Introduction: Oral mucositis is an inflammatory and frequently ulcerative side effect of cancer therapy, which has been identified by patients as the most debilitating side effect of their treatment. Mucositis is a dose limiting toxicity which exerts a substantial clinical and economic impact and negatively affects patient quality of life. The patient experience of mucositis is under-reported in the literature. To date, no interventions have been identified that have proven successful in the prevention of mucositis for patients receiving all types of therapy. Vitamin E has shown conflicting results in clinical trials. This thesis combines appraisal of the literature and empirical research,and uses lessons learned from previous studies together with the results of a feasibility study to identify a best practice model for future trials. Methods: The Cochrane risk of bias (ROB) instrument was used to assess the ROB in the studies included in the Cochrane prevention review. A sensitivity analysis was conducted after studies assessed at unclear or high risk of overall bias were excluded. A systematic review of assessment instruments was conducted which identified 50 instruments. Consideration of the appropriateness of these instruments for the use in a clinical trial for the prevention of mucositis was based on the practicality, comparability, and reproducibility, and the impact of these instruments on patients. Three of these instruments were chosen for use in a clinical trial of adults undergoing stem cell transplant. Finally, a feasibility study was designed, developed and conducted which investigated vitamin E for the prevention of mucositis in patients undergoing conditioning for bone marrow transplantation. Through lessons learned from previous studies, consultations with medical professional, the MHRA, ethics committee and suppliers, a protocol was developed for a double blind RCT. The process of gaining MHRA and ethical approval, and the repackaging of intervention and placebo products to meet MA-IMP requirements are described. Results: 130 articles were assessed for risk of bias. Only ten studies were assessed as being at low overall risk of bias. Blinding of outcome assessors and adequate allocation concealment were identified to be important considerations in the planning of future studies. Although only nine patients were recruited into the feasibility study, a number of issues affecting the design and conduct of future trials were identified. Recruitment in particular was identified to be problematic. Strategies for overcoming this problem in future trials were discussed. The methods of blinding and allocation concealment employed were found to be feasible for use in future trials. Expected adverse events patients undergoing stem cell transplantation were also reported. Conclusion: Further studies are required to investigate interventions for the prevention of mucositis. It is of upmost importance that these trials are rigorous in both their methodology and subsequent reporting in order to elicit the maximum benefit for patients taking part in clinical trials, and future patients undergoing therapy for cancer.

This study investigates the prevalence of peri-operative anxiety and the effective management of intra-operative anxiety during awake surgery. Plastic and vascular surgical patients were selected for the study as many procedures performed within these specialities are performed under local or regional anaesthesia. The study consists of two distinct stages. The first stage was a postal survey of patients (n=213) who had undergone awake plastic, renal access or carotid surgery up to two weeks previously, in order to determine retrospectively the prevalence of peri-operative anxiety. The second stage of the study was a randomised controlled trial of interventions for the effective management of intra-operative anxiety in patients (n=128) having undergone the same surgical procedures described in stage one. The interventions tested in stage two were handholding and an anxiety management package involving a relaxation technique and a procedural information leaflet, against a ¿usual care¿ control. The findings from stage one of the study suggest that peri-operative anxiety prevalence is low, although unacceptable levels of anxiety are seen to elevate during the intra-operative phase. The RCT in stage two demonstrated that intra-operative anxiety was no more effectively managed by the interventions tested than by usual care alone. The validity and reliability of retrospective anxiety measurement was investigated by comparing anxiety scores from stage one with contemporaneous and post-hoc anxiety scores from stage two and found to be an accurate measure of anxiety experienced at the time of the event.

Yes / prevent obesity at this age. This study tested the acceptability and feasibility of evaluating a theory-based intervention aimed at reducing risk of obesity in infants of overweight/obese women during and after pregnancy: the Healthy and Active Parenting Programme for Early Years (HAPPY). Methods: A feasibility randomised controlled trial was conducted in Bradford, England. One hundred twenty overweight/obese pregnant women (Body Mass Index [BMI] ≥25 kg/m2) were recruited between 10–26 weeks gestation. Consenting women were randomly allocated to HAPPY (6 antenatal, 6 postnatal sessions: N = 59) or usual care (N = 61). Appropriate outcome measures for a full trial were explored, including: infant’s length and weight, woman’s BMI, physical activity and dietary intake of the women and infants. Health economic data were collected. Measurement occurred before randomisation and when the infant was aged 6 months and 12 months. Feasibility outcomes were: recruitment/attrition rates, and acceptability of: randomisation, measurement, and intervention. Intra-class correlations for infant weight were calculated. Fidelity was assessed through observations and facilitator feedback. Focus groups and semi-structured interviews explored acceptability of methods, implementation, and intervention content. Results: Recruitment targets were met (~20 women/month) with a recruitment rate of 30 % of eligible women (120/396). There was 30 % attrition at 12 months; 66 % of recruited women failed to attend intervention sessions, but those who attended the first session were likely to continue to attend (mean 9.4/12 sessions, range 1–12). Reaction to intervention content was positive, and fidelity was high. Group clustering was minimal; an adjusted effect size of −0.25 standard deviation scores for infant weight at 12 months (95 % CI: −0.16–0.65) favouring the intervention was observed using intention to treat analyses. No adverse events were reported. Conclusions: The HAPPY intervention appeared feasible and acceptable to participants who attended and those delivering it, however attendance was low; adaptations to increase initial attendance are recommended. Whilst the study was not powered to detect a definitive effect, our results suggest a potential to reduce risk of infant obesity. The evidence reported provides valuable lessons to inform progression to a definitive trial. / National Institute for Health Research

No / Newcastle Upon Tyne Hospitals NHS Foundation Trust

Background: Breast cancer is the most frequently diagnosed cancer and a leading cause of cancer death among females, both worldwide and in the UK. Although, UK incidence of breast cancer is rising, breast cancer mortality rates are falling, due largely to early detection and improved treatment. As a result there are more women living with a diagnosis of breast cancer than ever before. Due mainly to side-effects of adjuvant therapy, breast cancer patients may require diagnostic, therapeutic, supportive or palliative services many years post-diagnosis, which poses a major challenge to already stretched healthcare services. Accordingly, effective and inexpensive interventions that can alleviate treatment side-effects, improve health, quality of life and potentially reduce risk of early mortality are required for breast cancer patients. Awareness of the positive influence that physical activity can have on breast cancer development and outcome is an important determinant of physical activity levels. A higher level of physical activity before and after breast cancer diagnosis is related to a lower risk of all-cause and breast cancer-related mortality. Randomised controlled trials have reported beneficial effects of physical activity interventions on outcomes relating to health, quality of life and mortality risk among breast cancer survivors. Aims: The present project aimed to: 1) assess awareness of the role of physical activity on breast cancer risk and the sufficiency of physical activity undertaken in women attending the NHS breast screening programme (NHSBSP), 2) compare physical activity levels of women at different stages of breast cancer pathway, 3) investigate the effects of a low-cost six-month home-based physical activity intervention on physical activity, body mass, health-related quality of life (HRQoL), insulin resistance and blood lipid profiles of breast cancer survivors and 4) assess the effects of our home-based intervention on cardiorespiratory fitness in a subset of breast cancer survivors. Methods: A total of 309 volunteers (188 NHSBSP attendees, 41 breast cancer patients undergoing chemotherapy and 80 post-treatment breast cancer survivors) participated in the current project. Physical activity was assessed via the International Physical activity Questionnaires (IPAQ). In studies one and two, Body mass and body mass index (BMI) were assessed directly in chemotherapy patients and breast cancer survivors, and indirectly from self-reported values in NHSBSP attendees. While in study three, body fat percentage was measured via bioelectrical impedance analysis, HRQoL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire and fasting blood samples were taken to measure lipid, glucose and insulin concentrations at baseline and post-six month home-based physical activity intervention. In study four, a random subsample of 32 breast cancer survivors undertook an exercise tolerance test to establish peak oxygen uptake values. Results: A high proportion (70%) of NHSBSP attendees engaged in low-moderate levels of physical activity and performed low amounts of recreational physical activity. Attendees demonstrated high awareness (75%) of the role of physical activity in reducing breast cancer risk but those categorised as “low activity” were significantly unaware of insufficiency of activity (p<0.05). Chemotherapy patients and breast cancer survivors had significantly lower levels of total physical activity than NHSBSP attendees (p<0.001 and p<0.05, respectively). The randomised controlled trial revealed significant improvements in total physical activity, body mass (p<0.05), BMI (p<0.05) HRQoL (breast cancer subscale, p<0.01; trial outcome index, p<0.05) and total (p<0.01) and low-density lipoprotein (p<0.05) cholesterol concentrations in the intervention group compared to usual care, and significant improvements in cardiorespiratory fitness (p<0.05) in a subsample of breast cancer survivors allocated to intervention. Conclusions: Physical activity interventions that incorporate strategies aimed at increasing awareness of recommended physical activity guidelines may be required in populations at risk of breast cancer. A relatively large proportion of women at risk of breast cancer may not be sufficiently exposed to the potential benefits of physical activity on breast cancer outcomes. Post-treatment breast cancer patients may be more receptive to physical activity interventions as the negative effects of chemotherapy begin to resolve, and therefore, may benefit from physical activity interventions. Results suggest that a low-cost home-based physical activity intervention with counselling and telephone support can improve the health and HRQoL of breast cancer survivors, which may in turn potentially reduce risk of breast cancer and cardiovascular disease-related mortality. Given the encouraging results and its highly portable and feasible nature, our intervention represents a promising tool for use in health and community settings to benefit large numbers of breast cancer survivors. The current project supports the inclusion of physical activity promotion as an integral component for the management and care of breast cancer survivors.

Objectives: To explore the pain mechanism and the origin of the pain and to evaluate a short-term pain relief treatment in women suffering from CPP persisting after childbirth in order to enable physiotherapeutic intervention. Material and methods: Thirty-six parous women with chronic pelvic pain persisting after childbirth were recruited at the Department of Physiotherapy, SundsvallHospital and by advertisements in newspapers and 29 parous women without chronic pelvic pain were recruited from an organized gynaecological screening at a midwifery surgery. All women were provoked by intra-pelvic palpation of 13 predetermined intra-pelvic landmarks. The provoked pain distribution was expressed in pain drawings and the pain intensity verbally on a Likert scale.Also, in a randomised controlled trial the 36 women with chronic pelvic pain were allocated to bilateral injection treatment with either triamcinolone or saline solutions, given once on the ischial spine with follow-up after four weeks. Results: Referred pain provoked on intra-pelvic landmarks follows a specific pattern. In general, pain provoked by palpation of the posterior intra-pelvic landmarks was mostly referred to the sacral region and pain provoked by palpation of the ischial and pubic bones was mostly referred to the groin and pubic regions. In women with chronic pelvic pain the provoked pain distribution area and pain intensity were magnified as compared to women without chronic pelvic pain. In the clinical trial decreased pain intensity, decreased distribution of pain and improved physical function was achieved among the triamcinolone treatment group as compared to the saline treatment group. Also, a positive correlation was shown between reduced pain intensity and improved function. Conclusions: Referred pain patterns provoked on intra-pelvic landmarks in women with chronic pelvic pain persisting after childbirth are consistent with sclerotomal sensory innervations and indicates allodynia and central sensitisation. This suggests that pain mapping can be used to evaluate and confirm the pain experience and contribute to diagnosis. Also, the pain intensity provoked by stimulation of the intra-pelvic landmarks is suggested to be useful to differentiate women with chronic pelvic pain from those without. Corticosteroid treatment to the ischial spine resulted in decreased pain and increased function.

Factorial randomised controlled trials (RCTs) evaluate two or more interventions simultaneously, enabling assessment of interactions between treatments. This thesis presents literature reviews, methodological reviews, simulation studies and applied case studies that explore methods for assessing cost-effectiveness based on factorial RCTs. My systematic review suggests that factorial RCTs account for around 3% of trial-based economic evaluations, although there is currently no guidance or methodological work indicating the most appropriate methods. Around 40% of published studies assumed no interaction between treatments and many were poorly-reported. Various mechanisms are likely to produce large interactions within economic endpoints such as costs, quality-adjusted life-years (QALYs) and net benefits. Failing to take account of interactions can introduce bias and prevent efficient allocation of healthcare resources. I developed the opportunity cost of ignoring interactions as a measure of the implications of this bias. However, allowing for small, chance interactions is inefficient, potentially leading to over-investment in research if trial-based evaluations are used to inform decisions about subsequent research. Nonetheless, analyses on simulated trial data suggest that the opportunity cost of adopting a treatment that will not maximise health gains from the healthcare budget is minimised by including all interactions regardless of magnitude or statistical significance. Different approaches for conducting economic evaluations of factorial RCTs (including regression techniques, extrapolation using patient-level simulation, and considering different components of net benefit separately) are evaluated within three applied studies, including both full and partial factorials with 2x2 and 2x2x2 designs. I demonstrate that within both trial-based and model-based economic evaluation, efficient allocation of healthcare resources requires consideration of interactions between treatments, and joint decisions about interacting treatments based on incremental cost-effectiveness evaluated “inside-the-table” on a natural scale. I make recommendations for the design, analysis and reporting of factorial trial-based economic evaluations based on the results of this thesis.

Producing speech is a highly complex task, involving the integration of sensory and linguistic information, with the precise, high-speed, co-ordination of muscles controlling breathing and the movement of the vocal folds and articulators. In spite of this complexity, producing fluent speech - moving smoothly from one speech sound to the next - can appear effortless. Speech fluency is highly socially valued, and the personal and societal costs of living with a disorder of fluency, such as developmental stuttering, are considerable. The outcomes of behavioural therapies to increase fluency are limited, however, especially for those seeking treatment in adulthood. The overarching aim of this thesis was to investigate how anodal transcranial direct current stimulation (A-TDCS) can be used to increase speech fluency, with a particular focus on the potential application to developmental stuttering. A-TDCS is a noninvasive brain stimulation technique that can enhance the effects of motor, speech, and language training. First, in a series of single-session experiments in typically fluent speakers, I demonstrated that applying A-TDCS over the left IFC increased speech motor learning relative to a sham control, but did not improve consolidation of this learning (chapter 2). Furthermore, I found that neither increasing stimulation intensity from 1 mA to 2 mA, nor changing from a unihemispheric to a bihemispheric configuration, had an additional effect on learning. Next, in single-session study with adults who stutter, I assessed the feasibility of using A-TDCS to improve fluency (chapter 3). Fluency was temporarily induced, by speaking in unison with another person, but the concurrent application of 1-mA unihemispheric A-TDCS over left inferior frontal cortex did not significantly prolong this fluency. Nevertheless, a trend towards stuttering reduction gave some indication that fluency might be increased using a multiple-session approach. Furthermore, I gained a number of important insights from these single-session studies, which I used to inform the design of the final multiple-session trial. In this final study, I completed a randomised controlled trial in 30 adult males with moderate to severe stuttering. Participants were randomized to receive either 1-mA A-TDCS or sham stimulation over left inferior frontal cortex combined with temporary fluency inducing behavioural techniques, for 20 minutes a day over 5 days (chapter 4). A-TDCS significantly reduced disfluency for at least 5 weeks following this intervention. The effect was specific to the speech impairment of development stuttering, as measures of the psycho-social consequences of stuttering were not modulated by A-TDCS. The findings of these studies offer significant promise for the future application of non-invasive stimulation as an adjunctive therapy for adults who stutter. In the concluding chapter, I discuss the important implications of my findings for the future use of this technique.

<p>Aim: The overall aim of this thesis was to acquire knowledge about whether tactile touch as a complementary method can (i) promote comfort and (ii) reduce stress reactions during care in an intensive care unit (ICU) Method: In Paper I, five nurses with a touch therapist training were interviewed about their experiences of preparation before giving tactile touch in an ICU. To analyse the meaning of preparation as a phenomenon, Giorgi’s descriptive phenomenological approach was used. In Paper II and III a randomised controlled trial was set up to investigate the effects of a five-day tactile touch intervention on patients’ oxytocin levels in arterial blood (II), on patients’ blood pressure, heart rate and blood glucose level, and on patients’ levels of anxiety, sedation and alertness (III). Forty-four patients were randomised to either an intervention group (n = 21) or a control group (n = 23). Data were analysed with non-parametric statistics. In Paper IV, six patients who had received the tactile touch intervention were interviewed to illuminate the experience of receiving tactile touch during intensive care. To gain a deeper understanding of the phenomenon and to illuminate the meaning, Ricoeur’s phenomenological hermeneutical method, developed by Lindseth and Norberg, was used. Findings: The nurses need four constituents (inner balance, unconditional respect for the patients’ integrity, a relationship with the patient characterized by reciprocal trust and a supportive environment) to be prepared and go through the transition from nurse to touch therapist (I). In the intervention study, no significant differences were shown for oxytocin levels between intervention and control group over time or within each day (II). There were significantly lower levels of anxiety for patients in the intervention group. There were no significant differences between the intervention and control groups for blood pressure, heart rate, the use of drugs, levels of sedation or blood glucose levels (III). The significance of receiving tactile touch during intensive care was described as the creation of an imagined room along with the touch therapist. In this imagined room, the patients enjoyed tactile touch and gained hope for the future (IV). Conclusion: Nurses needed internal and external balance to be prepared for providing tactile touch. Patients did not notice the surroundings as much as the nurses did. Patients enjoyed the tactile touch and experienced comfort. The impact on stress parameters were limited, except for levels of anxiety which declined significantly. The results gave some evidence for the benefit of tactile touch given to patients in intensive care.</p>

<p>Non-adherence to medication is a major obstacle in the treatment of depression. The objectives of the present study were to explore the effect of two interventions aiming to increase antidepressant treatment adherence, and to examine long-term consequences and costs of depression in adherent and non-adherent primary care patients. </p><p>A randomised controlled design was used to assess the respective effects of a written educational adherence enhancing programme and therapeutic drug monitoring in patients with major depression treated with sertraline for 24 weeks. All patients were prospectively followed during two years. </p><p>Treatment adherence was found in 41% of the 1031 included patients. None of the interventions resulted in a significant increase in adherence rate. However, significantly more patients in the group receiving the written educational material had responded at week 24 as compared to patients in the control group. </p><p>The overall remission rate after two years was 68%. In total, 34% of the responders experienced at least one relapse. Response and remission rates at week 24, year 1 and year 2 were significantly higher in adherent as compared to non-adherent patients. No relationship between adherence and relapse rate was seen. </p><p>The mean total cost per patient during two years was KSEK 363 whereof indirect costs represented 87%. No significant differences in costs between intervention groups or between adherent and non-adherent patients could be demonstrated. However, the mean cost per patient was 39% lower for treatment responders as compared to non-responders. </p><p>Non-adherence was predicted by age below 35 or above 64 years, no concomitant medications, personality disorder, sensation seeking personality traits and substance abuse. </p><p>The results indicate a strong positive relationship between treatment adherence and clinical outcome. In addition, the study shows that depression is a costly disease and that certain patient characteristics predict non-adherence.</p>