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.

The analgesic effect of 600 mg and 1500 mg of a pain killing drug to metastatic bone pain, and associated side effects, were assessed. The experimental design was a double-blind cross over clinical trial involving 44 patients known to suffer from metastatic bone pain. Each patient received the active drug in one of two dosages and the placebo in a random order, each lasting about 14 consecutive days. The data consisted of daily measurements of several pain and side effect variables. A few covariates were available. It was found that the patient and the investigator achieved a high degree of agreement on the blinded preference of the active drug to the placebo. A multivariate analysis of variance (MANOVA) on three different summary scores (mean, median, trmean) calculated on the daily measurements for which the patient received the active drug and on those for which the patient received the placebo was conducted. It was found that for the group of pain variables the order of application and the treatment do not have a significant effect marginally, but that they interact significantly. Variation between subjects was also significant. For the group of side effect variables, however, only significant variation between subjects was found. This suggests that the drug does not have noticeable overall side effects. To account for correlations among the response measurements within each patient, the methodology of generalized estimating equations was used to assess the significance of the effects of the predictors. Although the results are less reliable as they depend on the asymptotic behaviour of statistics, it was found that regardless of the level of correlation within patient response measurements, only the interaction of order of application with treatment has a significant effect on each of the pain variables. All the statistical analyses were carried out using Minitab, SAS, Matlab and Splus. / Thesis / Master of Science (MS)

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).

Rationale & Background: Gaining excessive adiposity in pregnancy is associated with altered cardiometabolic profile and adverse pregnancy outcomes. Lifestyle interventions may reduce excess weight gain, but the effect on fat gain is unclear. Our study explored this question by 1) comparing measures of body fat (BF) by bioelectrical impedance analysis (BIA) and 4-site skinfold thickness (SFT); 2) assessing the impact of a nutrition+exercise intervention on adiposity changes; 3) elucidating associations between adiposity changes and cardiometabolic biomarkers and adverse pregnancy outcomes. Study Design: Participants randomized to receive a high dairy protein diet and exercise program (intervention) or standard care (control) in the Be Healthy in Pregnancy RCT (NCT 01689961) had adiposity measured at 12-17, 26-28, and 36-38 weeks gestation by BIA (%BF) and SFT (sum and %BF), and at 6 months postpartum also by DXA. Fasted blood samples collected at 12-17 and 36-38 weeks gestation were analyzed for glucose, lipid profile, insulin, leptin, adiponectin, and CRP. Pregnancy outcomes were abstracted from medical charts. Results: In 181 participants, BIA %BF and SFT %BF had good agreement in early pregnancy and postpartum, but low agreement in late pregnancy. Adiposity changes across pregnancy were similar between study arms but were greater in normal weight compared to overweight women. Insulin and leptin were negatively associated with change in SFT (sum and %BF). Triglycerides were negatively associated with change in BIA %BF, while HDL was positively associated. Neither caesarean section nor operative vaginal delivery were associated with adiposity change. Conclusion: Adiposity measured by sum of SFT and BIA %BF increased across pregnancy but was not influenced by the diet+exercise intervention. Associations of adiposity change with cardiometabolic biomarkers varied between measurement tools. The lack of adiposity measurement tools appropriate across pregnancy and in clinical settings presents a concern for assessing clinical responses to adiposity change across pregnancy. / Thesis / Master of Science (MSc) / Pregnancy is associated with a natural gain in body fat, but it can reach excessive amounts. Excess body fat is of clinical consequence as it is associated with poor cardiovascular health and abnormal pregnancy outcomes. Improving diet and physical activity habits may reduce excess weight gain, but little is known about how it influences fat gained during pregnancy. In our study body fat gain during pregnancy was similar between the lifestyle intervention and control groups. However, entering pregnancy with greater BMI was associated with less fat gain during pregnancy. Changes in body fat influenced cardiovascular blood markers, but results differed between body fat assessment tools. We also found that methods to measure body fat produce different results at different stages of pregnancy. Our findings provide insight on the factors that influence fat gain during pregnancy and highlight the need for better tools to measure body fat accurately in pregnancy.

Yes / This chapter focuses on the forms of legality and illegality produced by, and within, prison systems in Latin America where prison populations have risen five-fold, leading to a serious structural crisis in the criminal justice system. The chapter develops the concept of “prisoner capture”, a double-sided phenomenon of illegality in the state’s practices of detention, on the one hand, and informal, or parallel, governance exercised by those that it detained, on the other. State authorities held tens of thousands of people in extended and legally unjustifiable pretrial detention, and frequently denied convicted prisoners their legal rights, including timely release. This officially sanctioned form of kidnapping created such overcrowding and under-investment in prisons that national, constitutional, and international minimum norms on detention standards were routinely, systematically and grossly violated. These multiple illegalities on the part of the state in turn encouraged the emergence of prisoner self-defence and self-governance organizations. This resulted in “prisoner capture” of a different kind, when inmates took over the day-to-day ordering of prison life. In turn, this produced a parallel normative and pseudo-legal world in which inmates adjudicated on and disciplined other inmates in the absence of state officials within the prison walls. The chapter further examines what the study of Latin American prisons and penal practices can add to the field of socio-legal studies in the region and the implications of this phenomenon of prison capture for the dominant socio-legal literature on prisons and imprisonment.

Food grade soybean production is a high value alternative to conventional soybean use. The production of natto, a fermented soyfood, requires soybean cultivars that consistently express specific quality traits over a range of growing environments. Therefore, it is necessary to evaluate genetic and environmental influence for natto quality traits to ensure consistent performance. A multi location experiment was conducted in 2006 and 2007 to address the influence of soybean cropping system (double crop vs. full season) and environmental factors on traits associated with natto quality. Two statistical models were used to analyze the effects of planting system and environment on agronomic traits such as yield, maturity, and seed size and natto quality traits such as water absorption, water loss after steaming, seed coat deficiency, and rate of water absorption. Genotype variation was significant for all traits, but genetic differences for water loss after steaming were minimal. Planting system significantly influenced all natto quality traits. Seed coat deficiency and rate of water absorption displayed the most differential response and double crop plantings produced superior characteristics. Genotype à environment interactions were significant for all traits, but they did not confound selecting superior natto cultivars. Significant environment and year effects indicate environmental sensitivity, but genotype rankings rarely changed. The results indicate that genotype was the most important factor controlling the natto quality traits tested. These results suggest breeding for superior natto cultivars is possible but environmental influence must be accounted for and multi environment testing is necessary for genotype natto quality evaluation. / Master of Science

Yes / Introduction A key priority for the UK National Health Service and patients is to ensure that medicines are used safely and effectively. However, medication changes are not always optimally communicated and implemented when patients transfer from hospital into community settings. Heart failure is a common reason for admission to hospital. Patients with heart failure have a high burden of morbidity, mortality and complex pharmacotherapeutic regimens. The Improving the Safety and Continuity Of Medicines management at Transitions of care programme comprises a cluster randomised controlled trial which will test the effectiveness of a complex behavioural intervention aimed at improving medications management at the interface between hospitals discharge and community care. We will conduct a rigorous process evaluation to inform interpretation of the trial findings, inform implementation of the intervention on a wider scale and aid dissemination of the intervention. Methods and analysis The process evaluation will be conducted in six purposively selected intervention sites (ie, hospital trusts and associated community pharmacies) using a mixed-methods design. Fidelity and barriers/enablers of implementation of the Medicines at Transitions Intervention (MaTI) will be explored using observation, interviews (20 patients, 40 healthcare professionals), surveys and routine trial data collection on adherence to MaTI. A parallel mixed analysis will be applied. Qualitative data will be thematically analysed using Framework analysis and survey data will be analysed descriptively. Data will be synthesised, triangulated and mapped to the Consolidated Framework for Implementation Research where appropriate. The process evaluation commenced on June 2018 and is due to end on February 2021. Ethics and dissemination Approved by Research Ethics Committee and the UK Health Research Authority REC: 18/YH/0017/IRAS: 231 431. Findings will be disseminated via academic and policy conferences, peer-reviewed publications and social media. Trial registration number ISRCTN66212970.

Yes / Printed participant information about randomised controlled trials is often long, technical and difficult to navigate. Improving information materials is possible through optimisation and user-testing, and may impact on participant understanding and rates of recruitment. Methods: A study within a trial (SWAT) was undertaken within the CASPER trial. Potential CASPER participants were randomised to receive either the standard trial information or revised information that had been optimised through information design and user testing. Results: A total of 11,531 patients were randomised in the SWAT. Rates of recruitment to the CASPER trial were 2.0% in the optimised information group and 1.9% in the standard information group (odds ratio 1.027; 95% CI 0.79 to 1.33; p=0.202). Conclusions: Participant information that had been optimised through information design and user testing did not result in any change to rate of recruitment to the host trial. Registration: ISRCTN ID ISRCTN02202951; registered on 3 June 2009. / UK National Institute of Health Research Health Technology Assessment Programme (project number 08/19/04) / This article is included in the Studies Within A Trial (SWAT) collection (https://f1000research.com/collections/swat)

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

This thesis will explore the media's increasing impact on the criminal court system, specifically through prejudicial publicity given to criminal trials. In our society, the primary responsibility for gathering and disseminating information rests on the media. The media, consisting primarily of television and written publications, feel that they have a duty to provide citizens with important information about the community and the world. While the media have traditionally gathered news for informational purposes, they also provide news coverage of people and events for entertainment value. This is accomplished by focusing on the out-of-the ordinary and on stories of intrigue that capture the public's fancy. The media's desire to inform and entertain has carried over into the legal process, specifically the criminal court system. The media are typically drawn to cases that either provide a shocking, outrageous storyline, or that have a high-profile, famous defendant. The media love to exploit criminal trials for the suspense, drama, and sensationalism that they produce, as the viewing audience is longing for inside gossip and pure outrageousness. However, the media have the capability of publicizing a case beyond just mere hype, essentially turning the trial into a "media circus." Concerns arise when media outlets release prejudicial information before the case has been tried in front of the trier-of- fact, the jury. If the potential jurors consume this prejudicial, often-times inadmissible, information, then this increases the chances that jurors will pre-form opinions as to the guilt or innocence of the defendant prior to hearing the in-court evidence. If this occurs, the defendant's Sixth Amendment right to a fair trial by an impartial jury is in serious jeopardy. The media's First Amendment rights of free speech and press, coupled with a presumed right of access to criminal proceedings, lie in direct conflict with the defendant's Sixth Amendment due process rights. Exactly how courts go about balancing these rights delineated by the United States Constitution is still not definitive. The media feel that they can publicize criminal trials in any way they deem appropriate, while defendants argue that the jury pool is tainted by the media's coverage of the case. This prevents a truly unbiased jury from being chosen. Because of these constitutional issues, the United States Supreme Court has seen fit to enter the media publicity debate. While not providing, any definitive rules on when media publicity violates a defendant's Sixth Amendment's rights, the members of the Court have provided some recommendations and direction on these issues. When a case arouses the interest of media outlets nationally and internationally, the primary focus turns to the jury pool. Since jurors are seen as the trial participants most influenced by the media coverage, methods to keep the jury from being exposed to prejudicial pretrial publicity are utilized. At times, a skillfully and thoroughly conducted voir dire can find jurors unexposed to media coverage about the case. The judge's role has expanded in recent years as the media have become more pervasive in the criminal court system. The judge is responsible for supervising the media and for making sure that they do not infringe on the defendant's Sixth Amendment right to a fair trial by an impartial jury. To accomplish this duty, the trial judge has a number of mechanisms that he or she can employ against the media in order to ensure that a fair and unbiased jury is chosen for the case. However, these mechanisms are loathed by media outlets as they assert that these tools violate their First Amendment rights. Attorneys have been impacted by the media; however this relationship is unique in that it is a reciprocal one. The media publicize the trial of the attorney's client. In turn, the attorney uses this publicity as a weapon to advocate his or her client's case and proclaim guilt or innocence. Concerns about these extrajudicial statements arise when attorneys themselves release prejudicial information through the media to the representative community from which the jury will be chosen. As a result, the American Bar Association and various states have enacted rules designed to limit attorney speech so as to prevent any possibility of prejudice to the defendant in his or her trial. Indeed, the media have become more pervasive in the criminal court system, projecting events to the world as they happen. The coverage also tends to focus on the entertainment value of the case, releasing details that play on the viewer's emotions. However, an aggressive media impacts the due process rights of the accused, thus harming the search for justice. These are all issues and concerns that would not have arisen in this context, but-for the media's continuing impact on the criminal justice system.