When using evidence from non-randomized studies (NRS) to answer questions about the effects of environmental exposures on health, it is important to assess risk of bias (RoB) of individual studies as part of determining the certainty in the body of evidence. The recently released RoB in Non-randomized Studies of Interventions (ROBINS-I) instrument has undergone careful development and piloting on NRS of health interventions. A key feature of ROBINS-I is evaluating the RoB of studies against an ideal target trial, therefore establishing a structured comparison of RoB against a reference standard. While several instruments exist to evaluate the RoB of NRS of exposure, none of them use such a structured comparison of RoB. Using the fundamental design of ROBINS-I, we explored development of a version of the instrument to evaluate RoB in studies of environmental exposure. We identified important modifications necessitating a distinct instrument: The RoB instrument for NRS of exposures. This work highlights the importance of standardized methods for environmental health decision making, proposes a modified instrument to evaluate the RoB of NRS of exposures, provides guidance for the implementation of the instrument and integration into structured evidence-synthesis frameworks (such as GRADE [Grading of Recommendations Assessment, Development and Evaluation]), and presents evidence on the reliability and validity of the instrument. The RoB instrument for NRS of exposures delivers a standardized instrument that systematic review authors and guideline developers can use to evaluate RoB in NRS of exposures. The nature of these methodological changes allow better integration of RoB assessment in the environmental health field with GRADE. / Thesis / Doctor of Philosophy (PhD) / When making a decision about interventions to reduce or remove an environmental exposure, evidence is needed to weigh the desirable and undesirable consequences of the decision. No research study is perfect. Most of the studies documenting environmental exposures cannot control for the fact that people who might be highly exposed may have different characteristics compared to those who have low levels of exposure other than just the exposure itself. For example, people exposed to more environmental air pollution living in inner cities may also be more likely to smoke or have occupational exposures that could predispose them to lung cancer than those exposed to lower levels of air pollution. Understanding limitations in studies that address those questions informs our certainty that the data represents the truth. The greater the confidence we have in the data, the more likely we are to be certain that removing or reducing exposure will lead to a desirable outcome. A tool can be used to walk people through the evaluation of limitations within each study. However, it is important that the tool evaluates the correct limitations within the study. It is also important that people using the tool can apply it reliably. Without a reliable or valid tool to evaluate the limitations of the studies, it can be difficult to inform decisions on whether or not to implement specific policies. In our study, we tested the ability of a new and well-developed tool (ROBINS for interventions) to identify the limitations in studies linking environmental exposures to health outcomes. Based on the findings from our evaluation, we modified our protocol to see if we could improve our ability to evaluate these studies of environmental exposures. We asked people with an understanding of scientific methods to independently evaluate 35 studies with our modified tool (ROBINS for exposures). We compared those responses to see whether all the reviewers came up with similar decisions and if their decision was similar or different than the conclusion they made using more commonly used tools. Based on our results, we determined that our modified tool does provide a consistent evaluation of study limitations and accurately measures the limitations present in studies of exposure. This tool can be used to inform decisions about removing or reducing one’s exposure to environmental hazards.

Aging and age-related frailty are important public health problems. There is a need to develop rehabilitation interventions to reduce the prevalence and disabling effects of frailty. This thesis reports the rationale and design of two studies and findings of three studies aimed to optimize health outcomes of frail older adults and their caregivers. The second chapter describes the protocol of the first network meta-analysis to determine the comparative effect of interventions targeting the prevention or treatment of frailty. In the third chapter, the results of frailty network meta-analysis were presented and 89 RCTs were included. The review shows that physical activity and medication management are the most effective frailty interventions. The fourth chapter describes a protocol of pilot randomized controlled trial (RCT) to examine a preoperative multi-modal frailty intervention in pre-frail/frail older adults undergoing elective joint replacements. The fifth chapter describes the results of a subgroup analysis of a RCT examining the effect of complex primary care intervention to support caregivers of frail older adults. There were no differences between caregivers of frail older adults and non-caregivers in quality of life, social support, hospitalization, and emergency department visits. The sixth chapter examines the construct validity and discriminative properties of the fracture rating scale (FRS) (a tool designed for fracture risk assessment in long term care (LTC)). The FRS is a valid tool for identifying LTC residents at different risk levels for hip fracture in three Canadian provinces. The work presented in this thesis is proposing and examining the comparative effect of frailty interventions, a preoperative frailty intervention/ model, a primary care intervention to identify and support caregivers, and a predictive tool to optimize care planning of LTC residents. These findings will support the rehabilitation and care program for older adults and their caregivers and improve their health outcomes. / Thesis / Doctor of Philosophy (PhD) / There is a need to develop rehabilitation interventions to reduce the prevalence and disabling effects of frailty. This thesis reports the rationale and design of two studies and findings of three studies aimed to improve health outcomes of frail older adults and their caregivers. The second and third chapters of this thesis describe the protocol and results of a review aims to identify the effect of interventions targeting frailty, the review found that physical activity and medication management are the most effective frailty interventions. The fourth chapter describes a study examining the possibility of comparing a complex intervention to usual care in frail older adults undergoing joint replacements. The fifth chapter showed that a primary care intervention did not improve the caregivers’ health outcome. The sixth chapter presents the fracture rating scale, a valid tool for identifying Long-term care residents at risk of hip fracture in three Canadian provinces. These findings aim to improve the care for older adults and their caregivers.

Driving is the preferred mode of transportation among community-dwelling older Canadians. Unfortunately, drivers aged 70+ have a high risk of being injured or killed in a collision. Many collisions are caused by poor driving habits, which could be avoided by improving their behind-the-wheel behaviours. The manuscripts in this thesis describe the development of an evidence-based and user-informed driver training program aimed at refreshing older adults’ driving skills. First, a systematic review of older driver training programs was undertaken to examine evidence specific to the impact of this training on improving road safety knowledge, self-perceived driving abilities, and on-road performance. Results highlighted the breadth of approaches used to train older drivers. Interventions were most effective when feedback was tailored to the specific needs of an aging driver. The second manuscript outlines a qualitative descriptive analysis exploring older adults’ motivations to participate in driver training with key stakeholders (i.e., older drivers and service delivery providers). Findings indicated having insight into one’s driving abilities, experiencing a near-miss or crash, as well as an openness to improving behind-the-wheel skills were factors that could influence seeking out and participating in such training. Stakeholders also emphasized considerations for educating older drivers. The final manuscript describes the design and evaluation of a driver training program. In this randomized controlled trial, older drivers watched either a video of tailored feedback on their driving or a generic video on aging-in-place. When the on-road performance was compared between treatment groups, those who received tailored feedback significantly reduced the number of errors they made behind-the-wheel. Ensuring driver training programs are designed to consider the specific needs and preferences of older adults is critical, which can lead to innovations that help maintain driving ability and community mobility in later life. / Thesis / Doctor of Philosophy (PhD) / Being able to drive is important to many older Canadians. Unfortunately, drivers aged 70+ have a high risk of being injured or killed in a car crash. Many crashes could be avoided by improving their driving skills. This thesis describes the development of an older driver training program. The first study examined research evidence on such programs where tailoring feedback was key to improving on-road performance. In the second study, older adults and other stakeholders identified what was important when designing training for aging drivers. They felt the focus should be on areas of improvement as well as strengths when behind-the-wheel. In the final study, older drivers underwent training where they watched either a video with feedback on their driving or a generic video on aging-in-place. Those who received feedback made fewer mistakes behind-the-wheel. Findings emphasize the importance of including older adults’ needs and preferences when designing driver training programs.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13600号 / 論医博第2310号 / 新制||医||1072(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村井 俊哉, 教授 佐藤 俊哉, 教授 永井 洋士 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Adoption of new agricultural technologies by farmers in developing countries is sometimes limited, despite the associated benefits. Potato farmers in Carchi, Ecuador rely heavily on pesticides to limit pest and disease damage, rather than adopting a more sustainable and economically viable alternative: Integrated Pest Management (IPM). One reason IPM adoption is limited is that farmers are uncertain about the benefits of the complex technology. Information provision builds knowledge that reduces that uncertainty and leads to adoption. Another reason for limited adoption is that other farming activities compete for time, and farmers may forget or delay IPM adoption. One way to transfer information and remind farmers to adopt IPM practices is through text messages. To evaluate the impact of text messages on IPM adoption, we conducted a Randomized Control Trial (RCT) among potato farmers in Carchi, Ecuador. The RCT allowed us to identify the causal impact of text messages by comparing adoption rates and knowledge scores between farmers who received text messages (treatment), and farmers who did not (control). After attending a one-day training, the treatment received tailored IPM messages for approximately five and a half months. At the conclusion of the trial period, treatment and control farmers reported their adoption of individual IPM practices, and were tested on their IPM knowledge. Treatment farmers adopted both simple and complex practices at higher rates than the control. Farmers who received text messages also possess more knowledge about IPM techniques than non-recipients, which is evidence of the knowledge-building effect of text messages. Furthermore, text messages were shown to be effective in encouraging the adoption of practices for which no separate inputs were required, and ineffective in encouraging practices where a separate input was required. Text messages are an positive supplement to an in-person training program because they build knowledge and remind farmers, both of which encourage the adoption of IPM, which benefits the farmer, his community, and the environment. / Master of Science

<p dir="ltr">Continuous optimization is a fundamental topic both in theoretical computer science and applications of machine learning. Meanwhile, an important idea in the development modern algorithms it the use of randomness to achieve empirical speedup and improved theoretical runtimes. Stochastic gradient descent (SGD) and matrix-multiplication time linear program solvers [1] are two important examples of such achievements. Matrix sketching and related ideas provide a theoretical framework for the behavior of random matrices and vectors that arise in these algorithms, thereby provide a natural way to better understand the behavior of such randomized algorithms. In this dissertation, we consider three general problems in this area.</p>

Many antibiotic resistance genes (ARGs) conferring resistance to a broad range of antibiotics have often been detected in aquatic environments such as untreated and treated wastewater, river and surface water. ARG proliferation in the aquatic environment could depend upon various factors such as geospatial variations, the type of aquatic body, and the type of wastewater (untreated or treated) discharged into these aquatic environments. Likewise, the strong interconnectivity of aquatic systems may accelerate the spread of ARGs through them. Hence a comparative and a holistic study of different aquatic environments is required to appropriately comprehend the problem of antibiotic resistance. Many studies approach this issue using molecular techniques such as metagenomic sequencing and metagenomic data analysis. Such analyses compare the broad spectrum of ARGs in water and wastewater samples, but these studies use comparisons which are limited to similarity/dissimilarity analyses. However, in such analyses, the discriminatory ARGs (associated ARGs driving such similarity/ dissimilarity measures) may not be identified. Consequentially, the reason which drives the dissimilarities among the samples would not be identified and the reason for antibiotic resistance proliferation may not be clearly understood. In this study, an effective methodology, using Extremely Randomized Trees (ET) Algorithm, was formulated and demonstrated to capture such ARG variations and identify discriminatory ARGs among environmentally derived metagenomes. In this study, data were grouped by: geographic location (to understand the spread of ARGs globally), untreated vs. treated wastewater (to see the effectiveness of WWTPs in removing ARGs), and different aquatic habitats (to understand the impact and spread within aquatic habitats). It was observed that there were certain ARGs which were specific to wastewater samples from certain locations suggesting that site-specific factors can have a certain effect in shaping ARG profiles. Comparing untreated and treated wastewater samples from different WWTPs revealed that biological treatments have a definite impact on shaping the ARG profile. While there were several ARGs which got removed after the treatment, there were some ARGs which showed an increase in relative abundance irrespective of location and treatment plant specific variables. On comparing different aquatic environments, the algorithm identified ARGs which were specific to certain environments. The algorithm captured certain ARGs which were specific to hospital discharges when compared with other aquatic environments. It was determined that the proposed method was efficient in identifying the discriminatory ARGs which could classify the samples according to their groups. Further, it was also effective in capturing low-level variations which generally get over-shadowed in the analysis due to highly abundant genes. The results of this study suggest that the proposed method is an effective method for comprehensive analyses and can provide valuable information to better understand antibiotic resistance. / MS / Antibiotic resistance is a natural and primordial process that predates the use of antibiotics in humans for disease treatment and occurs when a bacterium evolves to render the drugs, chemicals, or other agents meant to cure or prevent infections ineffective. Antibiotic resistance genes (ARGs) conferring resistance to a wide range of antibiotics have been widely found in rivers, surface waters, and hospital and farm wastewater discharges. Even treated wastewater from treatment plants is a concern as ARGs have frequently been detected in effluent discharges which poses questions on the effectiveness of treatment plants in removing ARGs. Since, these systems are interconnected there’s a possibility of dissemination and proliferation of ARGs which may pose serious threat to human health. Hence, it is desirable to perform comparative studies among these aquatic habitats. In previous studies, researchers compared different habitats which tells how similar and dissimilar the environments are in terms of ARGs present in these samples. While these analyses are important, it doesn’t tell which ARGs are unique or which ARGs are responsible to create those similarities or dissimilarities. This information is crucial in order to understand the water environments in terms of occurrence and presence of ARGs, the risk posed by them, and in identifying factors responsible for resistance gene proliferation. In this research, a methodology was developed which could capture such ARG variations in the environmental samples, using data analysis algorithms. Further the developed methodology was demonstrated using environmental samples such as wastewater samples from different geographical locations (to understand the spread of ARGs globally), untreated vs treated wastewater (to understand the effectiveness of treatment plants in removing ARGs), and different aquatic habitats (to understand the impact and spread of ARGs within these habitats). It was determined that the proposed method was efficient in differentiating samples and identifying discriminatory ARGs. The comparison between environmental samples showed that the samples from different locations have specific ARGs which were unique to wastewater samples from certain locations suggesting that site-specific factors can have certain effect in shaping the ARG profiles. Comparing untreated and treated samples revealed that treatment plants were able to remove certain ARGs but it was also observed v that some ARGs proliferated after the treatment irrespective of location and treatment plant specific variables. Analyzing different environments, the approach was able to identify certain ARGs which were specific to certain environments. The results of this study suggest that the proposed method is an effective method for comprehensive analyses and can provide valuable information to better understand antibiotic resistance. In essence, it is a valuable addition for improved surveillance of antibiotic resistance pollution and for the framing of best management practices.

Yes / Introduction: Skin ageing involves senescent fibroblast accumulation, disturbance in extracellular matrix (ECM) homeostasis, and decreased collagen synthesis. Objective: to assess a cell therapy product for aged skin (RCS-01; verum) consisting of ~25 × 106 cultured, autologous cells derived from anagen hair follicle non-bulbar dermal sheath (NBDS). Methods: For each subject in the verum group, 4 areas of buttock skin were injected intradermally 1 or 3 times at monthly intervals with RCS-01, cryomedium, or needle penetration without injection; in the placebo group RCS-01 was replaced by cryomedium. The primary endpoint was assessment of local adverse event profiles. As secondary endpoints, expression of genes related to ECM homeostasis was assessed in biopsies from randomly selected volunteers in the RCS-01 group taken 4 weeks after the last injection. ­Results: Injections were well tolerated with no severe adverse events reported 1 year after the first injection. When compared with placebo-treated skin, a single treatment with RCS-01 resulted in a significant upregulation of TGFβ1, CTGF, COL1A1, COL1A2, COL3A1, and lumican mRNA expression. Limitations: The cohort size was insufficient for dose ­ranging evaluation and subgroup analyses of efficacy. Conclusions: RCS-01 therapy is well tolerated and associated with a gene expression response consistent with an improvement of ECM homeostasis. / Replicel Life Sciences Inc, Vancouver, Canada.

Yes / Background: Online communities hold great potential as interventions for health, particularly for the management of chronic illness. The social support that online communities can provide has been associated with positive treatment outcomes, including medication adherence. There are few studies that have attempted to assess whether membership of an online community improves health outcomes using rigorous designs. Objective: Our objective was to conduct a rigorous proof-of-concept randomized controlled trial of an online community intervention for improving adherence to asthma medicine. Methods: This 9-week intervention included a sample of asthmatic adults from the United Kingdom who were prescribed an inhaled corticosteroid preventer. Participants were recruited via email and randomized to either an “online community” or “no online community” (diary) condition. After each instance of preventer use, participants (N=216) were required to report the number of doses of medication taken in a short post. Those randomized to the online community condition (n=99) could read the posts of other community members, reply, and create their own posts. Participants randomized to the no online community condition (n=117) also posted their medication use, but could not read others’ posts. The main outcome measures were self-reported medication adherence at baseline and follow-up (9 weeks postbaseline) and an objective measure of adherence to the intervention (visits to site). Results: In all, 103 participants completed the study (intervention: 37.8%, 39/99; control: 62.2%, 64/117). MANCOVA of self-reported adherence to asthma preventer medicine at follow-up was not significantly different between conditions in either intention-to-treat (P=.92) or per-protocol (P=.68) analysis. Site use was generally higher in the control compared to intervention conditions. Conclusions: Joining an online community did not improve adherence to preventer medication for asthma patients. Without the encouragement of greater community support or more components / Funded by a pilot grant from the University of Leeds School of Psychology. A Fulbright Scholarship from the US-UK Fulbright Commission supported the first author

No / OBJECTIVES: To compare the effects of community hospital care on independence for older people needing rehabilitation with that of general hospital care. DESIGN: Randomized, controlled trial. SETTING: Seven community hospitals and five general hospitals in the midlands and north of England. PARTICIPANTS: Four hundred ninety patients needing rehabilitation after hospital admission with an acute illness. INTERVENTION: Multidisciplinary team care for older people in community hospitals. MEASUREMENTS: The primary outcome was the Nottingham extended activities of daily living scale (NEADL); secondary outcomes were the Barthel Index, Nottingham Health Profile, Hospital Anxiety and Depression Scale, mortality, discharge destination, 6-month residence status, and satisfaction with services. RESULTS: Loss of independence at 6 months was significantly less likely in the community hospital group (mean adjusted NEADL change score group difference 3.27; 95% confidence interval 0.26–6.28; P=.03). The results for the secondary outcome measures were similar for the two groups. CONCLUSION: Postacute community hospital rehabilitation care for older people is associated with greater independence.