Introduction: The placenta is essential for fetal development and pregnancy prolongation. Its dysfunction can lead to short and long-term health consequences for mother and child. A subset of diseases resulting from placental dysfunction have been collectively termed placental-mediated diseases (PMD) - which includes the common and serious hypertensive disorder of pregnancy preeclampsia (PE), among others. PMDs are independent risk factors for maternal cardiovascular disease (CVD) in later life. This thesis presents a multi-pronged body of work, which includes: 1) A systematic review, aimed at summarizing the current state of knowledge on the risk for future maternal CVD after PMDs; 2) A cohort study, aimed at assessing the utility of placenta pathology examination at delivery to identify women at high lifetime risk for CVD following PE; and 3) An assessment of an immunohistochemistry screening panel for 3 placenta protein markers of interest, aimed at determining if these markers can accurately identify women deemed to be at high-risk for future CVD following a PE pregnancy. Methods: 1) We searched 4 databases for observational studies evaluating clinical and biochemical markers of CVD risk and/or a subsequent calculated risk score based on these parameters in women with a history of PMD. We excluded interventional studies and studies measuring these outcomes during or prior to pregnancy. 2) A cohort study was established across two clinical sites (Kingston, Ottawa), in which patients with PE (N=85) underwent cardiovascular risk assessments at 6-months postpartum. The placentas from these pregnancies also underwent detailed placenta histopathology examination to determine the presence, absence, and severity of 35 distinct placental lesions. The associations between distinct placental lesions and estimated lifetime cardiovascular risk were evaluated by odds ratios (OR) and receiver operator curve analysis (ROC). 3) Immunohistochemistry (IHC) analysis was performed on placental samples from a subset of the previously described cohort (N=41; Ottawa site only). Protein expression for FLT-1, ENG, and CD68 was quantified. Using a multivariate logistic regression model, the association between placenta protein expression, with and without clinical and placenta pathology findings, and cardiovascular risk was assessed. Results: 1) The search yielded 11,039 articles of which 104 met our inclusion criteria. All PMD types demonstrated evidence of increased CVD risk markers at varying timepoints postpartum. At least one study per PMD type had non-optimal measures of systolic blood pressure, BMI, and total cholesterol. 2) In the analysis of placenta pathology lesions within the cohort of individuals with PE, lesions of maternal vascular malperfusion (MVM) were found to be associated with elevated life-time risk for maternal CVD at 6 months postpartum (OR: 3.10[1.20-7.92]). We also found that adding these lesions to a logistic regression model improved the predictive accuracy for elevated maternal lifetime CVD risk (AUC: 73.0, sensitivity: 78.4%, specificity: 51.6%). 3) Individually, no significant differences were found in FLT-1, ENG, and CD68 expression between the individuals deemed to be at high and low-risk for lifetime CVD. Although, when added to a model that included placenta pathology lesions and clinical data the predictive accuracy for elevated maternal lifetime CVD risk increased (AUC: 1.0, sensitivity: 100%, specificity: 100%). Conclusions: In conclusion, this thesis provides further evidence of the utility of assessing placenta features in the prediction of future maternal CVD. This is evidenced by the association between PMDs, placental pathology, and placental protein biomarkers with elevated risk profiles for lifetime CVD. Thus, specific placental phenotypes of PMDs may be at increased risk for CVD. The use of placental data should be further explored as a triage strategy to identify these high-priority of women following delivery.

Radicalization is as a formidable challenge for several nations. While radicalization continues to flare across the world, empirical evidence and consensus regarding its determinants remain scarce. This cumulative dissertation aims to contribute to understanding the determinants of radicalization based on three research papers. The first paper undertakes a systematic review of the existing scientific literature on radicalization. The second paper empirically tests the predictive power of the most plausible factors identified in the systematic review. The third paper empirically investigates the existence of non-linearities in the relationship between radicalization and socioeconomic factors.:1. Introduction 2. Understanding the Determinants of Radicalization: A Systematic Review 3. An Empirical Assessment of the Determinants of Radicalization: Evidence from North-Western Pakistan 4. Socioeconomic Factors and Radicalization in Pakistan: A Non-Linear Exploration 5. References

Background. Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity, where gut peptides such as ghrelin, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) play an instrumental role in reduced appetite after RYGB. This systematic review and meta-analysis aimed to establish the magnitude of change of ghrelin, GLP-1, PYY and appetite sensation following RYGB. Methods. A systematic search was conducted in Medline Ovid, Embase, Scopus, and Cochrane Central Register of Controlled Trials up until March 2021. Two independent reviewers screened articles for studies that evaluated ghrelin, GLP-1, PYY or appetite sensation via visual analogue scales (VAS) before and after RYGB in adults. Risk of bias was assessed with the quality assessment tool for before-after studies with no control group from the National Heart, Lung and Blood Institute (NHLBI). A multilevel model with random effects for study and follow-up time points nested in study was fit to the data. The model included kilocalorie consumption as a covariate and time points as moderators. Results. Among the 2,559 articles identified, 47 met the inclusion criteria, among which k=19 evaluated ghrelin, k=40 GLP-1, k=22 PYY and k=8 appetite sensation via VAS. Our results indicate that fasting ghrelin levels are decreased 2 weeks post-RYGB (p = .005) but do not differ from baseline from 6 weeks to 1-year post-RYGB. Postprandial ghrelin levels at 6 months and 1-year post-RYGB were not different from pre-surgical values (p = .51). Fasting GLP-1 levels were not different from pre-surgical levels up to 2 years post-RYGB. Postprandial levels of GLP-1 increased significantly from 1 week (p < .001) to 2 years post-RYGB (p < .01) compared to before surgery. Compared to pre-RYGB levels, fasting PYY increased at 6 months (p = .034) and 1 year (p = .0299) post-surgery and postprandial levels were increased up to 1 year (p < .01). Heterogeneity was significant in most analyses. Insufficient data on appetite sensation was available to be meta-analyzed. Conclusion. Our analyses illustrate the magnitude of change of ghrelin, GLP-1 and PYY before and after RYGB surgery. Importantly, between study heterogeneity within the current literature warrants more standardized protocols and studies with longer follow-up periods for better comprehension of changes in gut peptides following RYGB surgery.

Patients with myelodysplastic syndromes (MDS) frequently receive red blood cell (RBC) transfusions to alleviate symptoms of anemia and improve health-related quality of life (HR-QoL). Patients can sometimes continue to feel unwell after transfusion and the age of the transfused RBCs could contribute to this observation. Three pilot studies were conducted to inform the design of a randomized crossover trial to determine if fresh blood to MDS patients could improve HR-QoL post-transfusion. A systematic review was performed to inform the background and rationale for the trial. The results showed a dearth of literature addressing the research question. Only two clinical trials have been conducted to date where fatigue and HR-QoL were the primary outcomes of interest. Although results of the trials were negative, several limitations and generalizability issues warrant additional research in this area. Crossover designs necessitate patients have a stable prognosis while being observed; hence, a chart review of adult MDS patients was conducted to assess clinical stability using the following criteria: interval of days between transfusions; pre-transfusion Hb; number of hospital admissions; and severe infections. Results indicated that the majority of patients who had received greater than 3 transfusions within the 6-month observation period had stable disease and were appropriate for a crossover trial. The criteria defining stability will be useful for identifying eligible patients. Finally, an applied qualitative study in adult MDS patients in Hamilton was conducted to inform the selection of an appropriate outcome measure (i.e. HR- QoL tool). Short semi-structured interviews were conducted with participants to elicit information about anemia related symptoms and changes in well-being in response to transfusion. The results of the study support clinical observations that suggest patients do not immediately recover post-transfusion. Findings indicate that an appropriate HR-QoL tool should be short, be disease specific, and have a short recall period. Currently, the Quality of Life-E tool, validated in patients with MDS, fits most of these criteria. In conclusion, data from the systematic review and the two pilot studies suggest that it may be feasible to conduct an age of blood crossover trial in MDS patients where the primary outcome of interest is HR-QoL. / Thesis / Master of Science (MSc)

Objectives: 1) To examine the effectiveness of Audiovisual (AV) interventions at reducing preoperative anxiety (PA) and its associated outcomes in children undergoing surgery; 2) To assess the psychometric properties of a new scale, the Children’s Perioperative Multidimensional Anxiety Scale (CPMAS); 3) To examine the feasibility and acceptability of a novel tablet-based intervention, Story-Telling Medicine (STM), for reducing children’s PA; 4) To examine the relation between temperament and PA in the surgical context. Methods: A systematic review of studies where the primary outcome was children’s PA was conducted (Study 1). A study of the reliability and validity of the CPMAS were assessed at preoperative assessment (T1), on the day of surgery (T2), and 1 month postoperatively (T3) was also undertaken (Study 2). The feasibility and acceptability of STM were then examined and compared its effect to Usual Care (UC) (Study 3). Finally, children’s temperament was examined using the Colorado Childhood Temperament Inventory at T1 along with the CPMAS assessed at T1 and T2 (Study 4). Results: Fourteen of the 18 studies led to reductions in children’s PA (Study 1). The CPMAS demonstrated good internal consistency, stability and convergent validity across all visits (Study 2). The participant recruitment and study procedures were shown to be feasible and children in the STM group demonstrated greater reductions in CPMAS compared to the UC group (Study 3). Shyness predicted lower PA at T1, while sociability predicted higher PA at T1 and T2 (Study 4). Conclusions: AV interventions appear useful but full-scale RCTs of these treatments are required to pinpoint those that are most effective. The CPMAS is a promising tool for evaluating children’s PA and preliminary evidence suggests that STM is a feasible intervention for reducing children's PA. Finally, our findings highlight the importance of considering individual differences in predicting anxiety in the surgical setting. / Thesis / Doctor of Philosophy (PhD) / Preoperative anxiety affects up to 5 million children in North America annually and is associated with many adverse psychological, behavioural, and health effects. These problems not only produce significant distress for children and families, but can have immediate and long-term effects on a child’s mental health and development. Current methods to reduce preoperative anxiety in children (e.g., medications and psychological preparation programs) are limited by their expense and/or time-intensive nature. In an attempt to reduce children’s preoperative anxiety and its associated negative outcomes, this work examined the usefulness of audiovisual interventions in reducing children’s preoperative anxiety, sought to develop a new instrument to measure children’s preoperative anxiety, tested a new tablet-based application to reduce children’s preoperative anxiety, and examined the relation between children’s temperament and preoperative anxiety. The goal is to improve the surgical experience for children and families, and to reduce psychological and physical problems in children undergoing surgery.

Neonatal abstinence syndrome (NAS) refers to the withdrawal symptoms experienced when an infant has been exposed to certain substances (e.g., opioids) in-utero, resulting in health challenges for infants. Previous studies have reported substantial variations in the clinical management of NAS, suggesting that some infants may not be receiving optimal care. High-quality clinical practice guidelines are crucial to support optimal patient outcomes and standardize care. In response, I conducted a systematic review and quality appraisal of available NAS guidelines and recommendations using the AGREE-II and AGREE-REX tools. I also developed and piloted a tool to measure family-centred care in guidelines. Most guidelines received low-quality appraisal scores on the AGREE-II and the AGREE-REX appraisals (16/20 and 10/20, respectively) and have conflicting pharmacological recommendations. Findings will improve clinicians’ awareness of the variation in the quality of guidelines and assist them to make care decisions that are from the best available evidence and family-centred.

Quinolones are a group of antibiotics that have gained significant popularity on a global scale since the end of the last century. This popularity was predominantly based on their proven potency, broad coverage against a wide range of bacteria, in addition to possessing a favorable pharmacologic profile. Whereas quinolone-associated adverse reactions are generally tolerable and self-limiting, some reactions have generated heightened concerns due to their serious nature, which have resulted in label changes or even market withdrawal in some instances. This thesis investigates the association between quinolone antibiotics and two adverse reactions of an acute and serious nature: acute liver failure and retinal detachment. Each adverse reaction is investigated through integrating evidence from three studies utilizing different designs based on data from different sources, with each source offering a unique perspective on this issue. The first study type (chapter 2 for acute liver failure ‘ALF’ and Chapter 5 for retinal detachment ‘RD’) analyzes spontaneous reports submitted to the US Food & Drug Administration (FDA) adverse event reporting system database. Chapters 3 and 6 systematically identified all relevant (published and unpublished) clinical trials for occurrences of ALF and RD, respectively, among trial participants. Finally, chapters 4 (ALF) and 7 (RD) involved case-control analysis of a major US database of electronic health records for nearly 70 million inpatients admitted to more than 500 hospitals between 2000 and 2016. The FAERS analysis revealed a positive ALF signal with ciprofloxacin and a marginal signal for RD with moxifloxacin. Examination of the evidence from clinical trials revealed only two cases of ALF, one associated with gemifloxacin and one with moxifloxacin. No cases of RD were reported in any of the identified clinical trials. Primary analyses of the Health Facts® data revealed no overall association between quinolones and the risk of ALF or RD. However, elevated risk was identified in some subgroups, including African Americans (ALF, RD), Caucasians (ALF), women (ALF, RD), men (ALF), those ≤60 years of age (ALF) or 56-70 years of age (RD), and those with no or few comorbidities (ALF). Evidence from analyses of data from spontaneous reports and clinical trials provided some evidence for an elevated risk of ALF or RD following the systemic administration of quinolone antibiotics. Some evidence of elevated risk was also identified in the case-control analyses of inpatient EHR records. Findings from our six epidemiologic studies are in line with current advisories by FDA and Health Canada.

A core construct in the lifespan theory of socioemotional selectivity, future time perspective (FTP) refers to individuals’ perceptions of their remaining time in life. Its adaptation to the work context, occupational future time perspective (OFTP), entails workers’ perceptions of remaining time and opportunities in their careers. Over the past decade, several quantitative studies have investigated antecedents and consequences of general FTP and OFTP in the work context (i.e., FTP at work). We systematically review and critically discuss this literature on general FTP (k = 17 studies) and OFTP (k = 16 studies) and highlight implications for future research and practice. Results of our systematic review show that, in addition to its strong negative relationship with age, FTP at work is also associated with other individual (e.g., personality traits) and contextual variables (e.g., job characteristics). Moreover, FTP at work has been shown to mediate and moderate relationships of individual and contextual antecedents with occupational well-being, as well as motivational and behavioral outcomes. As a whole, findings suggest that FTP at work is an important variable in the field of work and aging, and that future research should improve the ways in which FTP at work is measured and results on FTP at work are reported.

No description available.

Background: COVID-19 and antimicrobial resistance (AMR) are two intersecting public health crises. Antimicrobial overuse in patients with COVID-19 threatens to contribute to the growing threat of AMR. Guidelines are fundamental in encouraging antimicrobial stewardship. We sought to assess the quality of antibiotic prescribing guidelines and recommendations in the context of COVID-19, and if these guidelines incorporate principles of antimicrobial stewardship. Methods: We performed a systematic survey which included a search using the concepts “antibiotic/antimicrobial” in September to November 2022 of the eCOVID-19 living map of recommendations (RecMap) which aggregates and summarizes guidelines across a range of international sources and all languages. Guidelines providing explicit recommendations regarding antibacterial use in COVID-19 from any jurisdiction were eligible for inclusion. Guideline and recommendation quality were assessed using the AGREE II and AGREE-REX instruments, respectively. We extracted guideline characteristics including panel representation and the presence or absence of explicit statements related to antimicrobial stewardship (i.e., judicious antibiotic use, antimicrobial resistance or adverse effects as a consequence of antibiotic use). We used logistic regression to evaluate the relationship between guideline characteristics including quality and incorporation of antimicrobial stewardship principles. Results: Twenty-eight guidelines with 63 antibiotic prescribing recommendations were included. Recommendations focused on antibiotic initiation (n=52, 83%) and less commonly antibiotic selection (n=13, 21%), and duration of therapy (n=15, 24%). Guideline and recommendation quality varied widely. Twenty (71%) guidelines incorporated at least one concept relating to antimicrobial stewardship. Including infectious diseases expertise on the guideline panel (OR 9.44, 97.5%CI: 1.09 to 81.59) and AGREE-REX score (OR 3.26, 97.5%CI: 1.14 to 9.31 per 10% increase in overall score) were associated with a higher odds of guidelines addressing antimicrobial stewardship. Conclusion: There is an opportunity to improve antibiotic prescribing guidelines in terms of both quality and incorporation of antimicrobial stewardship principles. These findings can help guideline developers better address antibiotic stewardship in future recommendations beyond COVID-19. / Thesis / Master of Public Health (MPH) / COVID-19 and antimicrobial resistance (AMR) are two serious threats to public health. Inappropriate use of antibiotics in patients with COVID-19 can worsen AMR and make future infections harder to treat. Practice guidelines can help healthcare providers prescribe antibiotics wisely. Using antibiotics carefully to reduce their harms is called antibiotic stewardship. This study evaluated the quality of practice guidelines for antibiotic prescribing in patients with COVID-19. It also assessed if the guidelines included principles of antibiotic stewardship. We searched for guidelines in a database called the eCOVID-19 living map of recommendations (RecMap). We found 28 guidelines with 63 recommendations. Identified guidelines differed widely in quality. Just over two-thirds of guidelines addressed antibiotic stewardship. Guidelines developed along with infectious disease experts and guidelines with higher recommendation quality scores were more likely to address antibiotic stewardship. Our findings can help guideline developers better address antibiotic stewardship in future recommendations.