Indiana University-Purdue University Indianapolis (IUPUI) / Understanding the factors that increase patients susceptibility to orthodontically induced root resorption is of the utmost importance to the practicing clinician. Numerous studies have been conducted that investigated contributing and etiological factors that tend to increase the amount of external apical root resorption a patient may incur during orthodontic treatment. However, there has been little research that has attempted to determine if patients treated with different slot size orthodontic brackets exhibit the same amount of external apical root resorption. The purpose of this research was to determine if patients treated with the 0.018 x 0.025 slot size bracket and patients treated with the 0.022 x 0.028 exhibited similar amounts of external apical root resorption during orthodontic treatment. Pre and Post treatment panoramic films from 91 consecutively treated orthodontic patients from a private orthodontic practice were used for this study. Each case that was included in the study had been treated with standard edgewise brackets using the Tweed-Merrifield philosophy of treatment. Forty-three cases from the 0.018 group and 48 from the 0.022 group were obtained. Each film that was analyzed was blinded prior to measuring to minimize observer bias. Mitutoyo Digimatic® calipers accurate to the nearest tenth of a millimeter were used for obtaining tooth measurements. Measurements were made from the Cemento-enamel junction and from incisal/occlusal to most apical portion of each incisor and all first molars. Statistical analysis was performed and the results showed no significant correlation between the size of the bracket and the amount of root resorption. No significant correlations existed between the groups for patient age, time in treatment, gender, and angle classification. Statistically significant differences were noted for cases in which extraction of four bicuspids was performed. Subjects belonging to the extraction group demonstrated significantly more external apical root resorption than those in which extractions were not done. This study demonstrated that the incidence of EARR that a patient may incur during treatment is independent of the size of the slot of the orthodontic bracket.

No description available.

Adverse outcome pathways (AOPs) provide a framework to organize and weigh the evidence linking a toxicant’s initial interactions with molecules in the cell to adverse outcomes of regulatory concern. AOPs are constructed in modules that include key events (KEs) and key event relationships (KERs). Quantitative understanding of the KERs is critical for the development of predictive toxicological models. The objective of this project was to investigate the ability to define the quantitative associations of the KERs upstream, and contained in, an existing AOP (#296): “Oxidative DNA Damage Leading to Chromosomal Aberrations and Mutations”. The data supporting quantitative associations between these KERs was gathered through literature review and experimental methods. I first used systematic literature review tools to develop and apply a pragmatic and transparent method to search the literature for AOP evidence. A broad search, covering all of the KERs of interest, was initially conducted. This search, which retrieved more than 230 thousand articles, demonstrates the data-rich nature of the AOP. An artificial intelligence informed prioritization of the top 100 articles were then examined in detail. This approach identified 39 articles containing qualitative empirical support for the AOP, but limited quantitative evidence of the KERs. A second search was conducted to address the need for quantitative evidence as well as the lack of evidence for the KER between and increase in reactive oxygen species (ROS) and oxidative DNA damage. The second search retrieved 12 articles that could be used to define a quantitative relationship between cellular ROS and oxidative DNA damage. To begin to address gaps in quantitative understanding, I then conducted experiments in the laboratory to measure oxidative DNA damage, DNA strand breaks, chromosomal aberrations, and mutations in TK6 cells after exposure to a range of concentrations of 4-Nitroquinoline 1-oxide (4NQO: a prototype ROS producing agent). An increase in both oxidative DNA damage and DNA strand breaks was observed after 2, 4, and 6 h exposures with the high throughput comet assay (CometChip). An increase in the incidence of micronuclei was observed after a 24 h exposure to a low concentration of 4NQO, as measured with the flow cytometry micronucleus assay, while high cytotoxicity was found at higher concentrations. Lastly an increase in mutation frequency was observed with Duplex Sequencing, an error-corrected sequencing technology. Additionally, an increase in the proportion of C>A transversions was observed, consistent with the expected mutations following oxidative DNA lesions. Overall, my work contributes to the quantitative understanding of AOP #296 and this project serves as a key example of AOP-informed study design, highlighting notable challenges in characterizing quantitative relationships.

<p>Some individuals remain at risk for adverse outcomes such as chronic wrist/hand pain, falls, and fall-related osteoporotic fractures after distal radius fracture (DRF) remain. This thesis includes five studies that were conducted to establish prediction rules for assessing the risk of these adverse outcomes following DRF.</p> <p>The first manuscript outlines a theoretical framework (RACE - <strong>R</strong>educing pain, <strong>A</strong>ctivating, <strong>C</strong>ognitive reshaping, <strong>E</strong>mpowering) for managing the risk of adverse outcomes, mainly chronic pain, in individuals with DRF. The RACE is one of the first frameworks to suggest a risk-based management approach for individuals with DRF.</p> <p>The Patient-Rated Wrist Evaluation (PRWE) is a condition-specific measure for DRF used in research as well as clinical practice to measure pain and functions in individuals with different wrist/hand injuries. The second manuscript contributes to the literature by providing the first systematic literature review that synthesizes the evidence regarding the psychometric properties of the PRWE. The review determined that the PRWE has excellent reliability, construct validity, and responsiveness in individuals with DRF.</p> <p>The third manuscript indicates that the baseline pain intensity is an independent predictor of chronic pain in individuals with DRF. The results also suggest that the individuals who score ≥35/50 on the pain scale of the PRWE at baseline have 8 times greater risk for developing chronic wrist/hand pain compared to those who score < 35/50.</p> <p>The fourth and fifth manuscripts describe results of a two step study. The fourth manuscript is a structured literature synthesis that identified suitable measures for predicting the risk of falls and fall-related osteoporotic fractures following DRF. The fifth manuscript summarizes the results of preliminary analysis of psychometric properties of selected fall risk measures identified in the fourth manuscript. The fifth manuscript also provides feasibility and sample size requirements for conducting a fall prevention trial in individuals with DRF.</p> / Doctor of Philosophy (PhD)

Childhood trauma greatly impacts the lives of patients and their future health outcomes. Since the discovery of the utility of the Adverse Childhood Experiences (ACEs) screening tool in the 1990s, many providers have attempted to screen and intervene on these past experiences of trauma with mixed results. ACEs have an outsized impact on adult health. There is considerable literature documenting the changing state of screening for ACEs in adult populations, and the compelling rationales for doing so. There are also a number of interventions available currently, but providers face challenges to use them. Ethical considerations and issues with the current state of screening for ACEs exist, due to some of these challenges and differential availability of interventions between populations. Here, I use the principles of urban bioethics to explain the ethical obligation of screening for ACEs despite these challenges and to dispute previous discussions on this topic. This article will show that there are general strategies that providers can take to implement ACEs screening in an ethical manner and specifically discusses trauma-informed care’s utility to help achieve these strategies. Through this discussion, I hope to encourage providers to reconsider ACEs screening and give them strategies to do so. / Urban Bioethics

Maternal adverse childhood experiences (ACEs) are associated with difficulties in parent- child relationships, however, research to date has focused on cross-sectional associations. Parent and child behavior may be differently affected by ACEs as a child develops and caregiving demands change. Furthermore, poorer executive function (EF) is associated with both ACEs and problematic parenting processes, and may be one potential mechanism involved in the intergenerational transmission of ACEs. This study examined longitudinal associations between maternal ACEs, maternal EF, and patterns of change in maternal and child emotional availability (EA) using longitudinal multilevel modelling (MLM). Mother-child dyads (N = 114) were followed at five separate assessments over a 5-year period. Maternal ACEs were measured retrospectively at 3-months postpartum, maternal EF was assessed at 8-months, and mother-child interactions were videotaped at 18-, 36- and 60-months postpartum. Results revealed that maternal EA was stable, while child EA increased from 18- to 60-months postpartum. Maternal ACEs were negatively associated with maternal and child EA at 18-months postpartum and this effect decreased overtime. In contrast, there was a persistent, positive effect of maternal EF on EA trajectories. Maternal EF did not mediate the association between ACEs and EA. Findings also demonstrated significant within-dyad associations between maternal and child EA. These findings lead to a deeper understanding of the effects of maternal influences on parent-child relationships. We provide important evidence regarding the intergenerational transmission of ACEs, demonstrating that effects of maternal ACEs on parenting are not necessarily persistent. Findings also support sustained relations between maternal EF and maternal and child behavior across development, suggesting the utility of EF as an intervention target. / Thesis / Master of Science (MSc) / Adverse childhood experiences (ACEs), which are experiences of abuse, neglect, and household dysfunction, are risk factors for difficulties in parent-child relationships when individuals become parents themselves. In addition, ACEs are associated with deficits in higher-order cognitive abilities called executive functions (EF) in adulthood, which may also, in turn, compromise an individual’s ability to provide sensitive and nurturing care to their children. The following thesis explores the collective relationships between maternal ACEs, maternal EF, and emotional availability during parent-child interactions in a community sample of mothers and their children, followed from toddlerhood (18-months postpartum) to preschool (60-months postpartum). Findings from this study demonstrate unique trajectories of maternal and child emotional availability during this period in development. Higher maternal ACEs were associated with decreased emotional availability during parent-child interactions at 18-months postpartum and this effect decreased overtime. Mothers with higher EF, and their children, demonstrated increased emotional availability across development. Maternal ACEs was not associated with maternal EF. Findings are relevant in informing the development and adaptation of timely and preventative parenting interventions.

Yes / Patients' pharmacogenetic data could be used to improve adherence to antipsychotic medication by increasing the likelihood of therapeutic response and reducing the prevalence of adverse drug reactions.

L’assurance chômage (AC) est un dispositif central des politiques du marché du travail. Une revue de littérature détaille ce que l’on sait de la pertinence et de l’optimalité de ces régimes dans le contexte du marché du travail contemporain. Elle illustre que si la stabilisation de la consommation des chômeurs est le motif générateur de l’AC, peu de travaux ont évalué cet aspect ou les autres effets positifs de l’AC, se focalisant sur les effets pervers du dispositif, notamment l’alea moral des chômeurs, et sur l’optimisation des règles pour les contenir. Dans la dernière décennie, la prise en compte des firmes et de la dynamique économique a rendu la littérature plus fertile pour optimiser les dépensescomme les ressources de l’AC.Les régimes d’AC profitent-ils de ces enseignements ? L’évolution des règles du régime français depuis 50 ans, ainsi que l’extrême diversité de celles en vigueur dans 5 pays incline à douter que ces régimes sont optimaux, surtout si on se limite à l’AC plutôt que de tenir compte de l’ensemble des transferts aux chômeurs pour analyser leurs comportements.La situation du régime français montre que ses fréquentes évolutions n’ont pas résolu ses problèmes. Il a subi, mais aussi stimulé, la récurrence au chômage, au prix d’une pression fiscale accrue et d’une efficacité dégradée pour la majorité des salariés et des firmes. En France comme dans de nombreux autres pays, les ressources de l’AC sont un domaine de réformes délaissé, alors qu’à tous points de vue (équité, incitations, équilibre financier, etc.) les gains potentiels d’une révision de leurs modalités sont plus élevés que ceux à attendre d’un nouvel ajustement marginal des droits. / Unemployment Insurance (UI) is a key labour market policy.A comprehensive survey of UI literature assesses what we know about UI optimality and its relevance regarding present labour market conditions. Despite of being its founding rationale, jobseekers’ consumption smoothing is rarely assessed, as well as other UI gains. In contrast research has long focused on UI adverse effects, namely recipients’ moral hazard, and on benefits optimization to control it. Recent literature better integrates firm and economic dynamics, thus being richer regarding the way UI benefits and financing rules could be more optimal.Do UI regimes build on this knowledge? An historical approach of French UI rules, and up to date descriptions of 5 other UI regimes, show an extreme diversity of UI arrangements, raising doubts about their optimality. Comprehensive analysis of social transfers to unemployed should be preferred to analysis restricted to UI benefits, because less misleading about unemployed real situation and behaviour.An in depth analysis of French UI rules illustrates that numerous reforms didn’t solve structural problems. The regime suffered increasing spending due to labour market changes, but it also stimulated adverse expensive behaviours among specific groups and short term contracts, both leading to heavier taxes and reduced efficiency for the bulk of workers and firms. In France as elsewhere, UI systems’ funding is a forsaken part of reforms. Yet regarding justice, incentives, financial stability, etc. reviewing rules governing resources could be more rewarding than implementing usual UI benefits reforms.

Background: The causes of childhood brain tumors (CBT) are essentially unknown. Exposure to extremely low frequency magnetic fields (ELF-MF) (3-3000Hz) is an ubiquitous part of modern life. However, very few studies have investigated the possible effect of maternal occupational ELF-MF exposure on CBT and the available findings are inconsistent across studies. / Methods: We examined the role of maternal occupational exposure to ELF-MF shortly before and during pregnancy on the incidence of childhood brain tumors. A total of 548 incident cases and 760 healthy controls recruited between 1980 and 2002 from two Canadian provinces (Quebec and Ontario) were included and their mothers were interviewed. Tumors were classified as astroglial tumors, primitive neuroectodermal tumors (PNET), and other gliomas. Quantitative occupational ELF-MF exposure in microtesla units was estimated using individual exposure estimations or a job exposure matrix. We used three metrics to analyze exposure: cumulative, average, and maximum level attained. / Results: Using the average exposure metric measured before conception, an increased risk was observed for astroglial tumors (OR=1.5, and 95% CI=1.0-2.4). During the entire pregnancy period, a significantly increased risk was observed for astroglial tumors as well as for all childhood brain tumors with the average metric (OR=1.6, 95% CI=1.1-2.5 and OR=1.5; 95% CI=1.1-2.2, respectively). Based on job titles, a two-fold risk increase was observed for astroglial tumors (OR=2.3, 95% CI=0.8-6.3) and for all childhood brain tumors (OR=2.3, 95% CI=1.0-5.4) among sewing machine operators. / Conclusion: Results are suggestive of a possible association between maternal occupational ELF-MF exposure and certain brain tumors in their offspring. / Keywords: brain tumors, occupational exposures, maternal exposures, magnetic fields, childhood cancer, job exposure matrix

Background: Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and society in general. Post-marketing pharmacovigilance reporting databases with compiled individual case safety reports (ICSRs) have been shown to be particularly useful in the detection of novel drug - ADR combinations, though these reports have not been fully used to detect adverse drug interactions. Aim: To explore the potential to identify drug interactions using ICSRs and to develop a method to facilitate the detection of adverse drug interaction signals in the WHO Global ICSR Database, VigiBase. Methods: All six studies included in this thesis are based on ICSRs available in VigiBase. Two studies aimed to characterise drug interactions reported in VigiBase. In the first study we examined if contraindicated drug combinations (given in a reference source of drug interactions) were reported on the individual reports in the database, and in the second study we examined the scientific literature for interaction mechanisms for drug combinations most frequently co-reported as interacting in VigiBase. Two studies were case series analyses where the individual reports were manually reviewed. The two remaining studies aimed to develop a method to facilitate detection of novel adverse drug interactions in VigiBase. One examined what information (referred to as indicators) was reported on ICSRs in VigiBase before the interactions became listed in the literature. In the second methodological study, logistic regression was used to set the relative weights of the indicators to form triage algorithms. Three algorithms (one completely data driven, one semi-automated and one based on clinical knowledge) based on pharmacological and reported clinical information and the relative reporting rate of an ADR with a drug combination were developed. The algorithms were then evaluated against a set of 100 randomly selected case series with potential adverse drug interactions. The algorithm’s performances were then evaluated among DDAs with high coefficients. Results: Drug interactions classified as contraindicated are reported on the individual reports in VigiBase, although they are not necessarily recognised as interactions when reported. The majority (113/123) of drug combinations suspected for being responsible for an ADR were established drug interactions in the literature. Of the 113 drug interactions 46 (41%) were identified as purely pharmacodynamic; 28 (25%) as pharmacokinetic; 18 (16%) were a mix of both types and for 21 (19%) the mechanism have not yet been identified. Suspicions of a drug interaction explicitly noted by the reporter are much more common for known adverse drug interactions than for drugs not known to interact. The clinical evaluation of the triage algorithms showed that 20 were already known in the literature, 30 were classified as signals and 50 as not signals. The performance of the semi-automated and the clinical algorithm were comparable. In the end the clinical algorithm was chosen. At a relevant level, 38% were of the adverse drug interactions were already known in the literature and of the remaining 80% were classified as signals for this algorithm. Conclusions: This thesis demonstrated that drug interactions can be identified in large post-marketing pharmacovigilance reporting databases. As both pharmacokinetic and pharmacodynamic interactions were reported on ICSRs the surveillance system should aim to detect both. The proposed triage algorithm had a high performance in comparison to the disproportionality measure alone.