Class of 2008 Abstract / Objectives: 1) To determine if data on weight change in the placebo arm of RCT's for weight loss were available, and 2) to conduct a pilot meta-analysis to estimate the average weight change in the placebo arm. Methods: Four randomized placebo controlled trials of rimonabant for weight loss were retrieved. A draft data extraction form was developed to record weight loss and demographic data. Potential for bias was assessed on design issues related to withdrawals, blinding, allocation procedure, adherence, and manufacturer influence. Based on available data, a forest plot was constructed and heterogeneity was assessed. The a priori alpha level was 0.05. Results: The placebo groups from all studies were similar. The pooled data indicated that individuals in the placebo arm lost an average of 3.3 kg, p < 0.001. One study had a significantly greater completion rate than the other studies. Participants were prescribed a hypocaloric diet and were instructed to increase physical activity but no data were reported on calories consumed or amount of physical activity. Weight loss of 5% ranged from 15-20% of participants. There was potential for bias relating to reported adherence, allocation concealment process, and manufacturer funding. Conclusions: Participants in the placebo arm of rimonabant trials lost an average of 3.3 kg, which was statistically significant. Little can be learned about weight loss in the placebo arm because no data on calories consumed, amount of exercise, or hunger were reported. Information from other RCT's is needed to provide additional data and to confirm the findings.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21705号 / 人健博第71号 / 新制||人健||5(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 市橋 則明, 教授 黒木 裕士, 教授 妻木 範行 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

Objectives: To determine the subacute effects of cervicothoracic spinal thrust/non-thrust in addition to shoulder non-thrust plus exercise in patients with subacromial pathology. Methods: This was a randomized, single blinded controlled trial pilot study. This trial was registered at ClinicalTrials.gov (NCT01753271) and reported according to Consolidated Standards of Reporting Trials requirements. Patients were randomly assigned to either shoulder treatment plus cervicothoracic spinal thrust/non-thrust or shoulder treatment-only group. Primary outcomes were average pain intensity (Numeric Pain Rating Scale) and physical function (Shoulder Pain and Disability Index) at 2 weeks, 4 weeks, and patient discharge. Results: 18 patients, mean age 43.1(15.8) years satisfied the eligibility criteria and were analyzed for follow-up data. Both groups showed statistically significant improvements in both pain and function at 2 weeks, 4 weeks, and discharge. The between-group differences for changes in pain or physical function were not significant at any time point. Discussion: The addition of cervicothoracic spinal thrust/non-thrust to the shoulder treatment-only group did not significantly alter improvement in pain or function in patients with subacromial pathology. Both approaches appeared to provide an equally notable benefit. Both groups improved on all outcomes and met the criteria for clinical relevance for both pain and function. Level of Evidence: 2b.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第18908号 / 人健博第22号 / 新制||人健||2(附属図書館) / 31859 / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 菅沼 信彦, 教授 鈴木 眞知子, 教授 中原 俊隆 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

Study design of a randomized-controlled trial investigating the effects of probiotic supplementation on induction of prediabetes remission to normoglycemia in adults with prediabetes. / BACKGROUND: Patients with prediabetes are at a high risk of developing type 2 diabetes (T2D) and the current strategies to prevent the progression of prediabetes to T2D are difficult to implement at the population level. Recently, the role of gut microbiota has emerged as a possible link to metabolic disease. The modulation of the gut microbiota in individuals with prediabetes through probiotic supplementation may improve metabolic dysfunction and induce remission of prediabetes to normoglycemia. OBJECTIVES: The primary objective of this trial is to determine the effect of 900 billion CFU/day of VSL#3®, a multi-strain probiotic supplement for 20 weeks, on induction of drug-free remission to normoglycemia (HbA1c<6.0%) in adults with prediabetes compared to placebo 20 weeks post-randomization. METHODS: In a randomized, triple-blind, controlled multi-centre trial, 568 adults with prediabetes will undergo a 2-week run-in after which they will be randomly allocated to 20 weeks of either 900 billion CFUs of VSL#3® per day or placebo. Prediabetes remission will be measured using HbA1C at week 20 and 32. Change in insulin resistance (HOMA-IR), beta-cell function (HOMA-B), weight, BMI, waist circumference and fecal relative abundance of bacteria will be measured from baseline at week 20 and 32. Exploratory regression analyses will involve a multiple logistic regression model to assess whether the change in relative abundance of the Rosburia genus from baseline at week 20 is an independent predictor of drug-free prediabetes remission at week 20. DISCUSSION: Individuals with prediabetes are at high risk of developing T2D and the induction of prediabetes remission would be important to patients and clinicians. The role of microbiota in metabolic processes presents the potential for therapeutic applications of probiotics. If successful, probiotics would offer a therapeutic option for reversing prediabetes to normoglycemia that is simple, cheap and easy to incorporate into standard clinical care. / Thesis / Master of Science (MSc) / BACKGROUND: Patients with prediabetes are at a high risk of developing type 2 diabetes (T2D) and the current strategies to prevent the progression of prediabetes to T2D are difficult to apply at the population level. Recently, the role of gut bacteria has emerged as a possible link to metabolic disease. Changing the gut microbiota in people with prediabetes through probiotic supplements may improve metabolic function and result in remission of prediabetes to normal glucose control. OBJECTIVES: The primary objective of this study is to determine the effect of VSL#3®, a probiotic supplement, for 20 weeks, on induction of drug-free remission to normal glucose control in adults with prediabetes compared to placebo, 20 weeks after randomization. METHODS: In a randomized, triple-blind, controlled multi-centre trial, 568 adults with prediabetes will be randomly assigned to 20 weeks of either VSL#3® per day or placebo. Prediabetes remission will be measured using HbA1C at week 20 and 32. Change in insulin resistance (HOMA-IR), beta-cell function (HOMA-B), weight, BMI, waist circumference and fecal bacteria will be measured from baseline at week 20 and 32. DISCUSSION: Individuals with prediabetes are at high risk of developing T2D and the induction of prediabetes remission would be important to patients and clinicians. The role of gut bacteria in metabolic health presents the potential for probiotics to be therapy options. If successful, probiotics would be simple, cheap and easy to incorporate into standard clinical care.

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).

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

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.

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.