Background Some degree of cognitive decline is a normal, non-clinical part of aging. Physical exercise has been suggested as one strategy which may improve cognition in nondemented older adults. The findings of randomised, controlled trials conducted since the 1980s have been promising, but not unequivocal, and much remains to be understood about the relationship between exercise and cognition in older adults. There have also been suggestions that combining exercise and cognitive training may be beneficial. There has, however, been only one reported study comparing the benefits of exercise training, and combined exercise and cognitive training (Fabre, Chamari, Mucci, Masse-Biron, & Prefaut, 2002). While combined training was reported to be even more effective than exercise training alone for improving cognition in older adults, the study had some substantial limitations. Aims The overall aims of this thesis were to further explore the effect of exercise training on cognition in older adults, and to compare exercise training alone with combined exercise and cognitive training. Following a narrative review of the relevant literature, this thesis is presented in two parts. In Part One a randomized, controlled trial comparing the impact of exercise training, and combined exercise and cognitive training, on the cognitive functioning, physical functioning, functional performance, and psychological well-being of communitydwelling older adults is presented. For Part One, there were three specific aims: (1) To assess the efficacy of a 16 week exercise program (relative to control), on measures of cognitive functioning, physical functioning, functional performance, and psychological well-being; (2) To compare the efficacy of the 16 week exercise program with that of a 16 week combined exercise and cognitive training program; and (3) To identify the physical, psychological and training factors associated with changes in cognitive and physical functioning from baseline to post-test. In Part Two a qualitative evaluation of older adults’ experiences and perceptions of exercise training, and combined exercise and cognitive training, is presented. Methods Thirty-nine community dwelling, older adults (aged between 60 and 80 years) were randomly allocated to one of three groups: Exercise, Combination or Control. Participants in the Exercise group attended three aerobic and strength training sessions per week for 16 weeks. Participants in the Combination group attended two aerobic and strength training sessions, and one cognitive training session, per week for 16 weeks. Participants in the Control group were contacted every four weeks. Assessments were conducted at baseline, post-test (16 weeks) and six-month follow-up (40 weeks). Measures of physical function, cognitive function, functional performance, and psychological wellbeing were collected, along with anthropometric and physiological measures. For the qualitative evaluation, participants from the Exercise and Combination groups provided written feedback to questions about their experiences of the two training programs and their perceptions of the outcomes. These qualitative data were collected after post-test. Results Significant within-group improvements in physical and cognitive function, from baseline to post-test, were seen in Exercise and Combination participants. Combination participants also showed significant within-group reductions in symptoms of anxiety and depression. There were, however, only a few significant between-group differences among Exercise and Control participants, and among Exercise and Combination participants. There were no significant within-group improvements in functional performance, from baseline to post-test, among Exercise or Combination participants. Six-month follow-up data were difficult to interpret, due to the paucity of between-group differences at post-test and the small sample size. There were several significant associations between physical, psychological and training factors, and changes in cognitive and physical functioning. The most pertinent finding was that baseline functioning was consistently associated with change, such that participants with low baseline scores were most likely to improve from baseline to posttest. In the qualitative evaluation participants reported positive experiences of the training programs and reported improvements in physical, cognitive, functional and psychological wellbeing. Participants also highlighted components of the programs which require improvement and made recommendations for future programs. Conclusions The results of this thesis provide some cautious support for the notion that exercise, and combined exercise and cognitive training, may result in small improvements in cognition, physical functioning, and psychological well-being in older adults. Some of the findings must be interpreted with caution, however, given the small sample size. More research is required into the functional (or ‘real world’) impact of this type of training, the long-term effects of training, and the factors associated with changes in cognitive and physical function. Based on these findings, recommendations for the development and implementation of future research were made. As the population ages and the public health burden attributable to aging increases, research into the development and efficacy of programs to enhance well-being and independence in older adults is of great importance.

Rationale Within Australia, cardiac rehabilitation attendance is poor, with typically thirty percent of eligible patients attending programs. The majority of cardiac patients are not receiving the support or detailed information required to increase physical activity participation after hospitalisation. Further, many cardiac patients are not exercising independently, regardless of their attendance at cardiac rehabilitation. As physical activity is important in the prevention and treatment of heart disease, there could be substantial benefits to the individual and cost savings for the health system if cardiac patients were more active. Physical activity interventions based on social cognitive theory have demonstrated success in improving physical activity among people with chronic diseases. However, there is little research conducted with cardiac patients, in particular, with those who do not attend cardiac rehabilitation. This research addresses this gap in public health practice by providing an intervention to cardiac patients, irrespective of their attendance at cardiac rehabilitation, thereby addressing a population that is often overlooked and hard to reach. Research aims ?? To determine the uptake rate of cardiac rehabilitation in the north Illawarra and Shoalhaven areas of New South Wales and identify the characteristics of cardiac rehabilitation attendees and non attendees. ?? To evaluate the efficacy of a pedometer based physical activity intervention in cardiac patients referred to cardiac rehabilitation. Methodology This thesis consisted of three related studies: a cross sectional analysis of the characteristics of cardiac rehabilitation referrals (n = 944) over a 10 month period; and two randomised controlled trials conducted simultaneously. The Cardiac Rehabilitation Trial participants (n = 110) were patients who had attended cardiac rehabilitation; Community Trial participants (n = 215) were those who did not attend cardiac rehabilitation. The six week intervention evaluated in the trials included self monitoring of daily physical activity using a pedometer and step calendar, and two behavioural counselling and goal setting sessions delivered via telephone. Additional support for intervention group participants was provided through two brief telephone calls made after the six week intervention period. Self reported physical activity levels were collected at baseline, six weeks and six months. The questionnaire also collected information about psychosocial factors affecting physical activity participation. The exercise capacity of the participants in the Cardiac Rehabilitation Trial was objectively measured at baseline, six weeks and six months using a gas exchange analysis system. Results The cardiac rehabilitation uptake rate was 28.8 per cent of referred patients. Cardiac rehabilitation attendees were significantly younger and more likely to have had a coronary artery bypass graft surgery (CABGS) or percutaneous coronary intervention (PCI) procedure than non attendees. Study groups in both trials were not significantly different at baseline. In the Cardiac Rehabilitation Trial, improvements in total weekly physical activity sessions (p=0.002), walking time (p=0.013) and walking sessions (p<0.001) in the intervention group were significantly greater than the change in the control group at the end of the six week intervention. At six months, improvements in the intervention group remained significantly greater than the control group in total physical activity time (p=0.044), total physical activity sessions (p=0.016) and walking sessions (p=0.035) after adjusting for baseline differences. These self reported behavioural changes were corroborated by improvements in cardiorespiratory fitness at six months in the intervention group (p=0.010). Improvements in the intervention group in behavioural (p=0.039) and cognitive (p=0.024) self management strategy use were significantly greater than the controls at six weeks after adjusting for baseline differences. The improvement in cognitive strategy use (p=0.001) remained significantly greater in the intervention group compared to controls at six months after adjusting for baseline differences. Self efficacy, outcome expectancies and psychological distress were not significantly different between groups at six weeks or six months after adjusting for baseline differences. In the Community Trial, improvements in total weekly physical activity time (p=0.027), total physical activity sessions (p=0.003), walking time (p=0.013) and walking sessions (p=0.002) in the intervention group were significantly greater than the control group at six weeks after adjusting for baseline differences. At six months, improvements in total physical activity time (p=0.015), total physical activity sessions (p=0.019), walking time (p=0.002) and walking sessions (p=0.026) in the intervention group remained significantly greater than the control group after adjusting for baseline differences. Improvements in outcome expectancies (p=0.038) and cognitive self management strategy use (p=0.028) in the intervention group were significantly greater than the change in the control group at six weeks, after adjusting for baseline differences. However, these differences did not remain significant at six months. Conclusion This research showed that participation in a six week pedometer based intervention significantly increased the physical activity level and psychosocial status of people with heart disease. These findings suggest the pedometer based intervention could be offered as an effective and accessible option for those who do not attend cardiac rehabilitation to increase their physical activity levels. This intervention could also be promoted as an important adjunct to existing cardiac rehabilitation programs to promote adherence to physical activity after cardiac rehabilitation attendance. These studies provide community based evidence of an effective physical activity intervention for those eligible for cardiac rehabilitation, including those who do not attend. This provides a public health approach to cardiac rehabilitation programs and has the potential to improve health outcomes in this population.

The choice of suitable study populations in which to conduct large-scale phase III HIV prevention trials is a fundamental issue for communities, researchers, sponsors and donor organizations. In many developed and developing countries, such trials are feasible only among vulnerable, disadvantaged communities at high-risk of HIV and sexually transmitted infections, where high HIV incidence rates make randomised controlled efficacy trials feasible but where poverty, social exclusion, illiteracy, stigma and powerlessness mean ethical considerations are paramount. In such settings, preliminary feasibility studies are considered essential to inform the design of future phase III efficacy and safety trials. Researchers typically frame their assessment of feasibility within an ‘epidemiological paradigm’, focusing on a limited number of key biomedical outcome parameters to guide decision making. These include HIV, STI and pregnancy incidence; and the feasibility of recruiting and retaining sufficient numbers of subjects from a given study population. This Thesis argues that a more comprehensive assessment of feasibility, which combines epidemiological factors with other key constructs such as ethics and social justice, is critical to the successful conduct of high quality and ethically sound HIV prevention trials among vulnerable at-risk study populations in Africa. This work is based on a combination of epidemiological, applied social science and participatory action-orientated research conducted during a microbicide trial feasibility study and an on-going phase III randomised placebo-controlled efficacy and safety trial of the candidate vaginal microbicide PRO2000/5 Gel (Indevus Pharmaceuticals, USA) that I coordinated as the Clinical Site Principal Investigator in Tanzania from November 2002 until March 2007, and for which I remain a Co-Investigator. All fieldwork was carried out in Mwanza City, in the Lake Victoria basin region of northwest Tanzania, among an occupational cohort of women working in bars, guesthouses, hotels and other food outlets and recreational facilities. Some women in this occupational group are known to periodically engage in transactional and commercial sex to supplement their income and are therefore considered to be at increased risk of HIV and sexually transmitted infections, and to represent a potential study population for future microbicide and other HIV prevention trials.

This thesis describes the development of separate assays to measure coenzyme Q₁₀ (CoQ₁₀) and vitamin K. Coenzyme Q is essential for the mitochondrial electron transport chain, and vitamin K for the blood coagulation cascade. Vitamin K deficiency is associated with haemorrhagic disease of the new-born, and CoQ₁₀ deficiency with HMG-CoA-reductase inhibitor (statin) therapy and heart failure. Coenzyme Q and vitamin K are usually measured by HPLC, using electrochemical and ultraviolet, and electrochemical and fluorescence detection, respectively. For vitamin K1, the limit of detection achieved using fluorescence and electrochemical detection was 0.28 and 0.12 nmol/L, respectively. Sensitivity of fluorescence detection is improved by using protic solvents in the mobile phase, and platinum-black catalysed alcohol reduction. The lipophilicity and low endogenous concentrations of vitamin K1 hinder its measurement, and further work is required to produce a rapid, reliable and robust assay for its measurement in human plasma. The limits of detection achieved using fluorescence, ultraviolet and electrochemical detection to measure CoQ₁₀ were 29, 4.8, and 0.34 nmol/L, respectively. Plasma CoQ₁₀ is not stable during long term storage at -13 ℃, but at -80 ℃ it is stable for at least 18 months. The reference interval for plasma total CoQ₁₀ in the New Zealand population is 0.47 - 1.80 µmol/L. There is no clinical requirement for stratification of the reference interval according to gender. Coenzyme Q₁₀ in human plasma is homeostatically controlled, varying little over a two month interval in healthy young males. Coenzyme Q₁₀ supplements have significantly different bioavailability, with the median increase in plasma CoQ₁₀ ranging from 0.14 to 0.59 µmol/L for seven different supplement brands. There is a large inter-individual variation in CoQ₁₀ absorption, and hence plasma concentrations should be monitored during supplementation. A plateau in CoQ₁₀ absorption, from a single dose, at approximately 200 mg suggests that the maximum dose ingested at one time should be 200 mg or less. Q-Gel capsules containing 30 mg of CoQ₁₀ are twice as effective at raising blood CoQ₁₀ as 100 mg capsules. Plasma CoQ₁₀ in patients with chronic heart failure are significantly lowered by approximately 33% when these patients receive Atorvastatin for six weeks. The absolute decrease in CoQ₁₀ showed a significant correlation with worsening endothelial function (r = + 0.548, p = 0.011). Coenzyme Q₉ was shown to be present in human plasma with a reference interval of 8.8 - 47.0 nmol/L.

Abstract Background The randomised-controlled trial (RCT) provides the best evidence for evaluating treatment effects and is accepted as a gold standard for clinical and regulatory decision making (1;2). One of the major challenges to the conduct of RCTs is the recruitment of adequate numbers of participants. Inadequate numbers reduce the power of a study to detect statistically significant treatment effects, and may cause delays, increased costs and failure to complete trials. The need for clinical trials in children has been increasingly recognised by the scientific community, resulting in increased demands for the inclusion of children in trials. For several reasons, recruiting children to trials is more challenging than recruiting adults, as consent issues are more difficult because parents make decisions about trial participation on behalf of their child. Despite general professional and community support for paediatric clinical trials, parents and paediatricians express reluctance when their own child or patient is asked to participate. Although researchers working with children commonly experience difficulty with recruiting children to RCTs, little is known about this very important subject. The method by which potential participants are approached for trial participation, the influence of their health care provider and the attitude of potential participants (or their parents, in the case of children), are critical to the understanding of the decision making process for trial participation. This thesis is one of the first major attempts to explore the issues surrounding the recruitment of children to RCTs, and is divided into four studies which address these issues. Methods Recruitment strategies used to encourage participation in randomised controlled trials (systematic review) Eligible experimental and observational studies comparing methods of recruiting participants for RCTs were identified after a comprehensive search of Medline, Embase, the Cochrane Library and reference lists. Independent data extractions were completed by two reviewers who assessed the studies for eligibility and methodological quality. Outcome measures were consent rates, proportion enrolled by each method and cost of recruitment per participant. Summary estimators of effects were calculated using a random effects model and expressed as relative risk with 95% confidence intervals. Heterogeneity was analysed using the Q statistic. Paediatricians� attitudes to children�s participation in randomised controlled trials (focus group research) Qualitative analysis of focus group discussions involving 16 paediatricians and 5 trainees from a paediatric teaching hospital in Sydney was undertaken. Doctors varied in occupation, experience, research activity, age, gender, ethnicity and parenthood experience. A professional facilitator conducted the semi-structured group discussions. Recruitment ceased when informational redundancy was reached, after 4 focus groups involving 21 participants. The transcribed audiotapes were analysed by theme linkage using the constant comparative method. Australian paediatricians� and adult physicians� attitudes to randomised controlled trials (survey) A 44-item questionnaire was sent to 250 paediatricians and 250 adult physicians randomly selected from the membership list of the Royal Australasian College of Physicians. Questions assessing doctors� treatment philosophies and attitudes to trials were compared with demographic and practice variables. Parents� attitudes to children�s participation in randomised controlled trials (focus group research) Qualitative analysis of focus group discussions involving 33 parents from 5 different settings (representing parents of children with a life threatening, chronic or acute illness, with experience in trials and of healthy children) was undertaken. Parents varied in age, gender, ethnicity, level of education, research experience and their child�s health status. The transcribed discussions were analysed by theme linkage using the constant comparative method. Results Recruitment strategies used to encourage participation in randomised controlled trials (systematic review) Fifty papers were included (out of 8602 titles and abstracts searched) which described 8 RCTs, 2 quasi RCTs, 13 prospective cohort studies, 30 retrospective cohort studies and 2 before-after studies. These studies assessed how over 4 million people were approached for RCT participation using 87 different recruitment strategies, with 103,406 people enrolling in RCTs. Health care provider (HCP) referrals had the highest participant consent rates at the time of exposure to trial information (HCP referral versus target mailing: relative risk (RR) 1.84 (95% confidence interval (95%CI) 1.08, 3.13)). They also had the highest consent rates when potential participants respond to the recruitment material by further enquiry about the trial (HCP referral versus community presentation: RR 1.37 (1.06; 1.78); HCP referral versus worksite approach: RR 25.20 (20.19, 31.45); HCP referral versus general community approach: RR 2.53 (0.46, 14.05); HCP referral versus mailing: RR 3.29 (1.26, 8.60); HCP referral versus media: RR 2.66 (1.31, 5.41)). However, by the time potential participants attend eligibility assessment for trial participation, no difference in consent rates could be distinguished by method of recruitment. Higher proportions of study participants were recruited by methods that exposed larger numbers of potential candidates to trial information (despite their lower consent rates). The stated recruitment cost ranged from US$0 to $1108 per participant, with mailing being the most cost-effective method and community methods (such as community presentations, pamphlets and posters displayed at community sites) the least effective. Paediatricians� attitudes to children�s participation in randomised controlled trials (focus group research) From the focus group discussions, paediatricians thought parents balanced perceived gains and risks when deciding about trial participation. They also believed the child�s condition and parents� health beliefs and personal attributes influenced parents� decisions. Other factors thought to be important by paediatricians were the doctors� beliefs and their relationship with the investigators. Paediatricians perceived gains for trial participation including professional benefits for themselves, improved patient care, convenience for the families and themselves and scientific advancement. Perceived risks included inconvenience, inadequate resources and potential harms to the patient and the doctor-patient relationship. Paediatricians with previous research experience were most knowledgeable about RCTs and perceived greatest gains from trial participation. Paediatricians� personal treatment preferences hindered trial support. Australian paediatricians� and adult physicians� attitudes to randomised controlled trials (survey) Response rate from the paediatricians� and adult physicians� survey was 60% (300/500). Australian paediatricians and adult physicians are very similar in their treatment philosophies, and are clinician-oriented rather than research-oriented in their attitudes, with primary allegiance to their patients and preference for selecting treatment rather than referring for trial participation in the face of treatment uncertainty. Professional activities are clinically focused, with limited time assigned for research. Australian doctors perceive little reward for trial participation and claim that the opinions of referring doctors regarding RCTs does not influence them. Predictors of favourable attitudes to trial participation from the survey were time allocation for research, a history of referring patients to trials in the past and younger age (all p values less than 0.0001). Parents� attitudes to children�s participation in randomised controlled trials (focus group research) When parents were interviewed, they acknowledged balancing risks and benefits when deciding about trial participation for their child. Perceived benefits include the offer of hope, better care of their child, the opportunity to access new treatments, healthcare professionals and health information, meeting others in similar circumstances and helping others. Perceived risks include potential side effects, being randomised to ineffective treatments and the inconvenience of participation. The decision for trial participation is also influenced by parental factors (parents� knowledge, beliefs and emotional response), child factors (the child�s health status and preference about participation), trial factors (the use of placebos and the uncertainties of research) and doctor factors (doctor�s recommendations and communication of trial information). Conclusions There are many challenges to the successful conduct of RCTs. Ways of addressing these include: using effective methods of recruiting potential study participants (such as mailing of recruitment material to potential participants) and abandoning ineffective strategies (such as community methods): fostering greater willingness for trial participation by addressing parents� and paediatricians� concerns including enhancing communication between researchers, paediatricians and parents, and improving the gains-hazard balance (by increasing incentives while decreasing inconveniences); and reforming in the health care system to raise the priority placed on clinical research by restructuring clinical research in a clinically predominant workplace and with a clinically predominant workforce. The findings from this study have implications for researchers planning RCTs for children in the future. Careful consideration of the above will enhance RCTs participation for children improving efficiency, lowering costs and ultimately improving the future health care of children.

Philosophy(PhD) / This thesis presents a randomised controlled trial of the Lidcombe Program of Early Stuttering Intervention. The Lidcombe Program was developed for the treatment of stuttering in preschool-age children. The effectiveness of the Lidcombe Program was compared to a control group in a parallel group randomised controlled trial with blinded outcome assessment. A number of supplementary studies were conducted in support of the trial; two literature reviews, two retrospective file audits and a statistical simulation study. A review of randomised studies of treatments for stuttering showed that there have been 27 such studies published in English language journals. Of these only one was devoted to a treatment for early stuttering and that was the Lidcombe Program. The randomised study showed that 3 months of this treatment was associated with a lower level of stuttering compared to a control group who received no treatment. However, with a sample size of 23, this study lacked power and the children did not receive a full course of treatment. Despite these limitations, this study provided evidence that a medium to large effect size could be anticipated in an adequately powered and properly conducted randomised controlled trial. The second review was of sample size and power in stuttering research studies that had been published in two speech pathology journals; the Journal of Speech, Language and Hearing Research (Vol 39, No. 1 to Vol 40, No, 4) and the Journal of Fluency Disorders (Vol 21, No. 1 to Vol 22, No, 3). Results suggested that the majority (73%) of the 26 studies reviewed were insufficiently powered to detect even large effects. However it was acknowledged that it is very difficult to recruit even moderate sample sizes of people who stutter. It was concluded that one way to help improve this situation is collaboration of multiple research centres or, in the case of a randomised controlled trial, inclusion of multiple recruitment sites in one study. This strategy was adopted in the randomised controlled trial reported in this thesis. Two retrospective file audit studies of children treated with the Lidcombe Program were conducted in Australia and Britain. One purpose of these file audits was to obtain information relevant to the design and conduct of the randomised controlled trial. Data from the case reports on more than 300 children from the two sites were included in a meta-analysis. Results showed that a median of 11 weekly clinic sessions were required for children to attain the criteria for low levels of stuttering for completion of Stage 1 of the Lidcombe Program. Approximately 90% of children had achieved those criteria within 6 months of beginning treatment and almost all children had achieved them within 1 year. In addition two variables were found to be associated with longer treatment duration: more severe pre-treatment stuttering and shorter times from onset of stuttering to the start of treatment. The latter was apparent in the meta-analysis but not for the individual cohorts. As a result of these findings, pre-treatment stuttering severity was stratified along with other relevant variables in the randomised controlled trial and follow up for participants was a minimum of 9 months. A simulation study was conducted prior to analysis of data from the primary outcome measure of the randomised controlled trial: percentage of syllables stuttered (%SS). The distribution of %SS scores is positively skewed. Nonetheless, simulation showed t-test to be an appropriate analysis for this primary outcome measure. There were two treatment sites for the randomised controlled trial: the University of Canterbury (Christchurch, New Zealand) and the Stuttering Treatment and Research Trust (Auckland, New Zealand). A total of 54 preschool-age children were recruited: 29 to the Lidcombe Program and 25 to the control group. Half the proposed sample size was achieved due to slower than anticipated recruitment. This occurred because, as the trial progressed, treatment with the Lidcombe Program became common knowledge among parents in New Zealand and they became increasingly reluctant to agree to have their child randomised to the trial. Analysis with t-test showed a highly statistically significant difference (p = 0.003) at 9-months post-randomisation. The mean percentage of syllables stuttered (%SS) at 9-months post-randomisation was 1.5 (SD = 1.4) for the Lidcombe Program group compared to 3.9 (SD = 3.5) for the control group, resulting in a treatment effect of 2.3 %SS (95% confidence interval: 0.8-3.9). This treatment effect was more than double the minimum clinically worthwhile difference specified in the trial protocol. These results show that the Lidcombe Program is significantly more effective than natural recovery for reducing stuttering levels in preschool children. The Lidcombe Program is the first early stuttering treatment to be shown to be more effective than natural recovery in a randomised controlled trial.

Thesis (LL. M.)--Judge Advocate General's School, 1961. / "May 1961." Typescript. Includes bibliographical references. Also issued in microfiche.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (p. [167]-174).

Title from title page of PDF (University of Missouri--St. Louis, viewed March 22, 2010). Includes bibliographical references (p. 54-62).

Thesis (J.C.D.)--Catholic University of America, 1934. / Vita. Includes bibliographical references (p. 143-145) and index.