PGFM (P<0.0001) in group I and serum P4 (P<0.0001), PGFM (P<0.0001); uterine LDH (P=0.002), PGFM (P<0.0001) in group II were significantly higher at DER than at D7. At DER, group I was different to group II’ uterine and serum urea (P<0.0001 and P<0.0001), LDH (P<0.0001 and P=0.008), PGFM (P=0.002 and P=0.009), serum P4 (P=0.0002) and uterine TP (P=0.0003). There was no association between uterine bacteriology and cytology and the number of TE. However, TE was positively correlated with serum IGF-1 at D7 (r=0.45; P=0.001) and P4 at DER (r=0.43; P<0.05) and negatively correlated with both serum and uterine PGFM respectively at D7 (r=-0.54; P<0.005 and r=-0.67; P<0.001) and DER (r=-0.48; P<0.01 and r=-0.57; P<0.002). The present results infer that changes following SOV in both serum and uterine secretion may affect the number of TE.

O parto pré-termo é uma causa importante de morbidade e mortalidade neonatal. A medida do comprimento do colo uterino por ultrassonografia, atualmente, é utilizada para o rastreamento desta condição. Porém, não se sabe, exatamente, qual é a sua reprodutibilidade, ou seja, se a via vaginal é melhor que a abdominal e se a ultrassonografia tridimensional pode contribuir para melhorar a reprodutibilidade do método. O objetivo desse trabalho foi avaliar a reprodutibilidade da medida do comprimento do colo uterino no final do segundo trimestre da gestação por ultrassonografia bidimensional (2D) e tridimensional (3D), utilizando as vias abdominal e vaginal. Foram avaliadas 96 mulheres com idade gestacional entre 20 e 26 semanas. Durante as avaliações, foram realizadas três medidas completamente independentes e com mascaramento: duas feitas por um observador, intercaladas por uma medida de um segundo observador. Foram avaliados o coeficiente de correlação de concordância (CCC) e os limites de concordância (LoA). A precisão das estimativas será avaliada pelo intervalo de confiança de 95%. As principais características das 96 mulheres analisadas foram: idade = 25,0 ± 5,4 anos, IG = 22,5 ± 2,0 semanas, índice de massa corporal = 26,0 ± 3,2 Kg / m². TV-US e TA-US fornecem medições de CL semelhantes, no entanto, a US-TV apresentou uma reprodutibilidade ligeiramente melhor (CCC intraobservador: US-TV 0,90 (0,86-0,93) US-TA 0,83 (0,76-0,88); CCC interobservador: US-TV 0,77 (0,68-0,84) US-TA 0,60 (0,45-0,71). A medida do CL durante o segundo trimestre deve ser interpretada com cautela quando utilizada na prática clínica, pois sua reprodutibilidade é apenas fraca a moderada. Estudos que examinem refinamentos técnicos para melhorar sua reprodutibilidade devem ser encorajados / Preterm birth is an important cause of neonatal morbidity and mortality. Ultrasound measurement of uterine cervix length is currently used to predict this condition. Nevertheless, its reproducibility has not been clearly evaluating in the literature, in other words, what is the best ultrasound method to measure, for instance, the vaginal via or the abdominal. The objective of this study was to evaluate the reproducibility of the measurement of uterine cervix length at the end of the second trimester of gestation by two-dimensional (2D) using the via abdominal and vaginal. We evaluated 96 healthy singleton pregnant women with gestational age between 20 and 26 weeks. During the evaluations, three completely independent and masked measurements were performed: two made by one observer, interspersed by a second observer measurement. The correlation coefficient of agreement (CCC) and the limits of agreement (LoA) were evaluated. The accuracy of the estimates will be evaluated by the 95% confidence interval. The main characteristics of the 96 analyzed women were: age = 25.0 ± 5.4 years, GA = 22.5 ± 2.0 weeks, body mass index = 26.0 ± 3.2 Kg/m². TVUS and TA-US provides similar CL measurements; however, TV-US has a slightly better reproducibility (CCC intraobservador: US-TV 0,90 (0,86-0,93) US-TA 0,83 (0,76-0,88); CCC interobservador: US-TV 0,77 (0,68-0,84) US-TA 0,60 (0,45-0,71). The CL measurement during the second trimester should be interpreted with caution when employed in clinical practice because its reproducibility is only poor to moderate. Studies examining technical refinements to improve its reproducibility should be encouraged

Yuan, Qin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 112-119). / Abstracts in English and Chinese. / Acknowledgements --- p.III / Publications --- p.V / List of Abbreviations --- p.VI / List of Figures --- p.VII / List of Tables --- p.VIII / Abstract in English --- p.IX / Abstract in Chinese --- p.XII / Table of Contents --- p.XIII / Chapter CHAPTER1 I --- NTRODUCTION --- p.1 / Chapter 1.1 --- What is telemedicine --- p.1 / Chapter 1.2 --- What is telepathology --- p.4 / Chapter 1.2.1 --- Types of telepathology system --- p.7 / Chapter 1.2.2 --- Main events in the development of telepathology --- p.9 / Chapter 1.2.3 --- Diagnostic accuracy in telepathology and telecytology --- p.12 / Chapter 1.2.4 --- Applications of telepathology --- p.18 / Chapter 1.2.4.a --- Remote primary diagnosis --- p.18 / Chapter 1.2.4.b --- Remote expert consultation --- p.19 / Chapter 1.2.4.c --- "Image libraries, databases and archiving" --- p.20 / Chapter 1.2.4.d --- Quality assurance --- p.20 / Chapter 1.2.4.e --- Remote teaching and training --- p.21 / Chapter 1.3 --- Technical aspects of telepathology --- p.24 / Chapter 1.3.1 --- Image presentation --- p.24 / Chapter 1.3.2 --- Image acquisition and display --- p.25 / Chapter 1.3.3 --- Image compression --- p.27 / Chapter 1.3.4 --- Networking and line connections --- p.29 / Chapter 1.3.4.a --- Public (analog) telephone network --- p.29 / Chapter 1.3.4.b --- Integrated services digital network (ISDN) --- p.30 / Chapter 1.3.4.c --- Computer network --- p.30 / Chapter 1.3.4.d --- Asynchronous transfer mode (ATM) --- p.31 / Chapter 1.4 --- Legal and ethical aspects --- p.32 / Chapter 1.4.1 --- Licensure of the facility --- p.33 / Chapter 1.4.2 --- Licensure of the pathologist --- p.33 / Chapter 1.4.3 --- Accreditation --- p.34 / Chapter 1.4.4 --- The electronic medical record: privacy --- p.35 / Chapter 1.4.5 --- Malpractice liability --- p.36 / Chapter 1.4.6 --- Reimbursement --- p.38 / Chapter 1.4.7 --- Conclusion --- p.38 / Chapter 1.5 --- Telemedicine and telepathology in China --- p.40 / Chapter 1.6 --- Cytopathology practice in China --- p.42 / Chapter CHAPTER2 --- OBJECTIVES OF STUDY --- p.46 / Chapter CHAPTER3 --- MATERIALS AND METHODS --- p.48 / Chapter 3.1 --- Case materials --- p.48 / Chapter 3.2 --- Static image capture and display --- p.51 / Chapter 3.3 --- Static telecytology study --- p.55 / Chapter 3.4 --- Web-based tutorial program --- p.59 / Chapter 3.4.1 --- Pre-tutorial evaluation --- p.60 / Chapter 3.4.2 --- Cytology tutorial --- p.62 / Chapter 3.4.3 --- Post-tutorial evaluation --- p.66 / Chapter 3.4.4 --- Data analysis --- p.67 / Chapter 3.5 --- Dynamic telecytology study --- p.68 / Chapter 3.5.1 --- Equipment --- p.68 / Chapter 3.5.2 --- Trial design --- p.72 / Chapter 3.5.2a --- Telecytology diagnosis --- p.72 / Chapter 3.5.2b --- Light microscopy diagnosis --- p.73 / Chapter 3.5.2c --- Data analysis --- p.74 / Chapter CHAPTER4 --- RESULTS --- p.75 / Chapter 4.1 --- General information about participating cytology laboratories --- p.75 / Chapter 4.2 --- Static telecytology study --- p.78 / Chapter 4.2.1 --- Telecytology diagnostic agreement --- p.78 / Chapter 4.2.2 --- Confidence of telecytology diagnosis --- p.80 / Chapter 4.2.3 --- "The acceptance of the image quality, time required for each case" --- p.83 / Chapter 4.3 --- Web-based program on cervical cytology --- p.84 / Chapter 4.4 --- Dynamic telecytology study --- p.86 / Chapter 4.4.1 --- Diagnostic accuracy --- p.86 / Chapter 4.4.2 --- Time studies --- p.88 / Chapter 4.4.3 --- Diagnostic certainty --- p.89 / Chapter 4.4.4 --- Image quality --- p.91 / Chapter CHAPTER5 --- DISCUSSION --- p.92 / Chapter 5.1 --- Static image telecytology study linking 14 Mainland China hospitals --- p.93 / Chapter 5.2 --- Problems encountered in setting up links with Mainland China --- p.97 / Chapter 5.3 --- Web-based tutorial programme for remote teaching --- p.100 / Chapter 5.4 --- Dynamic image telecytology study for immediate diagnosis at a distance --- p.103 / Chapter 5.5 --- Limitations of this study --- p.105 / Chapter 5.6 --- Concluding remarks --- p.108 / REFERENCES --- p.112

研究背景： / 2009年起，中國政府發起並資助了一項覆蓋全國31個省221個鄉村、針對100萬名農村婦女的細胞學及肉眼觀察宮頸癌篩查試點項目。國家及地方政府需要對可行的篩查策略進行衛生經濟學評估，為下一步擴大規模的篩查提供政策依據。 / 研究目標： / 應用人群特異性Markov模型，對巴氏塗片及肉眼觀察的宮頸癌篩查策略進行成本效果及成本效用兩方面的衛生經濟學評估，進而為中國農村婦女宮頸癌篩查政策的制定提供依據。 / 研究方法： / 本論文工作建立了Markov人群動態擬合模型，該模型能夠整合與中國農村宮頸癌流行情況相吻合的成本及健康狀況的數據，進而用於擬合20年內35-59歲中國農村婦女在有/無篩查幹預下的成本、效用和效果。本文分析的八個備選篩查策略包括：採用醋酸染色肉眼觀察（VIA）或傳統細胞學（巴氏塗片）分別進行10年，5年，3年及1年一次的篩查。 / 本文從社會學角度出發，成本數據涵蓋篩查、診斷及治療過程中產生的直接及間接成本。模型在結構上綜合了已被廣泛認可的宮頸癌自然發展史模型，以及宮頸癌及其癌前病變（CIN）在中國農村進行篩查和治療的標準臨床路徑。模型輸入參數盡可能地使用了能夠反映中國農村婦女人群特異性的數據。通過對比國家報告數據與模型預測結果，本文從全死因死亡率、宮頸癌死亡率及宮頸癌發病率三個方面驗證了模型的可信度。 / 模型的結局變量包括：累計成本、累計生命年(LYs)、累計質量調整生命年(QALYs)、預期宮頸癌死亡率及發病率降低百分比(%)、CIN 相對風險、宮頸浸潤癌相對風險，增量成本效用比(ICUR, 表述為每挽救一個質量調整生命年消耗的成本)及增量成本效果比(ICER, 表述為每挽救一個生命年消耗的成本)等。與無篩查幹預相比，我們界定ICUR及ICER小於三倍人均國內生產總值（76,824元，2009年)的優勢策略為‘具有成本效益’的選擇，並將其中ICUR和ICER最低的策略，定義為‘最具成本效益’的策略，將具有最大健康效益的策略（挽救最多質量調整生命年或生命年的策略），定義為‘最有效’的策略。同時，我們對可能影響決策的不確定因素進行了敏感性分析。 / 結果： / 與無篩查幹預相比，肉眼觀察及巴氏塗片篩查均能夠減少宮頸癌患病例數，進而顯示出一定的健康效益。較短的篩查間隔具有更高的健康效益。模型預測在不同的篩查策略幹預下，宮頸癌死亡率和發病率分別有望降低6.67-31.95%和5.12-24.71%，預期CIN發病相對風險為0.89-0.98，預期宮頸癌發病相對風險為0.73-0.95。篩查幹預對健康的保護作用在本研究中得到了證實。 / 成本效用分析顯示，10年一次的肉眼觀察策略最具成本效益，其次為5年一次、3年一次、1年一次的肉眼觀察篩查策略及1年一次的巴氏塗片篩查策略。與無篩查幹預相比，如上策略每挽救一個質量調整生命年消耗的成本為11,921至26,069元（1,892-4,138美元，2012年）。同時成本效果分析也顯示，10年一次的肉眼觀察策略最具成本效益，其次為5年一次的肉眼觀察策略及5年一次的巴氏塗片篩查策略。同樣與無篩查幹預相比，如上策略每挽救一個生命年消耗的成本為37,211至68,226元（5,906-18,830美元，2012年）。 / 對於某一既定策略，相應的ICUR和ICER受當地經濟狀況相關因素的影響最大，這些因素包括治療成本、篩查成本和成本貼現率。從檢測技術水平上看，肉眼觀察對分析結果的影響小於巴氏塗片，原因是前者敏感度範圍較小。篩查覆蓋率、初篩陽性隨訪率、診斷陽性治療率也都與相應的ICUR和ICER呈負相關性。敏感性分析結果顯示本文中模型對於健康結局的預測，及相關的衛生經濟學分析，受自然史模型中HPV感染和CIN之間轉移概率的不確定性的影響最大。HPV感染與CIN間的進展和逆轉概率是該項模型研究的核心參數。 / 結論： / 本文中成本效用和成本效果分析均顯示，相較於傳統的細胞學篩查策略，採用間隔時間較長（10年或5年）的肉眼觀察篩查策略，對一般發病地區的35-59歲的農村婦女來說，是更具‘成本效益’的選擇。對於宮頸癌高發地區，其篩查頻率可以提高到1年一次。1年一次的巴氏塗片篩查策略，是最有效的篩查策略，可以挽救最多的生命。但採用該策略時，應在財政預算允許的前提下，確保篩查技術和項目完成的質量。 / 篩查項目的高覆蓋率，對篩查陽性患者良好的隨訪和診治，初篩檢測技術平均水平以上的表現，以及較低的篩查和治療成本是確保篩查項目具備成本效益優勢的核心因素。本文完成的成本效用及成本效果分析，能夠為公共衛生決策提供重要的輔助作用。 / Background: / A Chinese government-sponsored cytology/visual inspection pilot cervical cancer screening program covered 10 million rural women in 221 counties of 31 provinces was initiated in 2009. Both the local and national governments in China need health economic evaluations of feasible strategies so as to make better policies for the next-step enlarging screening. / Objectives: / To perform health economic evaluations of Pap smear and visual inspection cervical cancer screening strategies using population-specific Markov modeling cost-utility (CUA) and cost-effectiveness (CEA) analyses, in order to assist screening policy making for women in rural China. / Methods: / Markov simulation models were developed to synthesize the evidence on costs and health outcomes related to cervical cancer epidemiology in rural China, and applied to predict the long-term utility, effectiveness and costs for hypothetical cohorts of 35-59 years old rural Chinese women, with or without the presence of screening over 20 years. The eight alternative screening strategies assessed were visual inspection with acetic acid (VIA) or traditional cytology (Pap smear) each with ten-year, five-year, three-year and one year screening intervals. / The study was conducted from the societal perspective, thus both directed and non-direct costs related to screening, diagnosis and treatment interventions were considered. The model structures incorporated with the well-accepted the natural history model of cervical cancer and the standard clinical pathway of screening and treatment interventions for precancerous lesions (CIN) and cervical cancer in real practice in rural China. Population-specific data were used as much as possible to be the model inputs. The model estimates were validated by comparison of our predictions of all-cause mortality, cervical cancer mortality and cervical cancer incidence with the national reported data. / Outcome variables included cumulative cost, life years (LYs), quality-adjusted life years (QALYs), predicted reduction(%) in cervical cancer mortality and incidence, relative risk of CIN, relative risk of cervical cancer, incremental cost-utility ratio (ICUR, presented as cost per QALY saved) and incremental cost-effectiveness ratio (ICER, presented as cost per life year saved). Compared with no screening, not-dominated strategies with ICUR and ICER less than three times China’s GDP per capita (76,824 CNY, 2009) were considered to be ‘cost-effective’ options. Among the identified ‘cost-effective’ options, the strategy with lowest ICUR or ICER was defined as the most cost-effective strategy, and the strategy with the highest health benefit (largest QALY saved or life year saved) was defined as the most effective strategy. Sensitivity analyses were conducted to test the effect of uncertainties on decision making. / Results: / All of the VIA and Pap smear screening strategies of showed certain benefits due to the decreased number of women developing cervical cancer, when compared with no screening. A trend for shorter screening interval to have greater benefit was also found. Cervical cancer mortality and incidence were expected to be reduced by 6.67-31.95% and 5.12-24.71% with different screening strategies. And the predicted relative risks of CIN and invasive cervical cancer of 0.89-0.98 and 0.73-0.95, respectively, also demonstrated the protective effect of screenings. / Modeling cost-utility analysis identified ten years VIA screening as the most cost-effective strategy followed by VIA screening with five-, three- and one year interval and Pap smear screening with a one year interval. Compared with no screening, the incremental costs per QALY saved of these strategies ranged from 11,921 to 26,069 Yuan (1,892-4,138 US dollars, 2012). In the meanwhile, modeling cost-effectiveness analysis also identified ten-years VIA screening as the most cost-effective strategy followed by VIA screening with five-year intervals and Pap smear screening with five-year intervals. Compared with no screening, the incremental costs per life year saved of these strategies ranged from 37,211 to 68,226 Yuan (5,906-18,830 US dollars, 2012). / Both ICUR and ICER of a selelected strategy were greatest influnced by factors related to variations in local economies , including treatment cost, screening cost and discounting rate of the cost. The influence of primary test performance of VIA was rather less than that of Pap smear due to the narrower ranges of the VIA sensitivities. Screening coverage, follow-up rate and treatment rate were also negatively associated with ICUR and ICER. Health outcome predictions and health economic analyses were mostly influenced by the uncertainties in HPV infection and CIN transitions in the natural history. Progression and regression probabilities between HPV infection and CIN were considered to be the key parameters of the simulation models. / Conclusions: / Baseline CUA and CEA results suggested that in comparison with traditional cytology screening strategies, organized VIA screening with long intervals (ten or five years) were more cost-effective options than for 35-59 years old women in normal incidence areas of rural China. The VIA screening interval can be shorten to one year in high incidence areas. Pap smear strategy with one year interval can be utilized as the most effective strategy with most lives saved when budget allows and the performances of program and test are ensured. / High coverage of the screening program, good management of screening positives, average or above performance of primary test, and lower screening and treatment costs are key elements for a cost-effective screening program. Cost-utility and cost-effectiveness analyses, such as the one conducted in this thesis study, can be considered important adjuncts to policy decision-making about public health objectives. / 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. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Li, Xue. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 388-401). / Abstracts also in Chinese; appendixes includes Chinese. / Abstract of thesis --- p.i / 中文摘要 --- p.v / ACKNOWLEDGEMENTS --- p.viii / TABLE OF CONTENTS --- p.1 / LIST OF TABLES --- p.8 / LIST OF FIGURES --- p.11 / ABBREVIATIONS --- p.12 / Chapter CHAPTER 1 --- INTRODUCTION --- p.14 / Chapter 1.1 --- Epidemiological patterns and disease burden of cervical cancer --- p.14 / Chapter 1.1.1 --- Cervical cancer incidence and mortality worldwide --- p.14 / Chapter 1.1.2 --- Risk factors for cervical cancer --- p.15 / Chapter 1.1.2.1 --- Human Papillomavirus (HPV) --- p.15 / Chapter 1.1.2.2 --- Parity --- p.16 / Chapter 1.1.2.3 --- Smoking --- p.16 / Chapter 1.1.2.4 --- Human Immunodeficiency Virus (HIV) --- p.17 / Chapter 1.1.2.5 --- Contraception --- p.17 / Chapter 1.1.2.6 --- Sexual behavior, nutrition and other factors --- p.18 / Chapter 1.1.3 --- Disease burden of cervical cancer in China --- p.18 / Chapter 1.1.3.1 --- Epidemiology of Cervical Cancer in China --- p.18 / Chapter 1.1.3.2 --- Cervical cancer in different geographic areas of China --- p.20 / Chapter 1.2 --- The need for cost-effectiveness analysis of cervical screening strategies in China --- p.21 / Chapter 1.2.1 --- Cervical cancer prevention in China --- p.21 / Chapter 1.2.2 --- Why do we need a modeling cost-effectiveness analysis? --- p.23 / Chapter 1.3 --- Natural history of cervical cancer --- p.25 / Chapter 1.3.1 --- Terminology --- p.25 / Chapter 1.3.2 --- Natural history of cervical cancer --- p.27 / Chapter 1.4 --- Secondary prevention strategies of cervical cancer --- p.29 / Chapter 1.4.1 --- Screening tests --- p.29 / Chapter 1.4.1.1 --- Cervical cytology --- p.29 / Chapter 1.4.1.2 --- Visual Inspection --- p.32 / Chapter 1.4.1.3 --- HPV testing --- p.36 / Chapter 1.4.2 --- Summary of different screening strategies all over the world --- p.37 / Chapter CHAPTER 2 --- LITERATURE REVIEW --- p.40 / Chapter 2.1 --- Background --- p.40 / Chapter 2.2 --- Objectives of the literature review --- p.41 / Chapter 2.3 --- Search strategies and results --- p.41 / Chapter 2.3.1 --- Search strategies --- p.41 / Chapter 2.3.2 --- Inclusion and exclusion criteria --- p.42 / Chapter 2.4 --- Literature results summary --- p.44 / Chapter 2.4.1 --- Methodology, target population and analytical perspective --- p.44 / Chapter 2.4.2 --- Screening test and program performance --- p.47 / Chapter 2.4.3 --- Cost and utility estimation --- p.49 / Chapter 2.4.4 --- Model parameter sources and validation --- p.53 / Chapter 2.4.5 --- Alternatives and identified cost-effective strategies --- p.58 / Chapter 2.5 --- Conclusions --- p.63 / Chapter CHAPTER 3 --- OBJECTIVES --- p.64 / Chapter 3.1 --- General Objectives --- p.64 / Chapter 3.2 --- Alternative cervical cancer screening strategies in this study --- p.64 / Chapter 3.3 --- Decision rules for recommended cost-effective options --- p.65 / Chapter 3.4 --- Analytical perspective and time horizon --- p.65 / Chapter 3.5 --- Objectives --- p.66 / Chapter 3.6 --- Analytical scenario in this study --- p.66 / Chapter 3.6.1 --- Patterns of cervical screening program delivery in rural China --- p.67 / Chapter 3.6.2 --- Demographic profile of the simulated hypothetical cohort --- p.67 / Chapter 3.6.3 --- Summary of model assumptions --- p.68 / Chapter 3.6.3.1 --- Assumptions related to screening performance and clinical practice --- p.68 / Chapter 3.6.3.2 --- Assumptions related to epidemiological characteristics of cervical cancer --- p.68 / Chapter 3.6.3.3 --- Assumptions related to economic evaluation --- p.69 / Chapter CHAPTER 4 --- METHODOLOGY --- p.70 / Chapter 4.1 --- Alternative strategies in this study --- p.70 / Chapter 4.2 --- Markov Model Developments and Applications --- p.72 / Chapter 4.2.1 --- General introduction of Markov Transition Model --- p.72 / Chapter 4.2.2 --- Structure of Markov models --- p.76 / Chapter 4.2.2.1 --- Natural history model of cervical cancer --- p.76 / Chapter 4.2.2.2 --- Structure of Pap smear and Visual Inspection screening models --- p.82 / Chapter 4.2.2.3 --- Structure of precancerous lesion and invasive cancer treatment models --- p.83 / Chapter 4.2.2.4 --- Interaction of the models --- p.85 / Chapter 4.2.3 --- Demographic profile of the hypothetical cohort --- p.86 / Chapter 4.2.4 --- Probabilities --- p.88 / Chapter 4.2.4.1 --- Identification and converting between rate and probability --- p.89 / Chapter 4.2.4.2 --- Initial probabilities --- p.90 / Chapter 4.2.4.3 --- Transition probabilities --- p.91 / Chapter 4.2.5 --- Screening, diagnosis and treatment characteristics --- p.101 / Chapter 4.2.5.1 --- Screening program characteristics --- p.101 / Chapter 4.2.5.2 --- Diagnosis test performance --- p.104 / Chapter 4.2.5.3 --- Precancerous lesions treatment characteristics --- p.104 / Chapter 4.2.5.4 --- Invasive cancer and treatment characteristics --- p.106 / Chapter 4.2.6 --- Model validation --- p.111 / Chapter 4.3 --- Cost data collection --- p.112 / Chapter 4.3.1 --- Perspective of study --- p.112 / Chapter 4.3.2 --- Selection of study sites --- p.113 / Chapter 4.3.3 --- Screening cost data collection --- p.113 / Chapter 4.3.4 --- Treatment cost data collection --- p.115 / Chapter 4.4 --- Cost-utility analysis and cost-effectiveness analysis --- p.117 / Chapter 4.4.1 --- General introduction of these two analyses --- p.117 / Chapter 4.4.2 --- Utility Estimates --- p.118 / Chapter 4.4.3 --- Screening utility and effectiveness evaluation --- p.120 / Chapter 4.4.4 --- Cost-effectiveness and cost-utility analysis method --- p.122 / Chapter 4.5 --- Time horizon and discounting rate --- p.125 / Chapter 4.6 --- Summary of modeling assumptions --- p.126 / Chapter 4.6.1 --- Assumptions related to screening performance and clinical practice --- p.126 / Chapter 4.6.2 --- Assumptions related to epidemiological characteristics of cervical cancer --- p.127 / Chapter 4.6.3 --- Assumptions related to economic evaluation --- p.128 / Chapter 4.7 --- Sensitivity analysis --- p.128 / Chapter 4.8 --- Ethical approval --- p.129 / Chapter CHAPTER 5 --- RESULTS --- p.130 / Chapter 5.1 --- Model validation --- p.130 / Chapter 5.2 --- Cost analysis results --- p.134 / Chapter 5.2.1 --- Screening costs results --- p.134 / Chapter 5.2.2 --- Treatment cost results --- p.136 / Chapter 5.2.3 --- The proportional costs breakdown for different screening strategies --- p.139 / Chapter 5.3 --- Utility estimation results --- p.141 / Chapter 5.4 --- Cost-utility analysis results --- p.144 / Chapter 5.4.1 --- Baseline analysis --- p.144 / Chapter 5.4.2 --- Influence of screening program performance --- p.148 / Chapter 5.4.2.1 --- Coverage of the screening program --- p.148 / Chapter 5.4.2.2 --- Follow up rate and treatment rate of positives --- p.155 / Chapter 5.4.3 --- Influence of screening test performance --- p.159 / Chapter 5.4.4 --- Influence of costs --- p.165 / Chapter 5.4.4.1 --- Influence of screening costs --- p.165 / Chapter 5.4.4.2 --- Influence of treatment costs --- p.168 / Chapter 5.4.5 --- Influence of discounting --- p.171 / Chapter 5.4.6 --- Summary of factors and their influences on the baseline CUA results --- p.174 / Chapter 5.5 --- Cost-Effectiveness analysis results --- p.180 / Chapter 5.5.1 --- Baseline analysis --- p.180 / Chapter 5.5.1.1 --- Life year saved --- p.181 / Chapter 5.5.1.2 --- Cervical cancer mortality reduction --- p.185 / Chapter 5.5.1.3 --- Cervical cancer incidence reduction --- p.187 / Chapter 5.5.1.4 --- Relative risk of CIN and cervical cancer --- p.189 / Chapter 5.5.1.5 --- Effectiveness summary of alternative screening strategies on the hypothetical 100,000 rural Chinese women --- p.191 / Chapter 5.5.2 --- Factors that influence the CEA results --- p.195 / Chapter 5.5.2.1 --- Best scenario analysis --- p.196 / Chapter 5.5.2.2 --- Worst scenario analysis --- p.201 / Chapter 5.5.2.3 --- Summary of the possible ranges of costs and effectiveness in different scenarios --- p.206 / Chapter 5.6 --- Sensitivity analysis --- p.209 / Chapter 5.6.1 --- Sensitivity analysis of Cost-Utility analysis results --- p.209 / Chapter 5.6.1.1 --- Tornado analysis --- p.209 / Chapter 5.6.1.2 --- One-way sensitivity analysis --- p.213 / Chapter 5.6.2 --- Sensitivity analysis of Cost-Effectiveness analysis results --- p.220 / Chapter 5.6.2.1 --- Tornado analysis --- p.220 / Chapter 5.6.2.2 --- One-way sensitivity --- p.224 / Chapter 5.6.3 --- Summary of sensitivity results --- p.236 / Chapter CHAPTER 6 --- SUMMARY, DISSICUSSION AND CONCLUSIONS --- p.240 / Chapter 6.1 --- Summary of Markov model development and validation --- p.240 / Chapter 6.1.1 --- Category and source summary of input parameters --- p.240 / Chapter 6.1.2 --- Model validation --- p.244 / Chapter 6.2 --- Summary of modeling results --- p.245 / Chapter 6.2.1 --- Summary of Cost-Utility Analysis --- p.245 / Chapter 6.2.1.2 --- Baseline analysis findings --- p.245 / Chapter 6.2.1.2 --- Influential factors on the cost-effective manner of alternative strategies --- p.246 / Chapter 6.2.2 --- Summary of Cost-Effectiveness Analysis --- p.250 / Chapter 6.2.2.1 --- Baseline analysis findings --- p.251 / Chapter 6.2.2.2 --- Possible ranges for cost and effectiveness of alternative strategies under different scenarios --- p.253 / Chapter 6.2.3 --- Summary of CUA and CEA findings --- p.257 / Chapter 6.2.4 --- Summary of sensitivity analysis --- p.259 / Chapter 6.2.4.1 --- Important variables on health outcome predictions --- p.259 / Chapter 6.2.4.2 --- Sensitive variables to the baseline CUA and CEA recommendations --- p.260 / Chapter 6.2.4.3 --- Overview of the sensitivity analysis --- p.263 / Chapter 6.3 --- Discussion --- p.264 / Chapter 6.3.1 --- Alternative strategies of cervical cancer screening in rural China --- p.264 / Chapter 6.3.1.1 --- Target ages --- p.265 / Chapter 6.3.1.2 --- Screening intervals --- p.266 / Chapter 6.3.1.3 --- Feasible primary screening tests --- p.267 / Chapter 6.3.1.4 --- Service delivering patterns --- p.269 / Chapter 6.3.1.5 --- Time horizon of this thesis study --- p.270 / Chapter 6.3.2 --- Transition probability estimation --- p.271 / Chapter 6.3.3 --- Screening and treatment cost estimation --- p.276 / Chapter 6.3.3.1 --- Representativeness of the selected counties --- p.276 / Chapter 6.3.3.2 --- Screening costs of VIA and Pap smear --- p.277 / Chapter 6.3.3.3 --- Treatment costs --- p.279 / Chapter 6.3.4 --- Utility estimation --- p.280 / Chapter 6.3.4.1 --- Instrument selection --- p.280 / Chapter 6.3.4.2 --- Utility estimation between studies --- p.281 / Chapter 6.3.5 --- Baseline cost-utility and cost-effectiveness analyses --- p.283 / Chapter 6.3.6 --- Sensitivity Analysis --- p.284 / Chapter 6.3.7 --- Strengths and limitations --- p.286 / Chapter 6.3.7.1 --- Limitations --- p.286 / Chapter 6.3.7.2 --- Strengths --- p.288 / Chapter 6.4 --- Policy implications --- p.289 / Chapter 6.4.1 --- How to manage a cost-effective cervical cancer screening program? --- p.289 / Chapter 6.4.2 --- How can VIA screening be adopted? --- p.290 / Chapter 6.4.3 --- How can Pap smear screening be adopted? --- p.291 / Chapter 6.4.4 --- Framework for policy decision making --- p.292 / Chapter 6.5 --- Conclusions --- p.295 / Chapter APPENDIX --- p.300 / Chapter Appendix 1-1 --- The 2001 Bethesda System* --- p.300 / Chapter Appendix 1-2 --- The FIGO Staging for cervical cancers* --- p.301 / Chapter Appendix 1-3 --- Cervical Cancer Screening Program in different countries --- p.302 / Chapter Appendix 4-1 --- WHO World Standardized Population Distribution (%) --- p.305 / Chapter Appendix 4-2 --- Summary of transition probabilities literature review --- p.306 / Chapter Appendix 4-3 --- Price Indices from 1978 to 2010 --- p.326 / Chapter Appendix 4-4 --- Screening Cost Questionnaire --- p.327 / Chapter Appendix 4-5 --- Programmatic Cost Survey Questionnaire --- p.339 / Chapter Appendix 4-6 --- Treatment Cost Survey Questionnaire --- p.342 / Chapter Appendix 4-7 --- EQ-5D Algorism (UK) --- p.344 / Chapter Appendix 4-8 --- Chinese Version of EQ5D----HQOL score questionnaire --- p.345 / Chapter Appendix 5-1 --- Calibrated variables and its final settings --- p.348 / Chapter Appendix 5-2 --- Cervical cancer new cases and deaths all over the world in 2008 --- p.349 / Chapter Appendix 5-3 --- Data distribution of CIN2-3 and cervical cancer treatment costs --- p.350 / Chapter Appendix 5-4 --- Relative risk of CIN and cervical cancer by age groups of alternative screening strategies --- p.361 / Chapter Appendix 5-5 --- Influence of discounting rate of life years on the CEA results --- p.363 / Chapter Appendix 5-6 --- Tornado analysis results based on the effect on QALYs predictions --- p.367 / Chapter Appendix 5-7 --- Tornado analysis results based on the effect on life-year predictions --- p.372 / Chapter Appendix 6-1 --- Summary of Markov Model Inputs and Sources --- p.377 / REFERENCE --- p.388