Dissertations / Theses on the topic 'General Medical Clinic'

Acquired immunodeficiency syndrome (AIDS) remains an epidemic illness with no known cure. Survival time after infection with the human immunodeficiency virus (HIV), has been lengthened considerably. Rates of new infection among the at-risk male homosexual populations have decreased. Prevention is possible through effective, targeted interventions. This study is an exploration of the role or health locus of control, an individual difference construct from the area of social learning theory, in the maintenance of health-oriented behaviours, co-risk indicative behaviours, and high-risk behaviours in a population of adult male homosexuals attending a general medical clinic. The findings result in distinctly different past histories and present patterns of homosexual behaviours among the two serostatus subpopulations. Low internal expectancy of control over health repeatedly relates in distinctive patterns with the areas of level of happiness, condom usage, and hish-risk sexual behaviours. High internal expectancy of control relates significantly to knowledge-related variables. The physician plays a pivotal role as the source of useful information in this at-risk population. The study population as a whole reports accurate knowledge about HIV and AIDS. The men have reduced high-risk behaviours, increased safer sexual behaviours, and implemented the changes advocated. Serostatus differentiates for many high-risk behavioural patterns. There remains a small core of men among the study participants who continue to participate in high-risk sexual behaviours.

The Virtual TIA Clinic Protocol was developed as part of the Partners Care Redesign effort to reduce costs and increase quality in the care of patients presenting with symptoms of transient ischemic attack, through risk stratification, triage, and follow-up based on factors including the ABCD2 score. The work presented here is a small N, pilot cross-sectional study which compares actual practice in the MGH ED to what the protocol would suggest, in an effort both to validate the components of the protocol and to better understand further opportunities to create value in the care of this patient population. It was found that actual practice resulted in triage patterns similar to what would have been dictated by the protocol in question. This suggests that full implementation of the protocol – with the costs associated – may not be justified. Further work could involve refinement of the protocol to achieve the desired effect on triage, with future, similar studies made more effective by a code to designate patients in whom TIA is possible but who do not ultimately receive the code for such under the current documentation system.

This thesis tells a story of a single year in the life of a primary care teaching practice from the multiple perspectives of clinical learners and those supporting learning. This story involves many people from junior medical students to nurses and doctors with twenty years of experience. It explores how they learn as clinicians. The research takes the form of a single descriptive case study based within a purposefully chosen GP teaching practice in West Yorkshire, England. The case study comprises interview, observational and documentary data collected over a single academic year in 2008/9. Interview data from 33 subjects were transcribed and analysed using thematic analysis within a modified grounded theory approach. The evidence from interview data was strengthened through direct and indirect observation and from documents relating to learning and teaching. I present a theory of how clinical learning occurs within the chosen practice, and on the nature of being a teaching practice. The findings are presented in the context of the existing literature of learning in this setting and within a theoretical framework of literature on social learning and communities of practice. Clinical learning appears to occur through engagement and opportunity. Engagement in learning is made up of four elements; recognition, respect, relevance and emotion. The elements are remarkably consistent across learner groups. Opportunity includes the availability, authenticity and immediacy of patient encounters; and the opportunity to learn with and from peers and professional colleagues. The research findings are consistent with existing work on social learning from other settings, but add to the literature. Engagement appears possible through recognition, relevance and respect and in the absence of meaningful participation, belonging or a clear trajectory of learning. Meaningful opportunities for clinical learning include those where patient encounters are made powerful through the authenticity that arises from the social and personal context of illness, and from the immediacy of hearing patient narratives de novo. The teaching practice studied in the case study is not dissimilar to others described in the literature of primary care learning, but this case study offers a far more detailed exploration of the elements which contribute to learning in the practice. These elements include strong whole practice support for learning, a skilled and committed clinical and educational workforce and a more indefinable additional element which is best summarised as a passion for education.

Advances in medical technology have altered the need for certain types of surgery to be performed in traditional inpatient hospital settings. Less invasive surgical procedures allow a growing number of medical treatments to take place on an outpatient basis. Hospitals face growing competition from ambulatory surgery centers (ASCs). The competitive threats posed by ASCs are important, given that inpatient surgery has been the cornerstone of hospital services for over a century. Additional research is needed to understand how surgical volume shifts between and within acute care general hospitals (ACGHs) and ASCs. This study investigates how medical technology within the hospital industry is changing medical services delivery. The main purposes of this study are to (1) test Clayton M. Christensen’s theory of disruptive innovation in health care, and (2) examine the effects of disruptive innovation on appendectomy, cholecystectomy, and bariatric surgery (ACBS) utilization. Disruptive innovation theory contends that advanced technology combined with innovative business models—located outside of traditional product markets or delivery systems—will produce simplified, quality products and services at lower costs with broader accessibility. Consequently, new markets will emerge, and conventional industry leaders will experience a loss of market share to “non-traditional” new entrants into the marketplace. The underlying assumption of this work is that ASCs (innovative business models) have adopted laparoscopy (innovative technology) and their unification has initiated disruptive innovation within the hospital industry. The disruptive effects have spawned shifts in surgical volumes from open to laparoscopic procedures, from inpatient to ambulatory settings, and from hospitals to ASCs. The research hypothesizes that: (1) there will be larger increases in the percentage of laparoscopic ACBS performed than open ACBS procedures; (2) ambulatory ACBS will experience larger percent increases than inpatient ACBS procedures; and (3) ASCs will experience larger percent increases than ACGHs. The study tracks the utilization of open, laparoscopic, inpatient and ambulatory ACBS. The research questions that guide the inquiry are: 1. How has ACBS utilization changed over this time? 2. Do ACGHs and ASCs differ in the utilization of ACBS? 3. How do states differ in the utilization of ACBS? 4. Do study findings support disruptive innovation theory in the hospital industry? The quantitative study employs a panel design using hospital discharge data from 2004 and 2009. The unit of analysis is the facility. The sampling frame is comprised of ACGHs and ASCs in Florida and Wisconsin. The study employs exploratory and confirmatory data analysis. This work finds that disruptive innovation theory is an effective model for assessing the hospital industry. The model provides a useful framework for analyzing the interplay between ACGHs and ASCs. While study findings did not support the stated hypotheses, the impact of government interventions into the competitive marketplace supports the claims of disruptive innovation theory. Regulations that intervened in the hospital industry facilitated interactions between ASCs and ACGHs, reducing the number of ASCs performing ACBS and altering the trajectory of ACBS volume by shifting surgeries from ASCs to ACGHs.

Pharmacists have been identified to address the increasing workload in United Kingdom (UK) general practice. A pilot has been commissioned by National Health Service England (NHSE) to upskill pharmacists for this purpose. Evaluation is underway and early reports indicate that there have been integration issues. The value of pharmacists working in general practice and the level of training required for the role are not fully understood. The research reported in this thesis was started before the NHSE pilot. It was conducted to understand the background of Clinical Commissioning Group (CCG) practice pharmacists (PPs), and their interactions with stakeholders. The rationale was to provide an insight into their working relationships and to generate recommendations to support the integration of pharmacists into general practice. The project was conducted in four CCGs in the West Midlands in 2014 using an interpretive/collective case study approach incorporating mixed methods for data collection. Quantitative data was collected on the background, employment and activities of PPs. Qualitative data was collected on stakeholders’ views of the CCG PP role from commissioners, general practitioners (GPs), and patients. Different commissioning models for PPs were studied to provide a deeper understanding of PPs’ interactions. The workload problems in general practice subsequently modified the focus of this thesis to determine the value of PPs to general practice, the level of training required and to propose a model for the integration of pharmacists into UK general practice. The thesis study identified some determinants of integration found in previously published studies but also discovered new areas specific to the integration of pharmacists into UK general practice. These areas can be grouped into three elements - the pharmacist’s skills and attributes, practice level facilitation and national level support. They are presented as a unique Model for the Successful Integration of Pharmacists into General Practice Teams.

This thesis traces endeavours in the twentieth century to provide the 'intellectual' foundations for general medical practice as an independent, autonomous clinical discipline. The empirical focus of the study is upon the application of psychological and 'person-centred' approaches to general practice; above all, in the work of Michael Balint, and the Royal College of General Practitioners in the post-war period. The thesis is guided by two predominant theoretical concerns. First, to highlight the complex strategies and the wide range of means and resources that have been required to give substance to the claim that general practice is 'by nature' a person-centred endeavour. Second, to consider - and to question certain influential approaches to medical power in general, and to the social consequences of 'emancipator' - person-centred - forms of medicine in particular. Specifically, the 'power/knowledge' approach to medical sociology is contested both with regard to its empirical findings and in relation to its basis in the work of Michel Foucault (of whose writings on clinical medicine an alternative evaluation is offered).

Placebo effects constitute context-dependent medical phenomena, and exemplify the link between psychosocial factors and physiological processes. By surveying medical students (Study 1) and practicing physicians (Study 2), the present thesis explores the knowledge and attitudes towards the role of placebos, and their related effects, in the clinic. In addition, this thesis addresses the ethics of deception in clinical practice (Commentary Response 1). Findings from Study 1 demonstrate that medical students are unaware of many non-drug effects that influence response to treatment, and yet, approximately 40% reported that they would prescribe a placebo in clinical practice. Such placebo science knowledge is critical, moreover, considering recent reports documenting the widespread use of placebos in clinical practice. These findings may foster informed discussions regarding the inclusion of placebo science in medical curricula. Study 2 reveals substantive differences among subspecialties of medicine, specifically between psychiatrists and non-psychiatrists, on the issue of placebos. Moreover, approximately 20% of physicians in Canada reported that they have prescribed or administered a placebo in the course of routine clinical practice. Such findings have implications for formal policy regarding the use of placebos in the clinic. Altogether, these findings underscore the crucial role placebos and non-drug effects have within the medical community, and emphasize the value of further exploration into the intricacies of placebo knowledge, patterns of use, and efficacies within various practices.
Les effets du placebo constituent un phénomène médical lié au contexte et illustrent le lien entre les facteurs psychosociaux et les processus physiologiques. Suite à un sondage mené auprès d'étudiants en médecine (Étude 1) et auprès de praticiens (Étude 2), cette thèse explore les connaissances et les attitudes vis-à-vis du rôle des placebos et de leurs effets dans le cadre clinique. De plus, la présente étude aborde les questions éthiques qui reposent sur la tromperie en clinique (Réponse au Commentaire 1). Les résultats de l'étude 1 démontrent que les étudiants en médecine ignorent l'influence de divers éléments non médicamenteux sur la réaction aux traitements, pourtant, 40% d'entre eux ont déclaré qu'ils prescriraient un placebo lors de leur pratique clinique. Être au fait des dernières recherches sur le placebo est critique, tout particulièrement lorsque l'on considère les derniers rapports sur l'utilisation du placebo dans le cadre clinique. Ces recherches peuvent mener à des discussions éclairées sur l'ajout de cette science aux études médicales. L'étude 2 révèle qu'il existe à ce sujet des différences substantielles au sein des spécialisations, tout particulièrement entre les psychiatres et les non-psychiatres. Par ailleurs, environ 20% des médecins au Canada ont signalé qu'ils avaient prescrit ou administré un placebo au cours de leur routine clinique. De tels chiffres ont des conséquences sur la réglementation qui entoure l'usage des placebos lors de routines cliniques. En somme, ces résultats soulignent le rôle crucial joué par les placebos et les effets non médicamenteux au sein de la communauté de médecins et l'importance d'explorer davantage les connaissances liées au placebo, son usage et son efficacité dans le cadre de diverses pratiques.

Significant advances have been achieved in the fields of medical informatics and artificial intelligence in medicine in the past three decades and, having demonstrated an ability to support clinical decisions, knowledge-based systems are becoming increasingly ubiquitous in various clinical settings. Nonetheless, few systems have so far been successful in entering routine use. On the one hand, primarily due to methodological difficulties and with very few exceptions, developers have failed to show that pertinent systems are effective in improving patient care. On the other hand, support systems have not been sufficiently well integrated into the routine information processing activity of the clinical users. As a consequence, their clinical utility is disputed and constructive assessmenist further hindered. This thesis describes the development of an intelligent clinical information management support system designed to overcome these obstacles through the adoption of an integrated approach, geared toward the solution of the problems encountered in the acquisition, organisation, review and interpretation of the clinical decision supporting information utilised in the process of monitoring intensive care unit patients with acid-base balance disorders. The system was developed to support this activity incrementally, using the methods of object-oriented analysis, design and implementation, with the active participation of a clinical advisor who assessed the functional and ergonomic compatibility of the system with the supported activity and the integration of a previously validated prototype knowledge-based data interpretation system, which could not evaluated in the clinical setting for the reasons described above.

Background: Professionalism is contextual and varies with culture. It has multiple dimensions including individual, inter-personal, organizational, and societal components. The aim of this study was to add some new perspectives to understand professionalism. Professionalism was explored in the context of two different cultures, Scotland and Pakistan, to identify similarities and differences in perceptions of clinical faculty members and medical students. Methodology: The method used was qualitative multiple case studies in a constructivist approach. Cultural Historical Activity Theory (CHAT) was used as a theoretical framework to enhance understanding of the study. Faculty members from three Scottish and three Pakistani medical schools were interviewed. Focus group discussions were arranged with groups of 7-10 medical students from each of the six medical schools. The data was analysed using a thematic analysis to identify reasons for cultural similarities and differences across two countries. Results: The results were divided into nine themes, that is, the nature of the healthcare system, models and process of professionalism, attributes of professional doctors, approach of doctors towards their patients and other healthcare professionals, working in teams, self-regulation, the role of doctors in society and within families, dealing with ethical dilemmas and legally difficult situations, and resolving conflict situations in the work place. Discussion The variance of professionalism found in this study was mainly due to the health professionals working in two different healthcare systems. The cultural differences between the two countries were reflected in these systems and the activity of professionalism included conflicts and dilemmas, self-regulation, and professional attributes. Medical professionals were found to adopt different institutional models of professionalism when they perform their daily activities. Conclusions: This study showed that doctors and medical students from both countries have mostly similar perceptions about professionalism with some dissimilarities resulting from differences in the culture, history, institutional ethos, daily activities and the role of religion. There is a lack of training in professionalism and a need to include it in the formal curriculum in Pakistan. A training programme could be organized and incorporated into the curriculum using the themes, models and process of professionalism with attention to culturally sensitive situations to prepare medical students for their early professional years in both countries. A focus needs to be on the preparation of communication skills in different contexts and the improvement of the internal environment, which is within the control of every individual. A faculty development programme, with similar objectives, needs to be introduced for medical staff to enhance their understanding of professionalism.

It is standard practice in acute-care settings to screen patients upon admission to determine whether they need a nutritional assessment; however, there is limited information on the ability of the screening tools to detect patients at nutritional risk. The purpose of this study was to determine (1) the sensitivity and specificity of the screening tool used at Jackson Memorial Hospital and (2) whether a new proposed tool would be more sensitive and specific. Dietitians screened patients upon admission using the existing and proposed tools (n=141). Sensitivity and specificity of these tools in identifying patients at nutritional risk was calculated. Mantel-Haenszel chi-square statistics were used to identify indicators correlated with nutritional risk. A revised tool was tested and found to have a higher sensitivity than the existing tool but lower specificity. Odds ratios indicated that the revised tool had a higher degree of association with nutritional risk than the existing one.

Diabetes is linked to behavior and requires patients to engage in complex self-management practices to attain glycemic control and prevent complications. Group medical visits (GMVs)—which are shared medical appointments used in primary care—provide a model of care to help patients adhere to self-management behaviors. Developing, implementing, and translating this model of care in a clinical setting has proven challenging, and the underlying mechanisms related to improved outcomes found in participants of GMVs are undetermined. The purpose of this study was to implement and evaluate GMVs for diabetes care in a primary-care and residency-training facility and explore changes in behavioral intentions, self-management behaviors, and blood HbA_1c levels. The study also explored whether behavioral intentions and self-management behaviors functioned as mediators of changes in HbA_1C levels.

A repeated measures design with 37 participants examined the behavioral intentions to diet, to exercise, and to adhere to medication; self-management behaviors (i.e., diet, exercise, and adherence to medication); and HbA _1C levels of participants with Type 2 diabetes during and after the GMVs. Behavioral intentions and self-management behaviors were measured through self-report instruments at baseline, posttreatment, and 3-month follow-up; HbA_1C values were measured at baseline and 3-month follow-up. Self-reported adherence to diet changed significantly from baseline to posttreatment and remained at 3-month follow-up.

Self-reported exercise changed significantly from baseline to posttreatment; changes were not sustained at 3-month follow-up. Clinical and statically significant changes in HbA_1C levels were seen at 3-month follow-up. A reduction of 0.7% in blood glucose levels was observed; the majority of the participants (59.5%) attained diabetes control at 3-month follow-up. No mediation relationship was found between behavioral intentions, self-management behaviors, and HbA _1C levels.

This study is the first reported examination of GMVs that found significance in biophysical outcomes without research-based funding. GMVs focused on health-behavior change can be executed and sustained in primary care and residency-training facilities. This program modality is a promising model of care for motivated patients and may help patients reach self-care goals and diabetes control. Future research with a larger sample size and a control group is needed to enhance the current findings.

Review and analysis of current clinical research practice suggests a general trend towards excluding pregnant women from clinical research studies. Although exclusionary research practices are premised upon concerns for the well-being of the fetus and the pregnant women, such practices can also produce various inadvertent harms to both parties. In particular, exclusion of pregnant women from clinical research limits the quality of care provided to pregnant women by impeding individual access to innovative research protocols and by limiting data collection applicable to the pregnant population. A review and analysis of relevant historical, legal, ethical, clinical, scientific and political documents suggests that various changes should be made to current clinical practice. To produce many such changes there is a need for a comprehensive, progressive Canadian health policy to be used to guide and direct researchers and research ethics boards in the appropriate inclusion of pregnant women in clinical research studies.
La revue et l’analyse des procédures courantes dans la recherche clinique suggèrent une tendance générale d’exclure des femmes enceintes des études cliniques. Bien que ces pratiques de recherche exclusives soient basées sur la protection des fétus et de la femme enceinte, ces pratiques peuvent aussi amener des conséquences néfastes pour la femme et son fétus. L’exclusion des femmes enceintes de la recherche clinique limite particulièrement la qualité des soins donnés à ces femmes parce que l’accès individuel au protocole de la recherche innovatrice est proscrite et la compilation des données concernant la population des femmes enceintes est limitée. La revue et l’analyse des documents historiques, éthiques, cliniques et politiques pertinents suggèrent la nécessite d’apporter des modifications importantes aux protocoles courants de recherche clinique. Une politique de santé canadienne claire et progressive aurait pour but apporter les changements nécessaires et de guider les chercheurs et les comités d’éthique de recherche sur l’insertion appropriée des femmes enceintes dans les études cliniques.

Hypertension (HTN) is a major risk factor for cardiovascular diseases including stroke, coronary heart disease (CHD), chronic renal failure, peripheral vascular disease, myocardial infarction, congestive heart failure and premature death. The prevalence of HTN in Scotland is very high and although a high proportion of the patients receive antihypertensive medications, blood pressure (BP) control is very low. Recommendations for starting a specific antihypertensive class have been debated between various guidelines over the years. Some guidelines and HTN studies have preferred to start with a combination of an antihypertensive class instead of using a single therapy, and they have found greater BP reductions with combination therapies than with monotherapy. However, it has been shown in several clinical trials that 20% to 35% of hypertensive patients could not achieve the target BP, even though they received more than three antihypertensive medications. Several factors were found to affect BP control. Adherence and persistence were considered as the factors contributing the most to uncontrolled hypertension. Other factors such as age, sex, body mass index (BMI), alcohol intake, baseline systolic BP (SBP), and the communication between physicians and patients have been shown to be associated with uncontrolled BP and resistant hypertension. Persistence, adherence and compliance are interchangeable terms and have been used in the literature to describe a patient’s behaviour with their antihypertensive drugs and prescriptions. The methods used to determine persistence and adherence, as well as the inclusion and exclusion criteria, vary between persistence and adherence studies. The prevalence of persistence and adherence have varied between these studies, and were determined to be high in some studies and low in others. The initiation of a specific antihypertensive class has frequently been associated with an increase or decrease in adherence and persistence. The tolerability and efficacy of the initial antihypertensive class have been the most common methods of explaining this association. There are also many factors that suggest a relationship with adherence and persistence. Some factors in previous studies, such as age, were frequently associated with adherence and persistence. On the other hand, relationships with certain factors have varied between the studies. The associations of age, sex, alcohol use, smoking, baseline systolic blood pressure (SBP) and diastolic BP (DBP), the presence of comorbidities, an increase in the number of pills and the relationship between patients and physicians with adherence and persistence have been the most commonly investigated factors. Most studies have defined persistence in terms of a patient still taking medication after a period of time. A medication possession ratio (MPR) ≥ 80 has been used to define compliance. Either of these terminologies, or both, have been used to estimate adherence. In this study, I used the same definition for persistence to identify patients who have continued with their initial treatment, and used persistence and MPR to define patients who adhered to their initial treatment. The aim of this study was to estimate the prevalence of persistence and adherence in Scotland. Also, factors that could have had an effect on persistence and adherence were studied. The number of antihypertensive drugs taken by patients during the study and factors that led to an increase in patients being on a combination therapy were also evaluated. The prevalence of resistance and BP control were determined by taking the BP after the last drug had been taken by persistent patients during five follow-up studies. The relationship of factors such as age, sex, BMI, alcohol use, smoking, estimated glomerular filtration rate (eGFR), and albumin levels with BP reductions for each antihypertensive class were determined. Information Services Division (ISD) data, which includes all antihypertensive drugs, were collected from pharmacies in Scotland and linked to the Glasgow Blood Pressure Clinic (GBPC) database. This database also includes demographic characteristics, BP readings and clinical results for all patients attending the GBPC. The case notes for patients who attended the GBPC were reviewed and all new antihypertensive drugs that were prescribed between visits, BP before and after taking drugs, and any changes in the hypertensive drugs were recorded. A total of 4,232 hypertensive patients were included in the first study. The first study showed that angiotensin converting enzyme inhibitor (ACEI) and beta-blockers (BB) were the most prescribed antihypertensive classes between 2004 and 2013. Calcium channel blockers (CCB), thiazide diuretics and angiotensin receptor blockers (ARB) followed ACEI and BB as the most prescribed drugs during the same period. The prescription trend of the antihypertensive class has changed over the years with an increase in prescriptions for ACEI and ARB and a decrease in prescriptions for BB and diuretics. I observed a difference in antihypertensive class prescriptions by age, sex, SBP and BMI. For example, CCB, thiazide diuretics and alpha-blockers were more likely to be prescribed to older patients, while ACEI, ARB or BB were more commonly prescribed for younger patients. In a second study, 4,232 and 3,149 hypertensive patients were included to investigate the prevalence of persistence in the Scottish population in 1- and 5-year studies, respectively. The prevalence of persistence in the 1-year study was 72.9%, while it was only 62.8% in the 5-year study. Those patients taking ARB and ACEI showed high rates of persistence and those taking diuretics and alpha blockers had low rates of persistence. The association of persistence with clinical characteristics was also investigated. Younger patients were more likely to totally stop their treatment before restarting their treatment with other antihypertensive drugs. Furthermore, patients who had high SBP tended to be non-persistent. In a third study, 3,085 and 1,979 patients who persisted with their treatment were included. In the first part of the study, MPR was calculated, and patients with an MPR ≥ 80 were considered as adherent. Adherence rates were 29.9% and 23.4% in the 1- and 5-year studies, respectively. Patients who initiated the study with ACEI were more likely to adhere to their treatments. However, patients who initiated the study with thiazide diuretics were less likely to adhere to their treatments. Sex, age and BMI were different between the adherence and non-adherence groups. Age was an independent factor affecting adherence rates during both the 1- and 5-year studies with older patients being more likely to be adherent. In the second part of the study, pharmacy databases were checked with patients' case notes to compare antihypertensive drugs that were collected from the pharmacy with the antihypertensive prescription given during the patient’s clinical visit. While 78.6% of the antihypertensive drugs were collected between clinical visits, 21.4% were not collected. Patients who had more days to see the doctor in the subsequent visit were more likely to not collect their prescriptions. In a fourth study, 3,085 and 1,979 persistent patients were included to calculate the number of antihypertensive classes that were added to the initial drug during the 1-year and 5-year studies, respectively. Patients who continued with treatment as a monotherapy and who needed a combination therapy were investigated during the 1- and 5-year studies. In all, 55.8% used antihypertensive drugs as a monotherapy and 44.2% used them as a combination therapy during the 1-year study. While 28.2% of patients continued with treatment without the required additional therapy, 71.8% of the patients needed additional therapy. In all, 20.8% and 46.5% of patients required three different antihypertensive classes or more during the 1-year and 5-year studies, respectively. Patients who started with ACEI, ARB and BB were more likely to continue as monotherapy and less likely to need two more antihypertensive drugs compared with those who started with alpha-blockers, non-thiazide diuretics and CCB. Older ages, high BMI levels, high SBP and high alcohol intake were independent factors that led to an increase in the probability of patients taking combination therapies.

Includes bibliographical references.
Short-term treatment outcomes of children starting ART in the ICU, general medical wards and outpatient HIV clinics at Red Cross War Memorial Children’s Hospital (RCWMCH): A Retrospective Cohort Study. Background: Antiretroviral therapy (ART) has proven to decrease morbidity and mortality in HIV-infected children and improve immunologic, virologic and clinical outcomes. As clinical management policies evolved, an emphasis on early infant testing was adopted resulting in an increasing number of children being diagnosed and commenced on therapy before the onset of severe disease progression. However, a fair proportion still remain untested and subsequently present to hospital with advanced immunosuppression and severe disease. Since the advent of the 2013 national Standard Treatment Guidelines which encourage expedited initiation of ART within 7 days of HIV diagnosis in all children under the age of 12 months and in those with advanced immunosuppression, it is likely that many HIV-infected children are being initiated on ART during hospitalisation in South Africa. No local published data on these outcomes exist. We assessed the short-term outcomes of children initiated on ART in the intensive care unit (ICU), general medical wards (GMWs) and outpatient HIV clinics (OHCs) at RCWMCH. Methods: Structured Literature Review A Pubmed search looking at outcomes of treatment naïve HIV-infected children and adolescents up to 19 years of age living in South Africa commenced on 1st line ART regimens in accordance to the national guidelines presiding at the time, over a 10 year period was performed. This served to identify gaps in knowledge around paediatric ART in a South African context warranting further research. Retrospective Cohort Study We conducted a retrospective cohort study of HIV-infected children <13 years of age, commenced on first line ART between January 2008 and December 2011 at RCWMCH. Outcome measures included death, virologic suppression and changes in CD4 count and percentage. Kaplan-Meier estimates, multivariate Cox proportional hazard ratios and logistic regression were used to estimate outcomes 6 months after ART initiation. Results: Structured Literature Review This review identified several knowledge gaps. One of these gaps, the treatment outcomes of children started on ART at different service levels within tertiary health care settings was addressed in our retrospective cohort study and described in section C of this dissertation Retrospective Cohort Study Seven hundred and forty-nine children were included: 106 were commenced on ART in the ICU, 509 in the GMWs and 127 in the OHCs. Four hundred and ninety-two (65.7%) children were <12 months old. Children in the ICU and GMW cohorts were significantly younger than the OHC cohort (median ages: 3 and 5 months respectively vs. 22 months) and had lower WAZ scores (-2.48 and -2.33 respectively vs -1.14). Three hundred and eighty-five (51.4%) children qualified for rapid ART initiation within 7 days of HIV diagnosis or hospitalisation, based on CD4 criteria in the 2013 national Standard Treatment Guidelines. Overall mortality was 6.4% (CI: 4.9 - 8.4). Mortality was significantly higher in the ICU cohort i.e. 14 (13.2%) deaths compared to 28 (5.5%) and 5 (3.9%) deaths in the GMWs and OHCs cohorts, logrank p=0.004. Predictors of mortality included being moderately underweight HR 2.4 (CI: 1.1 – 5.2; p=0.02), severely underweight HR 3.2 (CI: 1.6 – 6.5; p=0.001), absence of caregiver counselling sessions HR 2.9 (CI: 1.4 – 6.0; p=0.005) and ART initiation in ICU HR 2.6 (CI: 1.4 – 4.9; p=0.003). Conclusion: The findings of our retrospective cohort study serve as a basis for understanding the implications of ART initiation in children during hospitalisation.

This thesis defines the time impact of precepting medical students on rural general practitioners and explains how and why they commit the time to precept. To answer this question, original research was undertaken within the context of the innovative community-based medical education program, the Parallel Rural Community Curriculum (PRCC), using the parallel consulting model. Chapters One to Three detail the context of this study, appraise the existing evidence in the literature, and establish the rigour of the study design. In line with the constructivist theoretical perspective presented by the author, a case study methodology was chosen for this study. The thesis is constructed in two parts. Results from a prospective cohort study of GPs� videotaped consulting, with and without students, are described in Chapters Four and Five. No increase in consultation time or non-consulting time was found when precepting medical students. GPs� activities changed, suggesting they adapted their behaviour when students were present. An interpretive study, using a grounded theory approach, was used to explain the �how� and �why� of the research question. Interview data from GP preceptors, practice managers and students was used to construct a transferable explanatory theory as it emerged from the data. These results are presented in Chapters Six and Seven. The majority of GPs considered precepting more time consuming than consulting alone. This finding was not consistent with the videotaped data. GPs consistently experienced time pressure in their roles due to constant intrusion of competing priorities. This increased when precepting students. Frequent descision making by GPs as a response to their drive to remain on time was found to be a significant contributing factor to the changes found in consultation activities. Although many types of professional enrichment were identified by GP preceptors as adding value to precepting, the doctor-student relationship was clearly defined as the most important motivator for precepting in this study. The case study analysis explains how and why this occurred, and documents the maturation of the doctor-student repationship over time in the year long PRCC attachments. Through a grounded theory analysis of the data, four precepting consultation models emerged: student observer, teacher-healer, doctor orchestrator and doctor advisor. In Chapter Eight, the study defines these models in the context of legitimate peripheral participation of a novice member of the rural GP community of practice. The corroborative evidence from the literature suggests that these models may be applicable to other settings, particularly other community-based medical education sites.

Hollow-fibre liquid-phase microextraction (HF-LPME) was introduced in 1999 as a miniaturised version of liquid-liquid extraction (LLE) in order to reduce the consumption of organic solvents and offer an environmentally-friendly approach to extraction procedures. Since then, several studies have been published in the field of forensic and clinical toxicology applying the technique to a broad range of analytes; however more studies are necessary regarding its applicability to bioanalyses. The principle of HF-LPME is the extraction of analytes across a thin supported liquid membrane within the walls of a hollow fibre from a donor phase (DP) into an acceptor phase (AP). It is an extraction technique that encompasses several parameters that require optimisation for an efficient method; this is most effectively achieved by utilising a design of experiment (DoE) approach rather than the conventional one-factor-at-a-time (OFAT) approach. The main aim of this work is to further investigate the applicability of HF-LPME to the fields of forensic and clinical toxicology by developing and validating methods to extract various drugs from different biological matrices. Complex matrices, such as whole blood, are commonly used in forensic toxicology. Considering that not many studies have been performed on the application of HF-LPME to whole blood (only 10 up to the present day), this is an aspect that requires further investigation. For this, a fast, accurate and precise 3-phase HF-LPME method followed by LC-MS/MS analysis was developed and validated to simultaneously quantify 5 NBOMe drugs in human whole blood. NBOMe drugs are a group of substances part of the so-called “novel psychoactive substances” (NPS); drugs that have been emerging with increasing frequency over the last few years. NBOMes are associated to deaths as the causa mortis, and due to their high potency, these drugs are normally abused in micrograms. For that reason, the HF-LPME method developed had to present high sensitivity (LOD of pg/mL). The aim of the second part of this project was to challenge HF-LPME further by developing and validating methods to assess the potential application of HF-LPME in multi-drug analyses. Urine was selected as biological matrix, and the group of chosen analytes were 14 anti-hypertensive drugs and their metabolites with very different physical-chemical properties. HF-LPME has never been applied to such a broad spectrum of substances in previous bioanalytical studies. These drugs were divided into two groups (acidic and basic/neutral), and a total of four extraction methods (two for each group of analytes) were developed and optimised using chemometrics (DoE) then analysed by LC-MS/MS. Two of these methods were liquid-liquid extraction (LLE) methods that were developed and validated to be used as reference to which the two HF-LPME methods were compared. The LLE methods were sensitive, accurate, precise, and valid for application to real case samples. The HF-LPME methods presented some limitations due to the lack of isotopically-labelled analogues of each specific analyte as internal standards (IS); for non-exhaustive methods the use of these IS should be adopted as standard practise. Real urine samples from genuine patients were extracted using all 4 methods followed by LC-MS/MS analysis. By applying the methods to real case samples, it was possible to define that the HF-LPME methods were suitable for qualitative screening of urine to determine the level of compliance of patients under anti-hypertensive pharmacotherapy. However, for quantification of the drugs applying HF-LPME, further development is required to incorporate the use of isotopically labelled analogues. This study proved that HF-LPME is a potential asset not only for forensic but also for clinical toxicology. It can be a very powerful tool which, mainly due to its green-chemistry approach and pre-concentration capabilities, which allows direct injection into the analytical instrument, could potentially become a more used technique in the future. However, the analyst should be careful when developing HF-LPME methods, to bear in mind its limitations so that methods that are fit-for-purpose can be developed.

The prevalence of obesity worldwide has more than doubled since 1980. The World Health Organisation (WHO) estimates that more than one in ten adults in the global population is obese. Cardiovascular and metabolic health can be improved with moderate weight loss; losses of 5%–10% have been found to improve conditions such as diabetes, hypertension and cholesterol and low-density lipoprotein (LDL) levels. Within the UK, a number of weight management programmes that depend on lifestyle intervention (tier 2) and others that supplement this with drug therapy (tier 3) and surgery (tier 4) are available. The guidelines produced by the Scottish Intercollegiate Guideline Network (SIGN) advocate that weight management programmes address changes to diet, physical activity and behaviour. For patients with a body mass index (BMI) ≥30 kg/m2 or ≥28 kg/m2 in patients with comorbidities, orlistat can be considered as a drug intervention on a case-by-case basis following a full risk and benefit assessment. The objective of the Glasgow and Clyde Weight Management Service (GCWMS), a specialist weight-loss programme, is for patients to lose at least 5 kg. There are a number of metabolic disorders that are associated with obesity. One such disorder is type 2 diabetes mellitus, where weight loss is a standard recommendation to improve blood glucose control. Randomised controlled trials (RCTs) of orlistat indicate that the drug is effective in promoting weight loss and improving metabolic control for those patients with the comorbidity of type 2 diabetes and obesity. There are several different groups of anti-diabetic drugs that can be used to manage diabetes. The effects of the different medications on body weight are considerable. Some, such as biguanides (metformin), dipeptidyl peptidase-4 inhibitors (DPP-IV), Glucagon-like peptide-1 agonist (GLP-1) and sodium-glucose co-transporter-2 inhibitors (SGLT2), either have no effect on weight or can cause weight loss. Others, such as sulfonylureas (SUs) and thiazolidinediones (TZDs) can lead to weight gain. This thesis explores the impact of lifestyle interventions in weight management services, and the impact of drug interventions, on weight loss and glycaemic control. It is supported by the results of five complementary studies that reviewed the effect of orlistat on type 2 diabetes and assessed the impact of the prescription patterns of anti-diabetic drugs in addition to the effects of these pharmacological interventions on weight change in comorbid patients. The first aim of this thesis is to review the evidence of the effects of orlistat on diabetic outcomes. The second aim is to evaluate the lifestyle interventions, and phase 2 of the GCWMS. Finally, the third aim is to determine the prescribing patterns of anti-diabetic drugs, and to observe the association between anti-diabetic medications and weight change. This thesis addresses the following objectives: 1. To undertake a systematic review and meta-analysis of published studies in order to review the evidence of the effects of orlistat on weight loss, specifically concerning glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG), using the Cochrane review methodology; 2. To investigate the proportion of patients losing 5 kg of weight, commencing from their entry into the GCWMS programme, until the end of the lifestyle phase of treatment, for individuals of different ages, genders, and socioeconomic groups; 3. To study the proportion of patients losing 5 kg of weight, commencing from their entry into the GCWMS programme, until the end of phase 2, with the three different interventions of orlistat, low-calorie diet (LDL), and further weight loss (FWL); 4. To investigate the proportion of patients referred to the GCWMS on weight-neutral, mixed, and weight-gaining anti-diabetic medications; 5. To investigate the effect of baseline anti-diabetic medications on weight change for patients within a weight management programme. Chapter 2 presents the first study, which was a systemic review that considered the evidence collected in RCTs on the efficacy of orlistat for type 2 diabetes and weight loss. The effects were considered at the biochemical level and included the levels of glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG) in people with overweight and obesity. The results, collected from 2,802 participants in 12 trials, were combined into a meta-analysis. The overall finding was that a combination of orlistat and lifestyle intervention yielded superior results. When the results were compared, it was evident that patients who are overweight or obese who were subjected to combined lifestyle and drug intervention lost more weight and had better glycaemic control than patients who were subjected to lifestyle interventions only. Chapter 3 presents the second study which appraised the effectiveness of a real-life NHS lifestyle weight management intervention in reducing body weight by ≥5 kg. The study followed 23,650 patients referred to the GCWMS, of whom 7,329 attended at least two lifestyle intervention sessions. Those individuals had either a BMI of ≥30 kg/m2, with obesity-related comorbidities, or a BMI of ≥35 kg/m2 and were aged ≥18 years. The lifestyle interventions included a combination of a 600 kcal deficit diet, exercise, and behavioural changes. 30% of the overall group succeeded in losing ≥5 kg. Out of those who completed the programme, however, a considerably higher number (46%) lost ≥5 kg. The greatest losers were men, those aged ≥40 years, those with a BMI ≥50 kg/m2, and those from areas that are more affluent. Chapter 4 presents the third study which focused on patients who lost ≥5 kg in phase 2 of the treatment provided by GCWMS which comprised a low-calorie diet (LCD), orlistat 120 mg, three times a day, or further weight loss (FWL). Participants on LCD were prescribed a 1,200 or 1,500 calorie plan; however, those on FWL repeated the lifestyle phase. There were 3,262 participants who attended at least two sessions in phase 2; these were divided into three categories: 536 who took orlistat, 1,043 who followed a LCD and 1,683 who were selected FWL. By the end of phase 2, the levels of success in terms of weight loss across the groups varied from 31% of participants in the orlistat group to 22% of participants in the LCD group and 83% of participants in the FWL group who lost ≥5 kg. Chapter 5 presents the fourth study, which evaluated the pattern of anti-diabetic drug prescriptions for comorbid patients referred to the GCWMS. The study also looked at the proportion of patients who were referred prior to and after the publication of updated SIGN guidelines for the prescription of anti-diabetic medication. In total, the study enrolled 3,063 participants who received anti-diabetic medications, of whom 47.8% received weight-neutral medications, 39.4% had mixed-effect medications and 12.7% took weight-gaining drugs. Prior to the publication of the SIGN guidelines, 11.6% of participants were on weight-gaining drugs, a proportion that did not change significantly one year after the release of the guidelines. Weight-neutral drugs were more commonly prescribed to women, those with a higher BMI and young people. No relationship was observed between the Scottish Index of Multiple Deprivation (SIMD) and anti-diabetic drug prescriptions. Weight-gaining drugs such as SUs and TZDs were more commonly prescribed to older patients and those with lower BMIs. Chapter 6 presents the fifth and final study, which investigated the effect on body weight of anti-diabetic medications in 998 participants following the lifestyle phase of the GCWMS. By the end of the programme, patients who were on weight-neutral anti-diabetic drugs achieved a mean weight change of -3.3 kg (95% confidence interval [CI]: -3.8 to -2.9 kg) and those on weight-gaining drugs achieved a mean weight change of -2.5 kg (95% CI: -3.2 to -1.8 kg), p =0.05.
Among those who completed the programme, the difference was statistically significant (p =0.005). The association between weight change and anti-diabetic drug type was not explained by differences in sex, initial BMI or age. To conclude, there was a clinically and statistically significant change in weight, HbA1c and FPG in patients with obesity and type 2 diabetes who used orlistat. Of the patients following the GCWMS lifestyle phase, less than 50% succeeded in losing at least 5 kg, with patients who completed the programme being more successful. Participants who lost weight in the lifestyle phase were selected for FWL and experienced the greatest weight loss by the end of phase 2. Those who were unsuccessful in losing 5 kg through the lifestyle programme, were offered orlistat and LCD. The large sample size increased the precision of the results, while the stratification for potential confounding factors increased the study’s validity. A higher proportion of patients were prescribed weight-neutral medications, compared with mixed and weight-gaining anti-diabetic medications. The proportion of patients on weight-gaining diabetes drugs referred to the GCWMS did not alter appreciably following the release of the SIGN guidelines. By the end of the lifestyle treatment phase, patients receiving weight-neutral drugs (metformin, DPP-IV, GLP-1, and SGLT2) were more successful in losing weight than those receiving weight-gaining drugs (SUs, TZDs, and any combination including insulin). The main recommendation from this research are, that further studies are carried out to better establish the best timing of use of orlistat within a weight management programme, that the intensity of phase 2 of the GCWMS is increased, and that prescribers take account of a patient’s current BMI prior when prescribing anti-diabetic medication, especially when recommending weight loss and referring to a weight management programme.

The search for new anti-HCV therapeutics continues, as current standard of care based on pegINF and ribavirin is limited and can cause significant side effects. Several families of modified nucleoside are known to inhibit HCV RNA dependent RNA polymerase (RdRp). The 2’-C-!-methylguanosine (2’CMeG) has been identified as one of the most potent RdRp inhibitors (IC50 = 0.26 μM as NTP). Despite its very good activity at the triphosphate level its poor cell uptake and presumably poor phosphorylation lead to significant decrease in active in HCV replicon assays (EC50 = 3.5μM). The ProTide approach was applied to 2’-Cmethylguanosine in order to by-pass the first phosphorylation limiting step and enhance cellular uptake. Modified nucleoside phosphoramidates with improved efficacy and selectivity may become a future of HCV therapies. In the present work, the pronucleotide approach based on aryloxyphosphoramidate, phosphorodiamidate or oxazaphosphorine cyclic prodrugs has been applied to 2’-C-!-methylguanosine and related nucleoside analogues bearing modifications in C6-, C8- and C2- of the purine base. These modifications were mainly introduced to increase lipophilicity of 2’CMeG and consequently enhance cellular uptake and to deliver the 2’-C-methylguanosine 5’-monophosphate intracellularly. In general, most of the newly synthesised compounds exhibited excellent potency in HCV replicon assay. The most potent compounds were up to 1000-fold more active than the corresponding parent nucleoside. Base modification combined with the ProTide approach provide compounds that possess not only excellent antiviral activity but also good cell permeability. Extensive in vitro and in vivo studies lead to the selection of INX-08189 that has now progressed into human clinical trials for HCV, being currently in phase IIa clinical development.

In order for a medication treatment to be considered successful, several roles and functions along the pharmacological treatment chain must function and cooperate effectively. The chain can most easily be described as five transitions; diagnosis, prescription treatment, dispensing, drug use and finally results and follow-up. Unfortunately, there are many problems and inefficiencies in the pharmacological drug chain. Unfortunately, those who study medication errors and their solutions have focused on individual parts of the pharmacological treatment system. However, for this reason, this study aims to develop a general framework for system analysis of inefficiencies along the pharmacological treatment chain. Due to the size of the problem, this project focused on medication adherence. Adherence can be defined as to what extent the patient follows the medication treatment plan. Adherence has many known problems and difficulties, among other things, it has major financial consequences. It can also be difficult to measure compliance, and there is no recognized perfect method. A system dynamic model is a theoretical image of a real system or object, which is a model used to understand the nonlinear behavior of complex systems. These models are useful when considering interventions and their effects when there are complex relationships. The project started with a literature study, and then went into data collection. Here, a search design and refinements were designed to find relevant articles. Once the articles were selected, the data was compiled from the articles and the analysis began. Here, factors and effects on adherence were identified as well as other interesting information from the articles. When the information was compiled and analyzed, the system dynamic model was created. The model was then sent via email to experts in the field to validation and revise the model. During the data collection, 23 relevant articles were found, compiled into 38 factors associated with compliance. In addition to these factors, 8 were excluded because they were too disease-specific or too ambiguous in their effect of adherence. The various articles studied many different chronic diseases, but hypertension was the most common. How adherence was measured in the articles also varied greatly, however, some form of self-report or questionnaire was most common method used. Three out of seven experts responded to the sent-out model and provided valuable comments. Although these are not sufficient to validate the model, their views showed that a validation can be designed in this way. The model would have to be sent to a larger set of experts and stakeholders, but because these experts are recognized in their fields, it gave weight to the results even though they were few reviewers. With the support of the literature and the experts’ statement, it was concluded that this model provides a good foundation and structure to continue to build upon. In addition, the model has proven to have many key relationships and cornerstones with important and relevant factors. It is also concluded that it is possible to translate the model into quantitative patterns, which is based on the fact that the factor itself can be translated quantitatively. Overall, it is also finally concluded that the model created in this project could be of great use in future projects when working towards a framework for system analysis of inefficiencies along the pharmacological treatment chain.

Le continuel développement des outils statistiques permet aujourd’hui la modélisation de nombreux phénomènes, toujours plus complexes. En combinant l’approche offerte par des modèles statistiques spécifiques, dit "multiniveaux", et leurs applications à différentes problématiques médicales, cette thèse s’inscrit à la croisée de divers domaines : celui des statistiques, de par la méthodologie sur laquelle reposent les résultats ; mais aussi, celui de l’économie de la santé et de la santé publique en général, au travers des applications présentées.La première partie de cette thèse s’intéresse aux aspects théoriques, et plus particulièrement à l’évolution des méthodologies, du modèle de régression linéaire simple aux modèles multiniveaux pour des liens non nécessairement linéaires. Le déroulé historique de la modélisation mais également les hypothèses, le principe, la stratégie d'analyse et enfin les limites y sont abordés.La seconde partie s’articule autour de deux applications multiniveaux distinctes. La première concerne les déterminants de l'observance et des interruptions de traitement, chez les personnes infectées par le virus du VIH/Sida suivant un traitement par antirétroviraux, dans le contexte du Cameroun. La seconde, quant à elle, s'intéresse au recours aux soins dentaires chez les personnes âgées de 60 ans et plus et vivant en domicile ordinaire. Ces deux applications sont comparables dans leurs méthodologies puisqu’il s’agit de déterminer les comportements étudiés par des variables individuelles habituellement retenues, mais aussi des variables de "contexte" (caractéristiques de l’offre de soins).La troisième partie est consacrée aux applications sur le panel de médecins généralistes et traite deux études autonomes. La première expose les réticences des médecins, et le rôle de leurs aprioris, face aux Recommandations de Bonnes Pratiques (RBP). Elle nous permet de déboucher sur quelques pistes pour améliorer l’usage des RBP en médecine de ville. La seconde analyse la similarité – ou parfois la dissimilarité – entre le cycle d’activité des médecins généralistes et la saisonnalité des épidémies, dans le but d’identifier les facteurs favorisant l’ajustement des médecins généralistes aux variations saisonnières des besoins des patients. Cette étude pourrait permettre, notamment, d’anticiper et de mieux gérer des situations de crise sanitaire, avec l’appui effectif de la médecine de ville
The continual development of statistical tools allows the modelling of numerous phenomena, including the complex ones. Using a set of statistical techniques and applications, based on the so-called “multilevel” modelling, this thesis deals with different aspects related to the statistical methodology and applications as per health economics and public health.The first part reconsiders the evolution of methodology, starting from the simple linear regression techniques to the more complex multilevel modelling as applied to both the linear and non-linear relations. It addresses issues related to the historical development, the hypotheses, the strategy of analysis, and the scope of applications. The second part presents two distinct multilevel studies. The first concerns the determinants of observance and interruptions of treatment for persons infected by the HIV/AIDS and treated with antiretroviral in Cameroon. The second one focuses on the use of dental services for the elderly. The two studies are methodologically comparable in that, besides integrating the usually retained individual variables, the analyses examine health seeking behaviours, particularly, the utilisation of health care services, while accounting for contextual determinants such as the characteristics of health supply (clinic, department or region).The third part is dedicated to the applications on GPs' panel and contains two different studies. The first one explains the GPs’ behaviours and the role of their aprioris vis-à-vis Clinical Practice Guidelines (CPG), and suggests solutions to overcome their negative attitudes. The second study analyses the similarity – sometimes the differences – between the cycle of GPs’ activity and the seasonality of epidemics with the aim of better understanding determinants favouring the adjustment of the GP in the seasonal variations of the patients needs. This study helps anticipate and manage situations of sanitary crisis, with the effective support of general practitioners

Most research on the mental life of medical patients has focused on personality characteristics said to influence the experience and reporting of physical symptoms. This is despite minimal support for personality as causally related to physical illness. The popularity of daydreaming (and dreaming) is widespread in the self-help market. Yet research definitions of mental life have seldom included imaginal activities. The aim of this research was to establish a health (and mental life) profile of patients in general practice to the west of Melbourne. The principal focus was to determine if the health of patients could be predicted by mental life. Two studies were conducted. The first study investigated mental life in the form of daydreaming. Patients, approached prior to their consultation with a general practitioner, completed the Short Form Health Survey (SF-36), Severity of Physical Symptoms Checklist (SPSC), Daydream Frequency Scale (DFS), and Short Imaginal Processes Inventory (SIPI). The mental health of the sample was below the norm in the general population. The physical health of males, but not females, was also below the norm. Most patients reported less frequent daydreaming. They did, nevertheless, report more negative daydreams (than the norm). Patients unable to maintain sufficient mental control reported more negative daydreams, but not more (or fewer) positive daydreams. More negative daydreams predicted lower mental health. Patients reported fewer positive daydreams than the norm, and more positive daydreams did not improve their mental health. These findings were only partially consistent with the research literature. The second study sought to explore these findings further by determining if they were mediated by life orientation. Patients completed the Revised Life Orientation Scale (LOT-R), in addition to the SF-36 and SIPI. There were important sex differences in relationships between measures of mental life and mental health. For females, more pessimism was related to more negative daydreams and predicted lower mental health. For males, insufficient mental control predicted lower mental health. Consistent with the first study, positive daydreams (and optimism in the second study) was not related to male or female mental health. Results for females support recent research indicating that it is pessimism, and not optimism, that is the principal determinant of mental health. It is clear, however, that much more research on the correlates of male mental health, and how these differ from those of females, is warranted. The findings of the present research suggest that daydreaming is not a mundane activity: rather it is an important dimension of mental life requiring further consideration in mental health research.

Aim: This thesis reports on the implementation of key alcohol research findings to the screening and clinical detection of alcohol risk and disorder in a general practice. it aims to provide a literature review which will explain the nature of alcohol risk and disorder, why alcohol screening is necessary, and how this screening could be undertaken in general practice using a model of screening by healthcheck. Alcohol risk is presented as the likelihood of an individual to develop alcohol-related complications. Definitions of alcohol disorder are discussed and the reasons for adopting the DSM111R criteria explained. A study is reported in which healthcheck screening is used to improve detection of alcohol risk and disorder in the author’s general practice. Selected cases are presented to highlight particular issues relevant to alcohol in general practice. The study findings are discussed with reference to the literature review and recommendations on the use of the healthcheck Screening model in general practice presented. Method: All English language medical journals reporting alcohol-related research were identified by contents review (specialist alcohol and New Zealand journals), medline search (using keywords and related articles/author-specific searching) or cross.referencing from other reports. other alcohol-related professional reports were identified from library searches or obtained from original sources. From the literature review, a format was developed for the healthcheck questionnaire which included a brief alcohol screen. This brief questionnaire included three questions on consumption of alcohol, and two questions identifying concern about alcohol use, modified from screening questionnaires available at the start of the study, particularly the Canterbury Alcohotism Screening Test (CAST) and the Self-Administered Alcoholism Screening Test (SAAST). Adult patients registered with the practice were offered a personal invitation by the doctor to attend a healthcheck appointment. Recruitment was undertaken over a 3 year period for 30-69 year olds (754 eligible patients), and a 5 year period for 18-29 year olds (339 eligible patients). Patients attending the healthcheck completed a self-administered questionnaire which was reviewed by the practice nurse, selected examination items performed, and the results were discussed with the patient by the doctor. Alcohol risk was assessed and laboratory tests arranged if appropriate with follow-up appointment offered to those requiring further alcohol assessment. Patients were classified at increased risk by reported consumption, and diagnosed with alcohol disorder by DSM111R criteria (alcohol abuse or dependence). At the completion of each study period, the clinical notes of all patients in the study were reviewed to determine the screening rate and to review all recorded alcohol information including clinical indicators of alcohol disorder, alcohol risk for all screened patients, and the effect of screening on the prevalence of alcohol disorder. Results: Alcohol information was obtained on 851 of 1093 study patients (78%). Screening increased the detection of alcohol disorder from 4% (44 patients) to 8% (84 patients). clinical detection of alcohol disorder was associated with physical, psychological and social factors. Clinical factors most commonly included abnormal liver function tests, gastro-intestinal symptoms, hypertension, gout and mental health symptoms. Personal and relationship problems were also commonly linked to detection in a clinical context. Recruitment for healthchecks was highest among women (78%) with a high level of screening in both 18-29 year old (80%) and 30-69 year old groups(76%). Recruitment of men (70%) was notably more successful in the 30-69 year old group (85%) than in the 18-29 year old group (44%).As a test for DSM111R alcohol use disOrder, the brief alcohol questionnaire included in the healthcheck had a sensitivity of 0.93, a specificity of 0.85, a positive predictive value of 0.25, and a negative predictive value of 0.99. The questions on alcohol consumption were the most sensitive items, identifying increased risk (intermediate or high risk consumption) in 86% of patients with alcohol disorder. The remaining patients were identified by abnormal liver function tests. A positive screening test (consumption male>20, female >15 standard drinks/week) indicated a 1 in 4 likelihood of alcohol disorder, increasing to 1 in 2 if concern was reported on a screening question, or a liver function tests was abnormal. The healthcheck screening programme increased the detected prevalence of alcohol disorder from 4% to 8%. DSM111R criteria identified 32 patients with alcohol dependence and 52 patients with alcohol abuse. lcDl0 criteria identified 16 patients with alcohol dependence and 54 with harmful use. Nearly half of the patients meeting DSM criteria for disorder (48%) were not drinking at high risk levels (consumption male >50, female>35 standard drinks/week). Case examples drawn from the clinical notes indicated that alcohol information may come from multiple sources, and that classification of this information may be difficult, influenced not only by the completeness of the data available but also by medical interventions and other influences on patient alcohol use over time. Classification was also more difficult in some patients due to the complexity of the particular case. There were advantages identified in classifying disorder including enhanced therapeutic options, increased awareness of related issues and completeness of medical problem lists, although interventions in both risk and disorder were possible without formal diagnosis. Conclusion: there is good evidence in the literature supporting the value of general practice screening for alcohol risk and disorder. This type of screening meets accepted criteria. The importance of alcohol as a health problem is supported by both the prevalence of alcohol-related problems in New Zealand, and the relationship between alcohol and morbidity and mortality. lt is possible to recognise a latent or early symptomatic phase (risk or early abuse/dependence) and it proved possible in the study to collect this information on most patients using the healthcheck screen. There is evidence supporting the value of intervention in heavy drinking and it is reasonable to conclude that intervention in a pre-symptomatic or early symptomatic phase is of more value than waiting until more severe disorder is established. There are good screening tests available including consumption measures, patient questionnaires and laboratory tests. These are relatively inexpensive, generally easy to deliver, and provide sufficient information to determine which patients require further assessment of alcohol use. The use of the brief alcohol screening questionnaire as part of the healthcheck screen proved acceptable to patients in the study and was effective at detecting a high proportion of patients with alcohol disorder. The literature suggests that the AUDIT questions have advantages as screening questions given its international acceptability and its use in several general practice-based New Zealand studies. Although the AUDIT was not available at the time the practice study commenced, it could be incorporated in the health check questionnaire. Laboratory screening has an established supportive role, particularly the selected use of liver function tests. The role of other laboratory tests including carbohydrate-deficient transferring remains unclear and general practice research is required to determine if it has a place in screening and in which patient groups. positive screening tests require further assessment. As indicated in the case examples, this assessment may be undertaken gradually as patients attend the surgery. However, there is benefit if the assessment can be completed more fully. An alcohol assessment package for general practice would be useful. The involvement of practice nurses was essential to the successful delivery of healthcheck screening and this role could be further developed. The practice study shows it was possible to implement evidence-based alcohol screening in a general practice. The healthcheck screening model was a successful method of providing screening though recruitment of younger men could be improved. Uptake of healthcheck screening by other New Zealand general practices would require attention to the organisational factors shown to limit screening and preventive health care delivery.

碩士
義守大學
管理科學研究所
92
Service encounter is the core of many service industries. Service encounter has been an important topic in the service industry management. Previous students on service encounter have focused on three subjects: the interaction between contact personnel and customers, the customers’ roles in service encounter and the interaction between customers and material service environment. Relatively, few research focused on service encounter will affect of it on service satisfaction. However, many relevant studies argue that the service encounter will affect customers’ evaluation of service satisfaction. Consequently, the objective of research is to investigate how the service encounter affects customer satisfaction. This research will adopt the study from Bitner(1990) which used The Evaluating Service Encounters Model to collect the effects of Physical Surroundings and Employee Responses. But the obstetrics and gynecology patients have different mood for receiving treatment and many conditions from the general clinic. This study merges theory and application; it will also have contribution on practice and academic value. This study helps hospitals set up and plan the distribution of medical resource and the direction of operation strategy. In order to examine the relationships between the service encounters and the medical treatment satisfaction, this research conducted an empirical studybased on 590 respondents of the customers in the general clinics and 339 respondents of the customers in the gynecology clinics of different medical science centers in the southern Taiwan. The following is the summary of analysis. By the factor analysis, the study extracted 4 influence factors as “doctor abilities”, “nurse staffs”, “service staffs” and “facility”. By the regression model, it’s found that the doctor abilities, nurse staffs, service staffs and facility are the effective forecast factor of the medical treatment satisfaction. We could see that the higher educated the people were, the lower satisfaction the people had , and it showed significant difference in the educational demographic factor of the general clinics. We also found that we could have the biggest extent in moving up the patients’ medical treatment satisfaction by improving patients’ satisfaction in the influence factor of doctor abilities, but have the smallest in the influence factor of service staffs in the general and gynecology clinics.

Most research on the mental life of medical patients has focused on personality characteristics said to influence the experience and reporting of physical symptoms. This is despite minimal support for personality as causally related to physical illness. The popularity of daydreaming (and dreaming) is widespread in the self-help market. Yet research definitions of mental life have seldom included imaginal activities. The aim of this research was to establish a health (and mental life) profile of patients in general practice to the west of Melbourne. The principal focus was to determine if the health of patients could be predicted by mental life. Two studies were conducted. The first study investigated mental life in the form of daydreaming. Patients, approached prior to their consultation with a general practitioner, completed the Short Form Health Survey (SF-36), Severity of Physical Symptoms Checklist (SPSC), Daydream Frequency Scale (DFS), and Short Imaginal Processes Inventory (SIPI). The mental health of the sample was below the norm in the general population. The physical health of males, but not females, was also below the norm. Most patients reported less frequent daydreaming. They did, nevertheless, report more negative daydreams (than the norm). Patients unable to maintain sufficient mental control reported more negative daydreams, but not more (or fewer) positive daydreams. More negative daydreams predicted lower mental health. Patients reported fewer positive daydreams than the norm, and more positive daydreams did not improve their mental health. These findings were only partially consistent with the research literature. The second study sought to explore these findings further by determining if they were mediated by life orientation. Patients completed the Revised Life Orientation Scale (LOT-R), in addition to the SF-36 and SIPI. There were important sex differences in relationships between measures of mental life and mental health. For females, more pessimism was related to more negative daydreams and predicted lower mental health. For males, insufficient mental control predicted lower mental health. Consistent with the first study, positive daydreams (and optimism in the second study) was not related to male or female mental health. Results for females support recent research indicating that it is pessimism, and not optimism, that is the principal determinant of mental health. It is clear, however, that much more research on the correlates of male mental health, and how these differ from those of females, is warranted. The findings of the present research suggest that daydreaming is not a mundane activity: rather it is an important dimension of mental life requiring further consideration in mental health research.

No
BACKGROUND: Dementia is said to be under-recognized and sub-optimally managed in primary care, but there is little information about actual processes of diagnosis and clinical care. AIM: To determine general practitioners' concordance with clinical guidelines on the diagnosis and management of patients with dementia. Design: Unblinded, cluster randomized pre-test-post-test controlled trial involving 35 practices in the UK. METHODS: Patients with a diagnosis of probable or confirmed dementia were identified in practices, and permission sought from the older person and/or their carer to study the medical records of these patients. Medical records were reviewed using a data extraction tool designed for the study and based on published guidelines, and unweighted scores for diagnostic concordance and management concordance were calculated. RESULTS: We reviewed 450 records of patients aged 75 and over with a diagnosis of dementia and found that: only 4% of cases were identified first in secondary care; two-thirds of those identified in primary care were referred immediately; about one-third identified had informant history and blood tests documented at the Index consultation and one-fifth underwent cognitive function testing. DISCUSSION: The records analysed in this study came from a period before the Quality Outcomes Framework and show that the documentation in primary care of the diagnostic process in dementia syndromes is good, although there were significant gaps, particularly around depression case-finding. Information about management processes were less evident in the records.

The primary object of this thesis was to investigate aspects of empirically-measured, anaesthesia-induced electroencephalographic (EEG) changes that could be explained by network models of cortical interactions. The thesis consists of a collection of various theoretical and clinical papers in three sections: (a) A background section summarizing previous relevant published works on the molecular actions of anaesthetic agents, and the origin and problems with the acquisition of the EEG. (b) A second section dealing with the development of various theoretical / computer models of general anaesthetic action. (c) A third section of various clinical and EEG studies of anaesthesia and sleep. These were done to confirm and clarify some of the theoretical results from the models. However there are many different ways of numerically capturing the information contained within the EEG. Because this problem needed to be overcome before the primary aim of the thesis could be accurately handled; the clinical studies tended to be diverted into this secondary "signal-acquisition" aspect of the EEG analysis in anaesthesia and sleep. Because the thesis has a constellation of different interlocking threads of investigation, I have summarized the various themes in the following table. (A) Background Section The relevant conclusions from the background section were: 1) The transition from aesthesia to anaesthesia involved the whole animal, and thus may not be entirely measurable by the EEG. In contrast the transitions from consciousness to coma - and even more specifically - from mnesis to amnesis were predominantly observable by changes in the activity of the cortex and in the resultant EEG signal. 2) The EEG signal arose largely from the summation of coherent post-synaptic potentials in the cortical pyramidal cells. These were, in turn, mainly controlled by cortical layer-l modulation - which was subject to ascending neuromodulatory systems. 3) The main artifacts in the EEG signal were eye-movements, blinks, and frontalis EMG. 4) The Bispectral index (BIS) consisted of three subcomponents. The first two (BetaRatio and SynchFastSlow) probably reflected the loss of high-frequency activity that is associated with the transition from consciousness to unconsciousness. 5) The state of the midbrain reticular formation projecting via the non-specific thalamocortical connections can profoundly alter the oscillatory state of the cortex and thence the EEG. Direct or indirect actions of general anaesthetic agents on these structures may be a major cause of the observed EEG changes. These changes are qualitatively similar to the changes observed during natural sleep. 6) Although there was variation between different agents, the most consistent action of commonly-used general anaesthetic agents was to prolong the fast inhibitory postsynaptic potential> 50% by GABAergic potentiation. This action was consonant with the observed EEG effects of anaesthesia - which are (1) an increase in EEG spectral power and frequency followed by, (2) a decrease in dominant frequency and overall power with increasing concentrations: the so-called "biphasic response" There were also a number of more specific features: namely loss of alpha band activity, an initial increase in relative beta activity, followed by a shift to lower frequencies, spindles - and in deep anaesthesia - burst suppression patterns. Other contributions to anaesthetic action may include: (1) inhibition of NMDA receptor function, (2) reduction of nicotinic acetylcholine modulation, and (3) a direct hyperpolarizing action by opening potassium channels. Anaesthetic agents disrupted cortical function at lower doses than those required for inhibition of brain stem function. (B) Theoretical Models The fact that the cerebral cortex consisted of, effectively, a two-dimensional interconnecting neural network was of overriding importance. All the theoretical models were constrained by this topological fact, and showed a remarkable degree of similarity. Regardless of whether the model was continuous (appendix 2) or discrete (cellular automata), some robust and consistent features emerged: 1) Some form of abrupt decrease in information flow within the network occurred when the interaction between the network elements was interrupted greater than certain critical threshold amount - the order/disorder phase transition. 2) This critical point was manifest as (i) a large change in the simulated mean soma potential (the order parameter), (ii) divergence of the spectral power of the simulated pseudoEEG signal, and (iii) decrease in frequency content (in the cellular automaton models). Unfortunately the order parameter for the EEG is probably unmeasurable in clinical practice. The first derivative is measurable, but not completely reliable as a proxy order parameter. 3) All models required some form of noisy external (subcortical) input to drive them. Variations in this input could explain some of the anomalies observed in the clinical section of the thesis. (C) Clinical Papers The clinical papers were a series of papers recording the clinical data, which then influenced the development of the theoretical models. The single most popular clinical measure of anaesthetic depth in present practice is the Bispectral Index (BIS). Many of these studies explore the strengths and weaknesses of this index in various clinical situations. The main disadvantage of the BIS was that crucial aspects of its formulation are not in the public domain for commercial reasons. We attempted to separate out the changes in the various subcomponents of the BIS in patients under general anaesthesia, and natural sleep. 1) In the first paper we described how the EEG changed during induction and recovery from general anaesthesia with propofol and isoflurane. We compared EEG vs heart rate variability changes as monitors of anaesthetic depth. This study served to evaluate a clinically accepted measure of anaesthetic depth, as well as gaining practical EEG experience in collecting experimental data, both using the ASPECT EEG monitor, and in devising the best clinical methods of quantifying levels of consciousness. The main results were that the BIS was relatively reliable in steady-state conditions, and better than the raw 95% spectral edge frequency, and the approximate entropy of the EEG. 2) Auditory recall and response-to-command during recovery from propofol anaesthesia. In this paper we were able to collect data in a very controlled situation, somewhat different from that pertaining to clinical practice. From this we were able to identify separate components of consciousness and mnesis and how they correlated with EEG changes. We were also able to compare frontal and parietal EEG data. We established that there is a clear divergence of spectral power around the time of loss-of-consciousness when the propofol was administered as a slow infusion. This is good evidence supporting the basis of the theoretical models. This experiment also established that it is possible for a patient to be conscious, not paralyzed, but not responding to verbal command. 3) Electroencephalographic measures of depth of anaesthesia: the importance of the gamma band and the electromyogram signal. This study was concerned with different technical aspects of EEG signal acquisition and processing. It suggested that usually the EMG is not a significant problem, and that the gamma (40-60Hz) frequency band is important in distinguishing the awake from the anaesthetized state. 4) The Bispectral Index: A Measure of Depth of Sleep? Because the EEG changes of general anaesthesia are very similar to those of sleep, this study was a simple observational study collecting some information about changes in the BIS with natural sleep. 5) The Bispectral Index and Sleep Stage: A Polysomnographic study. In this study we formally compared the BIS with a full polysomnogramnographic sleep staging. It confirmed the results of the previous study, and demonstrated that the subcomponents of the BIS (the BetaRatio and the SynchFastSlow) changed in a manner very similar to those observed under general anaesthetic. Conclusions The observed changes in the EEG on induction of anaesthesia can be explained by changes in relatively simple theoretical network models. These changes can be reliably reduced to univariate Parameters

碩士
國立中興大學
法律學系碩士在職專班
104
Background: The effective education method of medico-jurisprudence for medical students is unclear. Objectives: To evaluate the effectiveness of problem-based learning (PBL) model teaching medico- jurisprudence in clinical setting on General Law Knowledge (GLK) for medical students. Methods: A prospective cohort study Participants: Senior medical students attending either campus- based law curriculum or Obstetrics/Gynecology (OB/Gyn) clinical setting morning meeting attended interns from February to July in 2015. Measurements: Non-parametric methods Results: The interns attending clinical setting small group improvisation medico- jurisprudence problem-based learning education had significantly better GLK score important than the GLK of students attending campus-based medical law education course after the period studied. Conclusion: PBL teaching model of medico- jurisprudence is an ideal alternative pedagogy model in medical law education curriculum. Key words: medico-jurisprudence, PBL, GLK

The purpose of study is to investigate why state certified nurses on a conversion programme to become registered general nurses score higher marks on medical - related than on nursing assessments during their fourth practical assessments. The universal sample is made up of state certified nurses on a one year conversion programme. A purposive sample consisting of 20 student nurses, 10 nurse- assessors and 5 doctor­ assessors was recruited into the exploratory quantitative study which was done at Kwekwe Hospital. A questionnaire for each of the three sample groups was used to collect data to meet the study's objectives. Data analysis yielded the main finding that students scored higher marks on nursing - related areas than on medical- related practical assessments contrary to the study's assumption. The implication is that the student nurses were able to acquire nursing care focused skills and knowledge in spite of their former medical care biased training and nursing experience.
Health Studies
M.A. (Nursing Science)

This volume contains a series of linking chapters that follow the evolution of percutaneous intervention from conventional balloon angioplasty in the early to mid 1990s to stent implantation which has now become standard practice. It describes contributions to the extension of clinical situations in which percutaneous intervention has been found to be efficacious as well as refinements in practice and technique. I was fortunate to have been a fellow and then staff member of the Cardiology department of the Thoraxcenter, Rotterdam from 1993-1995, which was then, and remains, at the forefront of the development of percutaneous coronary interventional techniques. My continued links with the Thoraxcenter as well as new projects have allowed me to continue my research and complete this thesis. Part 1 contains two chapters on balloon angioplasty which was standard clinical practice for suitable obstructive coronary lesions until the mid 1990s. The first chapter describes an audit of immediate clinical outcome and thus rates of procedure related complications of contemporary practice in a high volume unit following 970 balloon angioplasty procedures over a one-year period. Although the rate of adverse events appeared to remain static when compared to the previous decade, the requirement for emergency bypass surgery appeared to be diminishing and it is suggested that may be due to the increasing availability of stents for "bail-out". The second chapter studies the long-term outcome with respect to major adverse clinical events in 856 consecutive patients treated by balloon angioplasty from 1980-1985. Although the long-term outcome was good and comparable to results of coronary bypass surgery, most patients suffered a further cardiac event during the 10 years following balloon angioplasty, most of which were repeat revascularisation. Part 2 contains four chapters that describe and document contributions to the evolution of percutaneous coronary interventional practice from balloon angioplasty to stent implantation. Chapter 1 is a review of the literature that describes the evolution of stenting from early animal experiments through early human studies to current practice and on to a vision of the future. Chapter 2 describes follow-up of patients enrolled in the Benestent I study, which was pivotal to the introduction of stenting into clinical practice. Patients, in many centres world-wide, were randomised to balloon angioplasty or stent implantation and underwent 6-month clinical and angiographic follow-up. We report the extended one-year clinical outcome. Chapter 3 documents the landmark Benestent II study. This was a randomised comparison of 827 patients in many centres worldwide (including Auckland) who were allocated to balloon angioplasty or a heparin-coated stent plus treatment with the anti-platelet agent ticlopidine. Patients randomised to stent implantation suffered fewer adverse events and less restenosis but this treatment was found to be more costly than balloon angioplasty. Chapter 4 analyses in more detail some data from the Benestent II study. As well as being randomised to balloon angioplasty or stent implantation, patients were also sub-randomised to 6 month clinical only or clinical and angiographic follow-up. We therefore set out to assess whether management and outcome were influenced as a result of a follow-up angiogram. We found that more interventions were undertaken in those who underwent angiography with no adverse effect on outcome. As a result of the above and other studies, stenting has become routine clinical practice with most patients (approximately 90%) undergoing percutaneous coronary intervention receiving a stent. Part 3 describes several studies which have expanded our knowledge of stenting in various clinical situations and conditions, and also incorporates studies that have added refinement to the technique of stenting. Chapter 1 studies the intermediate term clinical outcome of stent implantation in degenerated saphenous vein grafts. Although the immediate outcome is good, with respect to adverse clinical events, the long-term benefit is limited indicating that with the available technology and medication percutaneous treatment of vein graft is a palliative procedure. Chapter 2 describes the results of a prospective multicentre study assessing the outcome of stenting long native coronary artery lesions. The rates of restenosis were acceptable. The study also provides us with an opportunity to analyse, using quantitative coronary angiography, the location of and give insights into, the mechanism of the restenosis process. Chapter 3 studies the outcome of stenting smaller coronary arteries. Its unique design, in that patients were required to have a lesion in a "small" and a "large" vessel, has provided us with the opportunity to compare both the rates and nature of the restenosis process in the same patients. In this way we abolished clinical and procedure related variables that confound the results when using historical comparisons. Chapter 4 describes the introduction of a new stent, the MultiLink stent, into everyday clinical usage. As with all new devices and minor variations of contemporary devices, which slowly undergo small progressive changes, a careful assessment and audit must be undertaken to ensure it has resulted in improvement in, or at least no detriment to patient care. This chapter audits the clinical outcome of a new stent implanted in the first 126 patients in Auckland and Monash Medical Centre, Melbourne. Chapter 5 is a study that tests a refinement in interventional technique. With refinement and miniaturisation of angioplasty equipment including the profile of balloons and stents, the possibly of implanting a stent without predilating the lesions with a balloon was raised. In this study 81 patients with suitable coronary artery lesions were randomised to stenting with and without predilatation. It was found that in selected patients a strategy of direct stenting was feasible, faster and more rapid than stenting after predilatation. Chapter 6 describes a study which analyses data from 10 studies co-ordinated and managed by the Cardialysis core laboratory in Rotterdam The inclusion of risk factors allows the opportunity to perform meta-analyses looking for factors that may influence outcomes. In this case we attempted to identify clinical and angiographic factors that influence asymptomatic restenosis following percutaneous coronary intervention. Chapter 7 gives an overview of angioplasty numbers and practice in New Zealand by summarising data from the National Angioplasty Registry for the years 1995-1998. This period saw a steady growth in patients with coronary artery disease treated by percutaneous intervention and the number of patients who received stents rose from 23% in 1995 to 84% in 1998. This data attests to the data and results of the earlier studies reported in this thesis.

Objetivos: O objetivo deste estudo foi avaliar a existência de associação entre a abordagem anestésica (anestesia geral versus sedação) em pacientes submetidos a implantação de válvula aórtica transcateter (TAVI) e a incidência de lesão renal aguda (LRA) no pós-operatório. Como outcome secundário, também foi avaliada a associação entre o tipo de anestesia e a mortalidade. Desenho: Estudo retrospetivo, de centro único, observacional. Local: Centro Hospitalar Universitário de São João, um centro de referência português. Participantes: Foram incluídos todos os pacientes submetidos a TAVI na instituição dos autores de janeiro de 2015 a junho de 2018. Intervenções: Anestesia geral (AG) ou sedação para procedimentos TAVI. Medições e Principais Resultados: O outcome primário foi a incidência de LRA e o outcome secundário incluiu mortalidade intra-hospitalar e aos 30 e 90 dias. No período estudado, 107 pacientes foram submetidos a TAVI (AG: n=24; sedação: n=83) e a incidência de LRA foi de 14,02%. Encontramos uma maior incidência de hipotensão intraoperatória no grupo AG (83,3% vs 33,7%, p <0,001). Em relação aos resultados pós-operatórios, não houve diferenças significativas na incidência de LRA (20,8% vs 12,0%, p = 0,319) e mortalidade. A principal descoberta de interesse foi a associação significativa entre a incidência de LRA pós-operatória e doença renal crónica (DRC) pré-existente, classe funcional de insuficiência cardíaca pré-operatória, hipotensão intraoperatória, maior período de permanência na unidade de nível II e de internamento hospitalar, e agravamento do estádio prévio da DRC. Conclusões: Não foi possível estabelecer associação entre a abordagem anestésica para procedimentos TAVI e incidência de LRA pós-operatória e mortalidade. O nosso estudo reforça a importância de prevenir a incidência de LRA, considerando o seu impacto no agravamento da DRC basal e no aumento do período de internamento, levando a custos mais elevados de hospitalização.
Objective(s): The aim of this study was to assess the existence of association between anesthetic approach (general anesthesia versus sedation) for patients undergoing transcatheter aortic valve implantation (TAVI) and the postoperative acute kidney injury (AKI) incidence. As secondary outcome we also assess the association between anesthesia type and mortality. Design: Retrospective, single-center, observational study. Setting: Centro Hospitalar Universitário de São João, a Portuguese reference center. Participants: All patients undergoing TAVI from January 2015 to June 2018. Interventions: General anesthesia (GA) or sedation for TAVI procedures. Measurements and Main Results: The primary outcome was AKI incidence, and secondary outcome included in-hospital, 30-day and 90-day mortality. In the period studied, 107 patients underwent TAVI (GA: n=24; sedation: n=83) and the overall incidence of AKI was 14.02%. We found a higher incidence of intraoperative hypotension in the GA group (83.3% vs 33.7%, p<0.001). Regarding postoperative outcomes, there were no significant differences in AKI incidence (20.8% vs 12.0%, p=0.319) and mortality. The major finding of interest was the significant association between postoperative AKI and preexisting chronic kidney disease (CKD), preoperative heart failure functional class, intraoperative hypotension, longer length of stay in level II unit and longer hospital stay, and worsening of previous CKD stage. Conclusions: It was not possible to established association between the anesthetic approach for TAVI procedures and postoperative AKI and mortality. Our study reinforces the importance of preventing AKI incidence, considering its impact on the worsening of baseline CKD and on the length of stay, leading to higher hospitalization costs.

Objetivos: O objetivo deste estudo foi avaliar a existência de associação entre a abordagem anestésica (anestesia geral versus sedação) em pacientes submetidos a implantação de válvula aórtica transcateter (TAVI) e a incidência de lesão renal aguda (LRA) no pós-operatório. Como outcome secundário, também foi avaliada a associação entre o tipo de anestesia e a mortalidade. Desenho: Estudo retrospetivo, de centro único, observacional. Local: Centro Hospitalar Universitário de São João, um centro de referência português. Participantes: Foram incluídos todos os pacientes submetidos a TAVI na instituição dos autores de janeiro de 2015 a junho de 2018. Intervenções: Anestesia geral (AG) ou sedação para procedimentos TAVI. Medições e Principais Resultados: O outcome primário foi a incidência de LRA e o outcome secundário incluiu mortalidade intra-hospitalar e aos 30 e 90 dias. No período estudado, 107 pacientes foram submetidos a TAVI (AG: n=24; sedação: n=83) e a incidência de LRA foi de 14,02%. Encontramos uma maior incidência de hipotensão intraoperatória no grupo AG (83,3% vs 33,7%, p <0,001). Em relação aos resultados pós-operatórios, não houve diferenças significativas na incidência de LRA (20,8% vs 12,0%, p = 0,319) e mortalidade. A principal descoberta de interesse foi a associação significativa entre a incidência de LRA pós-operatória e doença renal crónica (DRC) pré-existente, classe funcional de insuficiência cardíaca pré-operatória, hipotensão intraoperatória, maior período de permanência na unidade de nível II e de internamento hospitalar, e agravamento do estádio prévio da DRC. Conclusões: Não foi possível estabelecer associação entre a abordagem anestésica para procedimentos TAVI e incidência de LRA pós-operatória e mortalidade. O nosso estudo reforça a importância de prevenir a incidência de LRA, considerando o seu impacto no agravamento da DRC basal e no aumento do período de internamento, levando a custos mais elevados de hospitalização.
Objective(s): The aim of this study was to assess the existence of association between anesthetic approach (general anesthesia versus sedation) for patients undergoing transcatheter aortic valve implantation (TAVI) and the postoperative acute kidney injury (AKI) incidence. As secondary outcome we also assess the association between anesthesia type and mortality. Design: Retrospective, single-center, observational study. Setting: Centro Hospitalar Universitário de São João, a Portuguese reference center. Participants: All patients undergoing TAVI from January 2015 to June 2018. Interventions: General anesthesia (GA) or sedation for TAVI procedures. Measurements and Main Results: The primary outcome was AKI incidence, and secondary outcome included in-hospital, 30-day and 90-day mortality. In the period studied, 107 patients underwent TAVI (GA: n=24; sedation: n=83) and the overall incidence of AKI was 14.02%. We found a higher incidence of intraoperative hypotension in the GA group (83.3% vs 33.7%, p<0.001). Regarding postoperative outcomes, there were no significant differences in AKI incidence (20.8% vs 12.0%, p=0.319) and mortality. The major finding of interest was the significant association between postoperative AKI and preexisting chronic kidney disease (CKD), preoperative heart failure functional class, intraoperative hypotension, longer length of stay in level II unit and longer hospital stay, and worsening of previous CKD stage. Conclusions: It was not possible to established association between the anesthetic approach for TAVI procedures and postoperative AKI and mortality. Our study reinforces the importance of preventing AKI incidence, considering its impact on the worsening of baseline CKD and on the length of stay, leading to higher hospitalization costs.

CI-921, an analogue of the antileukaemic agent amsacrine, was produced in an attempt to develop a cytotoxic agent with a broader spectrum of activity. CI-921 was selected for clinical trial on the basis of superior in vivo and in vitro solid tumour activity. Sixteen patients with histologically documented cancer for which there was no conventional cytotoxic treatment were entered into a phase I trial. The dose of CI-921 was escalated from 39mg/m2 to 810mg/m2 (total dose divided over 3 days) and repeated 3 weekly. Neutropenia was the major dose limiting toxicity and defined a maximum tolerated dose of 810 mg/m2. Pharmacokinetic studies revealed a biexponential pattern of drug distribution with a distribution half-life of 2.6 h. The kinetics appeared linear over the dose range tested. Less than 1% of total drug was excreted in the urine. Nineteen patients were entered into a limited phase II trial in non-small cell lung cancer using CI-921 at a dose of 648 mg/m2 in the same 3-day schedule. One of the 16 evaluable patients achieved a partial response lasting five months. Myelosuppression was the predominant toxicity as in the phase I trial, but the degree of toxicity confirmed this dose as being suitable for further phase II trials. One patient had a grand mal seizure temporally associated with three of four courses of CI-927 raising the possibility of neurotoxicity. Although drug-induced cardiotoxicity has been reported with the parent drug amsacrine, there was no evidence of this in the current study. It has been suggested that CI-921 undergoes hepatic metabolism and biliary excretion following conjugation with glutathione. There was no fall in whole blood glutathione levels in patients following CI-921 infusion, although a transient decrease in mouse hepatic GSH was demonstrated following both amsacrine and CI-921. The toxicity of CI-921 in mice was markedly increased following depletion of hepatic glutathione with BSO but was not affected by pre-treatment with morphine or the glutathione "protector" N-acetyl cysteine.

Morphine is an effective potent analgesic. However the side effects of nausea, constipation and sedation are seen frequently. Respiratory depression is not such a common problem clinically but is the most potentially dangerous toxicity. An analgesic inducing equivalent analgesic potency without these toxicities would be particularly valuable. Morphine 6-glucuronide (M6G), one of the major metabolites of morphine, has analgesic activity in animals and animal studies have suggested an improved therapeutic index. The initial study in this thesis confirms the analgesic activity of M6G in man and the pharmacokinetic profile after intravenous and oral administration has been determined. The elimination half life is approximately 1.6 hours with the rate of clearance closely correlating with creatinine clearance. Oral bioavailability at approximately 5%, however, is poor due to its hydrophilic nature. In an effort to more critically examine the comparative emetic potency of M6G and morphine, both compounds were administered to the ferret, a known emetic model for man. Surprisingly M6G had a greater emetic potency in this model. A pilot pharmacokinetic study performed on the ferret revealed that M6G is only a very minor metabolite accounting for approximately only 1% of the metabolic product of morphine compared to 10% in man. It is possible that other aspects of opiate handling are also different, and reminds us of the importance in studying the drug handling of any animal model used for the testing of any drug, particularly when metabolites are thought to play a role in clinical effect. No patients or volunteers in the initial open studies in man experienced any nausea or sedation. This observation prompted a double-blind randomized study comparing the analgesic potency, respiratory depression, nausea and sedation induced by morphine and M6G in normal volunteers. This study confirmed that M6G has an increased analgesic potency in man when compared to morphine and causes significanctly less respiratory depression, nausea and sedation. It has been previously hypothesized that the µ opioid receptor with lower affinity for morphine, the µ2 receptor, is responsible for the majority of morphine toxic side-effects, including respiratory depression. The last study presented in this thesis utilises radioligand binding studies to determine the opioid receptor binding affinities of morphine and M6G at the µ1, µ2, total µ and delta opioid receptors. This reveals that M6G has a 5-fold lower binding affinity to the putative µ2 opioid receptor and hence provides a possible explanation for the decreased toxicity seen compared to morphine. In light of the findings in man above, further investigation of this active morphine metabolite is therefore indicated as M6G could prove particularly beneficial to those patients with severe underlying pulmonary disease and for obstetric use.

Chapter 1 The part that 19th century Edinburgh medicine played in formulating the early concepts of motor neuron disease as a nosological entity is described, including some hitherto unrecognized descriptions by graduates of Edinburgh Medical School, including the first description of progressive bulbar palsy. Credit is given to the great European neurologists, especially charcot’s landmark contribution of the definitive clinico-pathological correlations. Terminology relating to MND is discussed and the problems which have arisen over the nosology relating to diseases of motor neurons. The requirement for a clearly defined classification system and the importance of measuring incidence in this disease are outlined. Chapter 2 A comprehensive review of previous studies of incidence, mortality and distribution is presented. It is suggested that the value of previous clinical descriptions and epidemiological studies of motor neuron disease (MND) have been limited by methodological problems. There appears to have been a real increase in mortality from MND over recent decades. Comparison of incidence in different places is complicated by non standardised methods of case-ascertainment and diagnosis but evidence is presented which challenges the traditional concept that the distribution of MND in developed countries is uniform and static. It remains uncertain, from the evidence available, if age specific incidence continues to rise into old age and the apparent “peak” in late-middle life is due to ascertainment bias. This is an important consideration on which to base aetiological hypotheses. In the northern hemisphere there is a weak positive correlation between standardised, age specific incidence and distance from the equator. There is a high prevalence focus of an atypical MND/ALS on Guam, and while an environmental factor is probably responsible, its nature is uncertain. The relevance of other reported clusters of MND is discussed and the requirements for the ideal study of MND incidence are outlined, which acted as the impetus for the Scottish Motor Neuron Disease Register (SMNDR). Chapter 3 The methodology of the SMNDR is described. This is the first collaborative, population based, prospective, epidemiological study of MND and illustrates the feasibility of such a study and the way in which Scotland is suited (in terms of size and National Health service structure) to such a project. Diagnostic criteria are outlined for application to this and other large scale studies. Of 257 patients registered with the SMNDR as possible MND diagnosed in 1989 and 1990 in Scotland, 229 with proven (by autopsy), clinically definite or probable, sporadic or familial MND, form the basis of the description of incidence, distribution, clinical features and natural history contained in this chapter. The crude incidence was 2.24/100,000/year and age specific incidence continued to rise steeply with age into the very elderly age bands. No evidence for clustering on the basis of Scottish regions was found. 5% of patients had a family history of MND; the clinical pattern varied according to sex and age, with elderly women most likely to present with, or develop, progressive bulbar palsy. Chapter 4 The utility of the 1989-90 Scottish Hospital In-patient statistics (SHIPS) and 1989-90 death certificate coding (Registrar General for Scotland) by International classification of Diseases (ICD)-9, 335 (MND) are analysed as a tool for epidemiological studies and heath care planning. Coded hospital discharge data were an inaccurate record of a diagnosis of MND with a positive predictive value of a diagnosis of MND as determined by SHIPS of 70%. Such data cannot, in their present form, be used as a reliable measure of incidence in Scotland. Greater care is required in the preparation of summaries and coding if these data are to be useful care planning and epidemiological research. However, as an important source of case notification for the SMNDR to achieve a complete sample of patients. There was also a problematic false positive rate (10%) for mortality data but this source more closely approximated true incidence. Chapter 5 A review of previous case control studies of environmental risks for MND is presented. In order to test the hypothesis that certain environmental factors may play a role in the aetiology of MND, a case control study of 103 incident patients (diagnosis date May 1990-october 1991; 57 from the above cohort (as described in chapter 3) and 46 diagnosed in 1991, age and sex matched with community controls was conducted and is described. Measures were taken to minimise potential sources of bias and these are discussed. Fractures were more common in patients than controls especially in the in the five years prior to symptom onset (odds ratio = 15 (95% CI, 2.3-654). Manual workers were over represented and a number of environmental exposures of potential toxicity including exposure to lead (OR = 5.3, 95% CI, 1.5-11) and solvents or chemicals (OR = 3.8, 95% CI 1.5-11) were found. The limited extent of these associations favours a multifactorial aetiology for MND. No relationship to social class, poliovirus infection or to factors which might increase the risk of enteroviral infection in childhood (home space and domestic amenities) was found. Chapter 6 A comprehensive review of previous prognostic studies in MND is presented. An actuarial analysis of the survival of the cohort of 229 incident patients (57 seen in person) in Scotland in 1989-90, with complete follow up for a mean of two years from diagnosis, is calculated on the basis of the SMNDR clinical classification system. The overall 50% survival from diagnosis was 1.2 years (95% CI, 1.0-1.4) and from symptom onset, 2.5 years (95% CI, 2.2-3.0 years). There were significant differences in survival with a poorer prognosis for: progressive bulbar palsy (PBP), female sex and age > 65 years. The presence of PBP and old age were the strongest predictors of outcome, the difference in survival between the sexes was due to the higher frequency of PBP in females. The overall five year survival from symptom onset was 27.7% (95% CI, 19.9-36.0%) but for patients with PBP as the presenting feature was only 3.5% (95% CI, 0.0-15%). These results suggest that, in well defined cohorts, survival can be predicted with some confidence and are useful for the planning of treatment trials. Chapter 7 In this concluding chapter I consider the work contained in this thesis.

Cette thèse porte sur les représentations sociales de la pharmacogénomique (PGx) chez deux groupes d’acteurs centraux du développement et des applications en PGx au Québec. L’objectif est de comprendre comment les chercheurs en PGx et les étudiants en médecine se positionnent à l’égard des découvertes en PGx et de leurs éventuelles applications en pratique médicale. Cette étude a aussi pour objectifs de mieux comprendre comment il est possible d’anticiper l’arrivée de la PGx dans la pratique médicale par le contraste des représentations des chercheurs et des étudiants et de concevoir comment les informations circulent entre les deux groupes. Pour atteindre ces objectifs, l’utilisation du cadre théorique des représentations sociales, et plus particulièrement des représentations sociales dites professionnelles, est retenue. Une démarche multiméthodologique est déterminée pour cerner les représentations des deux groupes. En effet, une approche qualitative par entretiens semi-dirigés est réalisée dans un premier temps auprès des chercheurs et, ensuite, une enquête par questionnaire est effectuée auprès des étudiants en médecine. Les positionnements des deux groupes sont contrastés au sujet de trois concepts clés : les médicaments, la génomique et la PGx. Les principes organisateurs des représentations sociales des étudiants en médecine et des chercheurs, eu égard à ces trois concepts, permet de positionner le niveau des représentations sociales des étudiants en médecine vers leur professionnalisation dans un schéma proposé par Bataille (2000). Ainsi, les étudiants en médecine fournissent des représentations des médicaments assez près de celles des chercheurs. Leurs représentations des avancées en génomique sont beaucoup moins professionnalisées, tandis que l’on remarque une organisation restreinte pour ce qui est de leur représentation de la PGx. Le contexte de formation médicale est interrogé dans cette thèse puisqu’il laisse peu de place aux découvertes et aux recherches de pointe. Les chercheurs autant que les étudiants affirment que la solution pour améliorer leurs connaissances dans le domaine de la PGx est d’ajouter ces connaissances dans leur cadre de leur formation médicale.
This thesis pertains to social representations of pharmacogenomics (PGx) in two groups of central actors in PGx development and application in Québec. The objective is to understand how PGx researchers and medical students stand with regard to PGx discoveries and their potential medical practice applications. This study also aims at better understanding how the arrival of PGx in medical practice can be anticipated, by contrasting researchers’ and students’ representations, and at grasping how the information flows between these two groups. To meet these objectives, the theoretical framework of social representations, and more particularly the so-called professional social representations, is used. The two groups’ representations are identified through a multi method approach. Indeed, a qualitative method consisting of semi-structured interviews with the researchers is used, followed by a questionnaire survey of the medical students. The two groups’ positions are compared with respect to three key concepts: medication, genomics and PGx. The organizing principles of the medical students’ and researchers’ social representations, in consideration of these three concepts, enables us to position the social representation levels of the medical students relative to their professionalization in a chart proposed by Bataille (2000). The medical students’ representations of medication are thus similar to those of the researchers. Their representations of advances in genomics are far less professionalized, while there is an absence of organization in their representation of PGx. The medical training context is questioned in this thesis since it leaves little room for discovery and advanced research. Researchers and students both say that the solution for improving their knowledge in the field of PGx is to make it part of their medical training.