Ce travail porte sur l’étude du risque de démence chez les personnes âgées ayant consommé des benzodiazépines. Ces médicaments méritent une attention particulière du fait de (i) leur utilisation trop systématique et le plus souvent chronique contrairement aux recommandations préconisant des durées d’utilisation courtes (ii) leurs effets délétères sur la cognition demeurant mal évalués à long terme. La plupart des études conduites sur ce sujet ont conclu à une augmentation du risque de démence chez les sujets ayant utilisé des benzodiazépines. Un biais protopathique pouvait cependant, en partie du moins, avoir expliqué ces résultats : la prescription de benzodiazépines pouvait avoir été motivée par des prodromes souvent observés au cours des années précédant le diagnostic de la maladie. Afin de mieux prendre en considération ce biais, le projet BENZODEM a utilisé les ressources de la cohorte PAQUID (3777 sujets ≥ 65 ans tirés au sort sur les listes électorales de Dordogne et Gironde bénéficiant d’un suivi de plus de 20 ans). Ce projet, combinant deux études de cohorte et une étude cas-­‐témoins, a conclu à un risque de démence augmenté de 46 à 62% chez les utilisateurs de benzodiazépines et retardé de 5 à 15 ans par rapport à l’initiation du traitement. La seconde partie du programme (BENZODEM2) a consisté en une étude cas-­‐témoins conduite sur un large échantillon de sujets de plus de 65 ans enregistrés sur la base de données de la Régie de l’Assurance Maladie du Québec (RAMQ). Ce programme a permis (1) de valider les précédents résultats (risque augmenté de 30 à 80% en fonction de la dose, la durée du traitement et la nature des molécules) (2) d’identifier les profils de consommation associés à un excès de risque : consommateurs de plus de 3 mois avec une relation dose-­‐effet marquée et molécules à longue demi-­‐ vie d’élimination. Des explorations complémentaires ont permis de conclure que cet excès de risque n’était pas expliqué par une mortalité différentielle entre groupes comparés ni par la prescription d’autres médicaments psychotropes. Une autre étude menée sur PAQUID montrait une absence de différence entre consommateurs et non consommateurs de benzodiazépines vis-­‐à-­‐vis de l’évolution des scores mesurant les fonctions cognitives. Ces résultats ont permis d’émettre des hypothèses concernant le mécanisme de l’association entre utilisation de benzodiazépines et démence: (1) les benzodiazépines pourraient constituer des marqueurs précoces de la maladie ; (2) les benzodiazépines pourraient aussi diminuer les capacités de recours à la réserve cognitive en réponses aux lésions précoces de la maladie au stade préclinique ; (3) il est aussi possible que ces deux explications soient combinées. / This work deals with the risk of dementia in elderly individuals who have used benzodiazepines. These drugs deserve particular attention because (i) their use appears to be too systematic and most often chronic despite good practice guidelines recommending short durations of use (ii) their deleterious effects on cognition remain underevaluated for the long-­‐term. Most of the studies conducted concluded that there was an increased risk of dementia among benzodiazepine users. In fact, a protopathic bias could, at least in part, have explained these results. Indeed, the prescription of benzodiazepines could have been motivated by the prodromes often observed several years before the clinical diagnosis of a dementia. With the aim of better controlling for this bias, the BENZODEM project used the resources of the PAQUID cohort (3777 subjects ≥65 years randomly sampled from electoral lists in South-­‐West France, with a 20-­‐ year follow-­‐up). This project combined two cohort studies and one case-­‐control. These studies concluded in a risk of dementia increased by 46 to 62% in benzodiazepine users and delayed by 5 to 15 years after treatment initiation. The second part of the programme (BENZODEM2) consisted of a case-­‐control study conducted in a large sample of subjects >65 years registered in the Quebec Health care database (Régie de l’Assurance Maladie du Québec, RAMQ). It was thus possible(1) to validate the previous results by using a different population (the risk was found to be increased by 30 to 80% depending on the patterns of use regarding dose, duration and type of molecule), (2) to identify the patterns of use which appeared to be at risk; excess risk was only apparent for uses of more than three months with a marked dose-­‐effect relationship, and was higher for molecules with a long elimination half-­‐life. Complementary explorations using the PAQUID cohort indicated that the excess risk in exposed was not explained by a differential mortality rate between the groups compared. Other studies suggested that the link found remained independently of the prescription of other psychotropics. Another analysis in the PAQUID cohort showed that, in the absence of dementia, no difference was observed between benzodiazepine users and non-­‐users with regards to the evolution of scores evaluating cognitive functions. These results led to several assumptions about the putative mechanism explaining the relationship found between benzodiazepine use and dementia: (1) benzodiazepines could be early markers of symptoms such as anxiety, depression or insomnia, which are potential prodromes or risk factors for this disease, (2) these drugs could also reduce the ability to use cognitive reserve in order to cope with early lesions of the disease during the preclinical stage, (3) the association found could also result from these two mechanisms.

Sleep problems have been defined using a variety of definitions. No study has assessed the longitudinal association between infant sleep problems and childhood overweight or obesity using existing definitions of sleep problems. This study used longitudinal data (n=895) from the multi-site Study of Early Child Care and Youth Development (SECCYD) to investigate the effects of infant sleep problems on childhood weight status in Grade 6. Infants with sleep problems in Phase I (1991) and with complete data through Phase III (2004) of SECCYD were included. Sleep problems were assessed using maternal reports of night wakings and duration of a waking episode. Sleep problems were defined using Richman (1981), Lozoff et al. (1985), and Zuckerman et al. (1987) definitions. Multinomial logistic regression was used to examine the association between sleep problems during infancy and childhood weight status in Grade 6 while controlling for birth weight, race, sex, breastfeeding, maternal poverty, family structure, and maternal education. After adjusting for all covariates, children with a history of sleep problems were found to be overweight in Grade 6 using Zukerman et al. (Odds ratio (OR)=1.68; 95% confidence interval (CI): 1.11–2.55) and Richman (OR=1.76; 95% CI: 1.05–2.97) definitions, but not using Lozoff et al. definition. Infant sleep problems were not found to be associated with being obese. The study found differential effects of infant sleep problems on childhood overweight in Grade 6 per different definitions of sleep problems. Findings highlight the need to construct a single definition of infant sleep problems.

Bibliography: p. 675-681. / This study, the first of its kind in Southern Africa, was undertaken in order to determine and compare the incidence of various alternate conceptions in some areas in mechanics amongst pupils from standards 4 through to 9, i.e. from ages ca. 11 to 17, in selected schools in the Western Cape and Transkei, South Africa. After a careful study of the relevant literature a questionnaire was designed for the purpose of identifying the frequency of various alternate conceptions in the selected areas in mechanics. This questionnaire was administered to 2326 pupils under carefully controlled conditions during August and September 1987. In analysing the data the frequency of particular alternate conceptions in the following groups of pupils were compared: (i) by school standard (ii) by geographical area (iii) by language group (iv) by gender (v) by urban and rural regions in the Cape (vi) by subject choice i.e. science pupils and non-science pupils An analysis of the data shows that in most of the areas in the field investigated remarkably small differences exist in the frequency with which different alternate conceptions are held by different groups of pupils. In most cases differences could be related to the pupils' school standard. However, in the fields of circular motion, projectile motion and static equilibrium, clear differences were found to exist between boys and girls as well as between pupils in schools in the Western Cape and Transkei. Furthermore, in most cases examined the accepted scientific conception was the least popular, particularly in the field of force and motion where conceptions linking force and motion were overwhelmingly selected by pupils in all of the groups. However, an exception was the standard 9 science pupils, i.e. 16- 17 year olds following the science course in high school, who in some cases favour the accepted scientific conceptions by a small majority. The implications of the findings of the study for classroom teaching are discussed.

A literature review indicated that psychopathological symptomology must be considered within the social context of the patient. Recent research has suggested that the psychopathological symptoms of the psychotic patient function on a covert level of communication as a strategy to control the threat of interpersonal intimacy. The present investigation similarly examined the interpersonal function of another class of patient symptomology, somatic symptoms. It was hypothesized that somatic symptom verbalizations of psychiatric outpatients also can serve as covert messages to avoid the risk of interpersonal intimacy. Results indicated that only the high-somatic-symptom patients significantly increased their symptom verbalizations in response to demand. When the interviewer modeled impersonal self-disclosures, both groups showed a low rate of somatic verbalizations. The groups did not differ. When the interviewer modeled personal self-disclosures, both patient groups significantly increased their psychological symptom verbalizations compared to their counterparts in the impersonal condition. In addition, low somatic symptom patients under the demand for personal disclosure showed significantly less avoidance behavior than any other group. No differences were found among the experimental groups in terms of self-disclosure level. The results clearly lend support to Haley's (1963) intimacy-avoidance corollary; that is, symptoms of non-psychotic patients function as covert messages that avoid the formation of intimate interpersonal relationships by redefining the reciprocal role available to participants. In view of these findings, several cross-study comparisons were made. In addition, directions for future research were suggested.

Guided by models of family unpredictability, this study was designed to identify the distinctive sequelae of disorganized interparental conflict, a dimension of interparental conflict characterized by abrupt, inexplicable changes in parental emotional lability, conflict tactics, and verbalizations. Participants included 208 kindergarten children (M age = 5.74 years; 56% girls), mothers, and their caregiving partners from racially diverse backgrounds (e.g., 44% Black) who participated in a longitudinal study with two annual measurement occasions. At Wave 1, trained observers assessed disorganized interparental conflict. Observational and survey assessments were used to assess several family (i.e., interparental conflict, parenting difficulties, parent psychopathology, family instability) and demographic (i.e., children's gender, household income, parent education) characteristics. Assessments of child functioning at each wave included psychological adjustment (i.e., externalizing and internalizing symptoms, prosocial behavior), social information processing difficulties, and attention to emotion cues. Findings from structural equation modeling analyses indicated disorganized interparental conflict significantly predicted decreases in children's prosocial behavior and increases in their externalizing problems, angry reactivity to social problems, and biased attention to angry and sad cues over a one-year period. Results were significant while controlling for established measures of interparental conflict, parenting difficulties, parent psychopathology, family instability, and demographic characteristics. The findings suggest that disorganized characteristics of interparental conflict may be an important domain of clinical change beyond the established targets of family harshness and adversity. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

This dissertation examines the challenges and opportunities of analyzing distinct sources of mental health data in the age of precision medicine and big data. The focus lies on two areas: leveraging real-time Ecological Momentary Assessment (EMA) data to understand individual-level variations in mental disorders, especially depression; and the integration of data from randomized clinical trials (RCTs) to assess treatment efficacy, with an application to schizophrenia. The multifaceted and heterogeneous nature of mental disorders calls for nuanced and personalized assessment methods. In the first part of this dissertation, through our proposed machine learning method, the Heterogeneous-Dynamics Restricted Boltzmann Machine (HDRBM), we examine symptom-level variations beyond the traditional one-size-fits-all summary scores and learn the heterogeneous group dynamics. We demonstrate the effectiveness of our approach on simulated and real-world EMA data sets. We show that by incorporating covariates, HDRBM can improve accuracy and interpretability, explore the underlying drivers of the group dynamics of participants, and serve as a generative model for EMA studies. In the second part of the dissertation, we present the challenges of integrating multiple randomized clinical trials (RCTs) in mental health research, proposing data fusion as a means to integrate individual patient data across similar studies to enhance statistical power. The dissertation introduces novel estimators tailored for multi-study, multi-outcome fused datasets, aiming for the optimization of health outcomes for each treatment. The method also addresses the utilization of similar trials with different outcome follow- up measurements, serving as proxies for unobserved outcomes. An application is provided on cognitive remediation (CR) therapy’s efficacy using the NIMH Database of Cognitive Training and Remediation Studies (DCTRS) as a resource, emphasizing the importance of leveraging surrogate outcomes in clinical trials.

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23771号 / 医博第4817号 / 新制||医||1056(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 藤渕 航, 教授 阪上 優, 教授 小杉 眞司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

I Sverige finns en hög frekvens av rotfyllda tänder med apikal parodontit och en praxis för behandling saknas. Denna studie syftar till att röntgenologiskt kartlägga progressionen av apikal parodontit vid rotfyllda tänder som ej blivit föremål för ytterligare endodontisk eller kirurgisk behandling och att identifiera variabler som påverkar progressionen för att ge ett bättre underlag för behandlingsbeslut. Röntgenbilder på rotfyllda tänder med apikal parodontit som lämnats utan åtgärd (n = 120) granskades avseende förändringen av den apikala parodontiten under minst en 3-års period under åren 2002-2011. Progression av den apikala parodontiten observerades i 22,5% av de studerade tänderna, trots att man sannolikt tidigare bedömt att den apika parodontiten inte behövde behandling eller att man kunde avvakta med behandling. Ingen av de studerade variablerna: den ursprungliga apikala parodontitens storlek, rotfyllningens längd, rotfyllningens täthet, typ av koronal restaurering eller den koronala restaureringens täthet befanns ha något samband med den apikal parodontitens progression. Oförändrad apikal parodontit observerades vid 50 % av tänderna och signifikant oftare i överkäken (p=0.02). / There is a high frequency of endodontically treated teeth with apical periodontitis in Sweden, but a lack of a well-established practice of how to deal with these. This study aims to investigate radiographic progression of untreated apical periodontitis in previously root-filled teeth left without intervention and to identify factors that affect the progression in order to reach a better foundation for making treatment decisions. Radiographs of root-filled teeth with apical periodontitis (n = 120) were examined with regards to the change of the apical periodontitis over at least three years during 2002-2011.Progression of the apical periodontitis was observed in 22.5 % of the studied teeth in spite of probable clinical decisions that treatment was not needed for the apical periodontitis or treatment could be postponed. None of the studied variables: the size of the apical periodontitis, the length of the root-filling, the sealing quality of the root-filling, the type of the coronal restoration or the sealing quality of the coronal restoration were found to be correlated to the progression of the apical periodontitis. The apical periodontitis was unchanged in 50 % of the teeth and observed more often in the maxilla (p=0.02).