Background: Many randomized controlled trials (RCTs) and meta-analyses include analyses of effect modification (also known as subgroup, interaction, or moderation analyses). Methodologists have widely acknowledged the challenges in deciding whether an apparent effect modification is credible or likely the result of chance or bias. Various sets of credibility criteria are available (Chapter 2 provides an example) but are inconsistent, vague in wording, lack guidance for deciding on overall credibility, and have not been systematically tested. Objective: To systematically develop a formal instrument to assess the credibility of effect modification analyses (ICEMAN) in RCTs and meta-analyses of RCTs. Methods: Key steps in the development process included 1) a systematic survey of the literature to identify available criteria, rationales, and previous instruments, 2) a formal consensus study among 10 leading experts, and 3) a formal user-testing study to refine the instrument based on interviews with trial investigators, systematic reviewer authors, and journal editors who applied drafts of the instrument to published claims of effect modification. Results: The systematic survey identified 150 relevant publications, 36 candidate credibility criteria with associated rationales, and 30 existing checklists (Chapter 3). The consensus study consisted of two main video conferences and multiple rounds of written discussion. The user-testing involved 17 users (including systematic review authors, trial investigators, and journal editors) who suggested substantial improvements based on detailed interviews. The final instrument provides separate versions for RCTs (five core questions) and meta-analyses (eight core questions) with explicit response options, and an overall credibility rating ranging from very low to high credibility. A detailed manual provides rationales, supporting references, examples from the literature, and suggestions for use in combination with other quality appraisal tools and reporting (Chapter 4). Discussion: ICEMAN is a rigorously developed instrument to evaluate claims of effect modification and addresses the main limitations of previous approaches. / Thesis / Doctor of Philosophy (PhD) / Randomized controlled trials and meta-analyses provide the best available evidence to evaluate whether effects of a therapy vary among individual patients. Efforts to decide whether treatment effects differ across patients are important and frequently done but difficult to interpret. The fundamental challenge is to decide whether apparent differences in effect are real or due to chance. To aid this decision, experts have suggested various sets of credibility criteria, all with important limitations. This thesis documents how we systematically addressed the limitations of previous approaches. Key steps were a systematic survey of the available credibility criteria, a consensus study among leading methodologists, and a formal user-testing study. The result is a new instrument for assessing the credibility of effect modification analyses (ICEMAN).

Yes / Smokers attend preferentially to cigarettes and other smoking-related cues in the environment, in what is known as an attentional bias. There is evidence that attentional bias may contribute to craving and failure to stop smoking. Attentional retraining procedures have been used in laboratory studies to train smokers to reduce attentional bias, although these procedures have not been applied in smoking cessation programmes. This trial will examine the efficacy of multiple sessions of attentional retraining on attentional bias, craving, and abstinence in smokers attempting cessation. This is a double-blind randomised controlled trial. Adult smokers attending a 7-session weekly stop smoking clinic will be randomised to either a modified visual probe task with attentional retraining or placebo training. Training will start 1 week prior to quit day and be given weekly for 5 sessions. Both groups will receive 21 mg transdermal nicotine patches for 8–12 weeks and withdrawal-orientated behavioural support for 7 sessions. Primary outcome measures are the change in attentional bias reaction time and urge to smoke on the Mood and Physical Symptoms Scale at 4 weeks post-quit. Secondary outcome measures include differences in withdrawal, time to first lapse and prolonged abstinence at 4 weeks post-quit, which will be biochemically validated at each clinic visit. Follow-up will take place at 8 weeks, 3 months and 6 months post-quit. This is the first randomised controlled trial of attentional retraining in smokers attempting cessation. This trial could provide proof of principle for a treatment aimed at a fundamental cause of addiction. / National Institute for Health Research (NIHR) Doctoral Research Fellowship (DRF) awarded to RB (DRF-2009-02-15)

Yes / Social isolation in older adults is associated with morbidity. Evaluating interventions to promote social engagement is a research priority. Methods: A parallel-group randomised controlled trial was planned to evaluate whether telephone friendship (TF) improves the well-being of independently living older people. An internal pilot aimed to recruit 68 participants by 30 September 2012, with 80% retained at 6 months. Randomisation was web based and only analysts were blind to allocation. A service provider was contracted to train 10 volunteer facilitators by 1 April 2012 and 10 more by 1 September 2012. Participants were aged > 74 years with good cognitive function and living independently in an urban community. The intervention arm of the trial consisted of manualised TF with standardised training: (1) one-to-one befriending (10- to 20-minute calls once per week for up to 6 weeks made by volunteer facilitators) followed by (2) TF groups of six participants (1-hour teleconferences once per week for 12 weeks facilitated by the same volunteer). Friendship groups aimed to enhance social support and increase opportunities for social interaction to maintain well-being. This was compared with usual health and social care provision. The primary clinical outcome was the Short Form questionnaire-36 items (SF-36) mental health dimension score at 6 months post randomisation. Qualitative research assessing intervention acceptability (participants) and implementation issues (facilitators) and an intervention fidelity assessment were also carried out. Intervention implementation was documented through e-mails, meeting minutes and field notes. Acceptability was assessed through framework analysis of semistructured interviews. Two researchers coded audio recordings of telephone discussions for fidelity using a specially designed checklist. Results: In total, 157 people were randomised to the TF group (n = 78) or the control group (n = 79). Pilot recruitment and retention targets were met. Ten volunteers were trained by 1 September 2012; after volunteer attrition, three out of the 10 volunteers delivered the group intervention. In total, 50 out of the 78 TF participants did not receive the intervention and the trial was closed early. A total of 56 people contributed primary outcome data from the TF (n = 26) and control (n = 30) arms. The mean difference in SF-36 mental health score was 9.5 (95% confidence interval 4.5 to 14.5) after adjusting for age, sex and baseline score. Participants who were interviewed (n = 19) generally declared that the intervention was acceptable. Participant dissatisfaction with closure of the groups was reported (n = 4). Dissatisfaction focused on lack of face-to-face contact and shared interests or attitudes. Larger groups experienced better cohesion. Interviewed volunteers (n = 3) expressed a lack of clarity about procedures, anxieties about managing group dynamics and a lack of confidence in the training and in their management and found scheduling calls challenging. Training was 91–95% adherent with the checklist (39 items; three groups). Intervention fidelity ranged from 30.2% to 52.1% (28–41 items; three groups, three time points), indicating that groups were not facilitated in line with training, namely with regard to the setting of ground rules, the maintenance of confidentiality and facilitating contact between participants. Conclusions: Although the trial was unsuccessful for a range of logistical reasons, the experience gained is of value for the design and conduct of future trials. Participant recruitment and retention were feasible. Small voluntary sector organisations may be unable to recruit, train and retain adequate numbers of volunteers to implement new services at scale over a short time scale. Such risks might be mitigated by multicentre trials using multiple providers and specialists to recruit and manage volunteers. / Funding for this study was provided by the Public Health Research programme of the National Institute for Health Research.

Background: Low health literacy and increased sugar-sweetened beverage (SSB) consumption are two broad public health concerns facing the United States. For example, it is estimated that 90 million Americans have insufficient literacy skills (IOMC, 2004) and low health literacy is associated with poorer health outcomes (Berkman et. al., 2011). Furthermore, SSBs contribute about 80% of added sugars in the diet (Nielsen & Popkin, 2004) and have been associated with poor health outcomes, including obesity, type II diabetes, bone fractures, dental caries, and coronary heart disease. Despite these findings, there is limited research related to how to effectively decrease SSB intake among adults. Additionally, there have been few studies investigating health literacy interventions that target health behaviors in community settings (Allen et.al, 2011). Objective: As guided by the Theory of Planned Behavior (TPB) and constructs of health literacy, this 5-week, 2-arm randomized controlled pilot trial, used mixed methods to examine the effects of an intervention to decrease SSB (SipSmartER), as compared to a matched-contact control condition targeting physical activity (Move More). The primary aims of this pilot project were to evaluate participant's feedback through process and summative evaluation as well as evaulate intervention content and/or delivery through process evaluation by staff tracking for quality improvements. Secondary aims included the assessment of changes in theorized mediating variables and health behaviors among participants. Methods: Twenty-five participants (mean age = 42±14 years, mean BMI = 34.3±7.5 kg/m₂, 19 females, 12 African Americans, 9 (high school education) residing in Roanoke, VA were randomized to either SipSmartER (n=14) or Move More (n=11) to begin the 5-week intervention. Inclusion criteria consisted of participants being 18 years of age or older, English speaking, consuming greater than 200 kcal/day of SSB, and being without medical conditions in which physical activity would be contraindicated. Both 5-week interventions included two interactive small group sessions (Weeks 1 & 5) and three support telephone calls (Weeks 2, 3 & 4). Pre-post data was obtained using previously validated instruments including Beverage Intake Questionnaire (Bev-Q), Theory of Planned Behavior constructs addressing SSB and physical activity, media literacy, subjective numeracy, Stanford Leisure-Time Activity Categorical Item (L-CAT), and quality of life. Descriptive statistics, ANOVA, and regression models were used in data analysis. Results: Although SSB consumption decreased more among the SipSmartER participants (-257±622.6 kcal/day) than Move More (-200±404.6 kcal/day) there were no significant group by time differences. However, among all participants, changes in TPB constructs significantly predicted changes in SSB (R²=0.592; F=2.485; p=0.080) and physical activity behaviors (R2=0.621; F=2.813; p=0.056). Participant and staff feedback were very positive, ranging from 4.2-5.0 on a 5-point likert scale that included questions about intervention organization, flow, effectiveness, engagement, and enjoyment. Favorite themes that emerged with SipSmartER participants when asking about small group sessions included, realizing how much sugar is found in SSBs, understanding the health risks associated with drinking too much sugar, realizing how much sugar was being consumed during the day, and learning about better alternatives. Conclusion: Findings suggest promise for the piloted intervention to reduce SSB consumption through targeted TPB and health literacy strategies. This pilot study has allowed further refinement and execution of a larger trial that includes a larger sample and longer study duration (i.e. 6-months) and follow-up period (i.e. 18-months). / Master of Science

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.

Disability due to low back pain is common. While evidence exist that exercise is effective in reducing pain and disability, it is still largely undetermined which kind of exercises that are most effective. The overall aim of this thesis was to evaluate and compare the effects of a high-load lifting exercise and individualized low-load motor control exercises for patients with nociceptive mechanical low back pain. A secondary aim was to evaluate which patients benefit from training with a high-load lifting exercise. All four papers in this thesis were based on a randomized controlled trial including 70 participants with nociceptive mechanical low back pain as their dominating pain pattern. Participants were randomized into training with either a high-load lifting exercise (HLL), the deadlift, (n=35) or individualized low-load motor control exercises (LMC) (n=35). Both interventions included aspects of pain education. All participants were offered twelve sessions during an eight week period. The effects of the interventions were evaluated directly after and twelve months after the end of the intervention period. Outcome measures were pain intensity, activity, disability, physical performance, lumbo-pelvic alignment and lumbar multifidus muscle thickness. There was a significant between-group effect in favour of the LMC intervention regarding improvements in activity, movement control tests and some tests of trunk muscle endurance. For pain intensity there were no significant differences between groups. A majority of participants in both intervention groups showed clinically meaningful improvements from baseline to two and twelve month follow-up regarding pain intensity and activity. There were no significant differences between HLL and LMC regarding the effect on lumbo-pelvic alignment or lumbar multifidus thickness. The participants who benefit the most from the HLL intervention were those with a low pain intensity and high performance in the Biering-Sørensen test at baseline. The results of this thesis showed that the HLL intervention was not more effective than the LMC intervention. The LMC was in fact more effective in improving activity, performance in movement control tests and some tests of trunk muscle endurance, compared to the HLL intervention. The results imply that the deadlift, when combined with education, could be considered as an exercise to produce clinically relevant improvements on pain intensity in patients who prefer a high-load exercise. However, before considering deadlift training, the results suggest that pain intensity and performance in the Biering-Sørensen test should be evaluated.

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.

Background: Although physical inactivity has been linked with numerous chronic health conditions and overall mortality, the majority of English adults report insufficient physical activity. To increase population physical activity levels, researchers have called for more community-level interventions. To evaluate these complex public health interventions, innovative study designs are required. The aim of this thesis was to evaluate whether a community-level physical activity intervention—‘Devon Active Villages’—increased the activity levels of rural communities. Methods: The Devon Active Villages intervention provided villages with 12 weeks of physical activity opportunities for all age groups. Community engagement helped tailor activity programmes for each village; communities were then supported for a further 12 months. 128 rural villages from south-west England were randomised to receive the intervention in one of four time periods, as part of a stepped wedge cluster randomised controlled trial. Data collection consisted of a postal survey of a random sample of adults (≥18 years), at baseline, and after each of the four intervention periods. The primary outcome of interest was the proportion of adults who reported sufficient physical activity to meet the current guidelines (≥150mins of moderate-and-vigorous, or ≥75mins of vigorous-intensity activity per week). The number of minutes spent in moderate-and-vigorous activity per week was analysed as a secondary outcome. Using data from all five periods, a comparison of study outcomes between intervention and control arms was performed, allowing for time period (as a fixed effect), and the random effect induced by correlation of outcomes (clustering) within villages. Additionally, the baseline data were analysed separately using logistic and linear regression models to examine the correlates of physical activity behaviour in rural adults. Results: Baseline study: 2415 adults completed the postal survey (response rate 37.7%). The following factors both increased the odds of meeting the recommended activity guidelines and were associated with more leisure-time physical activity: being male, in good health, greater commitment to being more active, favourable activity social norms, greater physical activity habit, and recent use of recreational facilities. In addition, there was evidence that younger age, lower body mass index, having a physical occupation, dog ownership, inconvenience of public transport, and using recreational facilities outside the local village were associated with greater reported leisure-time physical activity. Main study: 10,412 adults (4693 intervention, 5719 control) completed the postal survey (response rate 32.2%). The intervention did not increase the odds of adults meeting the physical activity guideline, although there was weak evidence of an increase in the minutes of moderate-and-vigorous-intensity activity per week. The ineffectiveness of the intervention may have been due to its low penetration—only 16% of intervention participants reported being aware of the intervention, and just 4% reported participating in intervention events. Conclusions: Baseline study: This study highlights potentially important correlates of physical activity that could be the focus of interventions targeting rural populations, and demonstrates the need to examine rural adults separately from their urban counterparts. Main study: A community-level physical activity intervention providing tailored physical activity opportunities to rural villages did not improve physical activity levels in adults. Greater penetration of such interventions needs to be achieved for them to have any chance of increasing the prevalence of physical activity at the community level.

Background Patients who experience a stroke or transient ischemic attack (TIA) are at high risk of recurrent stroke, but little is known about temporal trends in unselected populations. Reports of low adherence to recommended treatments indicate a need for enhanced secondary preventive follow-up to achieve the full potential of evidence-based treatments. In addition, socioeconomic factors have been associated with poor health outcomes in a variety of contexts. Therefore, it is important to assess the implementation and results of secondary prevention in different socioeconomic groups. Aims The aims of this thesis were to assess temporal trends in ischemic stroke recurrence and evaluate the implementation and results of a nurse-led, telephone-based follow-up program to improve blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels after stroke/TIA. Methods In study I, we collected baseline data for unique patients with an ischemic stroke event between 1998 and 2009 (n=196 765) from the Swedish Stroke Register (Riksstroke). Recurrent ischemic stroke events within 1 year were collected from the Swedish National Inpatient Register (IPR) and the cumulative incidence was compared between four time periods using the Kaplan-Meier survival analysis and the logrank test. Implementation (study II) and 1-year results (study III-IV) for the secondary preventive follow-up were studied in the NAILED (Nurse-based Age-independent Intervention to Limit Evolution of Disease) study. Between 1 Jan 2010 and 31 Dec 2013, the baseline characteristics of consecutive patients admitted to Östersund Hospital for acute stroke or TIA were collected prospectively (n=1776). Consenting patients in a condition permitting telephone-based follow-up were randomized to nurse-led, telephone-based follow-up or follow-up according to usual care. Follow-up was cunducted at 1 and 12 months after discharge and the intervention included BP and LDL-C measurements, titration of medication, and lifestyle counseling. In study II, we analyzed factors associated with non-participation in the randomized phase of the NAILED study, including association with education level. In addition, we compared the 1-year prognosis in terms of cumulative survival between participants and non-participants. In study III, we compared differences in BP and LDL-C levels between the intervention and control groups during the first year of follow-up and, in study IV, in relation to level of education (low, ≤10 years; high, &gt;10 years). Results The cumulative 1-year incidence of recurrent ischemic stroke decreased from 15.0% to 12.0%. Among surviving stroke and TIA patients, 53.1% were included for randomization, 35.7% were excluded mainly due to physical or cognitive disability, and 11.2% declined participation in the randomized phase. A low level of education was independently associated with exclusion, as well as the patient’s decision to abstain from randomization. Excluded patients had a more than 12-times higher risk of death within 1 year than patients who were randomized. After 1 year of follow-up, the mean systolic BP, diastolic BP, and LDL-C levels were 3.3 mmHg (95% CI 0.3 to 6.3), 2.3 mmHg (95% CI 0.5 to 4.2), and 0.3 mmol/L (95% CI 0.1 to 0.4) lower in the intervention group than among controls. Among participants with values above the treatment goal at baseline, the differences in systolic BP and LDL-C levels were more pronounced (8.0 mmHg, 95% CI 4.0 to 12.1; 0.6 mmol/L, 95% CI 0.4 to 0.9). In the intervention group, participants with a low level of education achieved similar or larger improvements in BP and LDL-C than participants with a high level of education. In the control group, BP remained unaltered and the LDL-C levels increased among participants with a low level of education. Conclusion The 1-year risk of ischemic stroke recurrence decreased in Sweden between 1998 and 2010. Nurse-led, telephone-based secondary preventive follow-up is feasible in just over half of the survivors of acute stroke and TIA and achieve better than usual care in terms of BP and LDL-C levels, and equality in BP improvements across groups defined by education level. However, a large proportion of stroke survivors are in a general condition precluding this form of follow-up, and their prognosis in terms of 1-year survival is poor. Patients with a low education level are over-represented within this group and among patients declining randomization for secondary preventive follow-up.

Insofar as forgiveness of oneself enables one to responsibly manage the consequences of wrongdoing, the practice of self-forgiveness may be essential to the preservation of one’s physical, psychological, relational, and spiritual health. In the present thesis, an intervention wait-list design was employed to investigate the efficacy of a 6-hour self-directed workbook designed to promote self-forgiveness. University students (N = 204) who reported perpetrating an interpersonal offense and who experienced some sense of remorse were randomly assigned to either an immediate treatment or wait-list control condition, and assessments were administered on three occasions. Participants’ self-forgiveness ratings increased in conjunction with completion of the workbook, and the effect of treatment depended upon self-administered dose and baseline levels of dispositional self-compassion in some cases. In summary, the workbook appeared to facilitate the process of responsible self-forgiveness among perpetrators of interpersonal wrongdoing, though replication trials are needed in which lower rates of attrition reduce the possibility of biased results.