L'intérêt du programme de dépistage du cancer du sein par mammographie résulte de la balance entre la réduction de la mortalité et les effets indésirables du programme. L'objectif de ce travail était d'évaluer trois aspects du programme de dépistage dans le département de l'Isère. Nous avons utilisé une méthode Approximate Bayesian Computation pour estimer le surdiagnostic lié au dépistage par mammographie de cancers non évolutifs. Ils représentaient respectivement 1,5% (IC95% : 0,3% - 2,9%) et 28,0% (IC95% : 2,2% - 59,8%) des cancers invasifs et in situ diagnostiqués. Nous avons réalisé une revue de la littérature des méthodes d'estimation du surdiagnostic et montré sur des données simulées que les méthodes basées sur les taux d'incidence annuels étaient les moins sensibles aux biais. Par ailleurs, l'incidence des cancers de l'intervalle était inférieure lorsque les mammographies étaient réalisées avec deux clichés par sein au lieu d'un seul, aussi bien à 12 que à 24 mois. Enfin, l'exclusion du diagnostic de cancer après la réalisation d'une imagerie supplémentaire, d'une biopsie ou un suivi radiologique diminuait la participation lors de la prochaine invitation au dépistage organisé. En conclusion, l'intérêt du programme de dépistage du cancer du sein par mammographie n'est pas remis en cause avec 1,4 décès évité pour un cancer surdiagnostiqué (in situ ou invasif).

L'objectif de ces travaux est de connaître et évaluer les caractéristiques épidémiologiques des cancers de la cavité orale et de l'oropharynx. Ces deux localisations partagent des facteurs de risque en commun, et sont de fait souvent regroupées dans les études épidémiologiques. Cependant, la découverte de facteurs de risque spécifiques, telle l'infection par le virus du papillome humain pour les cancers de l'oropharynx, nous conduit à fournir des taux d'incidence spécifiques avec la classification anatomique de ces cancers. En réorganisant les données disponibles dans la base des données du Centre International de Recherche sur le Cancer, nous avons recherché les cas incidents au niveau mondial et recalculé les taux d'incidence dans les registres de 60 pays, pendant la période 1998-2002. La classification TNM n'est pas disponible dans les bases de données du CIRC. Nous avons identifié et contacté les registres du cancer qui ont déclaré son recueil. Cela nous a permis de créer et structurer une base des données innovante et inédite, dont les informations ont été analysées par rapport à la qualité. Finalement nous avons comparé la distribution de stades précoces et avancés dans 8 pays. Les résultats montrent que l'incidence des cancers de la cavité buccale et de l'oropharynx est très hétérogène au niveau mondial par rapport à la sous localisation des tumeurs, à l'âge d'incidence, au ratio homme/femme et au stade clinique.

<p>Biological treatment optimization aim at improving radiation therapy by accounting for the radiobiological tumour and normal tissues response properties when optimizing the dose delivery. Generally traditional methods, using only dosimetrical measures, disregard the nonlinear radiation response of different tumours and normal tissues. The accumulated knowledge on tissue response to radiation, in the form of more accurate dose response relations, cell survival models and their associated biological parameters, alongside with the tools for biological treatment plan optimization, has allowed the present investigation on the potential merits of biologically based treatment optimization in radiation therapy.</p><p>With a more widespread implementation of intensity modulated radiation therapy in the clinic, there is an increasing demand for faster and safer treatment delivery techniques. In this thesis biological treatment plan optimization, using the probability to achieve complication free tumour control as the quantifier for treatment outcome, was applied to radiation therapy of early breast cancer and advanced cervix cancer. It is shown that very conformal dose distributions can generally be produced with 3 or 4 optimally orientated coplanar intensity modulated beams, without having clinically significant losses in treatment outcome from the optimal dose distribution.</p><p>By using exhaustive search methods, the optimal coplanar beam directions for intensity modulated photon beams for early breast cancer and the optimal non-coplanar directions for an advanced cervix cancer were investigated. Although time consuming, exhaustive search methods have the advantage of revealing most features involving interactions between a small number of beams and how this may influence the treatment outcome. Thus phase spaces may serve as a general database for selecting an almost optimal treatment configuration for similar patients. Previous knowledge acquired with physically optimized uniform beam radiation therapy may not apply when intensity modulated biological optimization is used. Thus unconventional treatment directions were sometimes found.</p>

<p>This thesis consists of three papers which evaluate the effects of the Adult Education Initiative (AEI) in Sweden relative to the vocational part of Labor Market Training (LMT).</p><p>Paper [I] studies unemployment incidence and unemployment duration for participants in the AEI relative to LMT. When evaluating the relative program effects on duration, one needs to take into account both the problem of selection and the fact that the outcome variable is right hand censored. The method used is an instrumental variable adaptation of the symmetrically trimmed least squares estimator. A bivariate probit model is used in order to study unemployment incidence. The results indicate a beneficial effect of the AEI relative to LMT on unemployment incidence, but longer duration in unemployment among the AEI participants.</p><p>Paper [II] uses annual wage earnings in 1999 to compare the AEI and LMT for individuals that do not continue in education following program completion. Two separate estimation methods are used, the classical selection model and the method of matching on the propensity score. The results of both methods indicate negative effects of the AEI relative to LMT on wage earnings. The earnings effect of the AEI for individuals with a weak position in the labor market is particularly poor, implying that the official target to assist those individuals appear not to have succeeded.</p><p>Paper [III] employs data for those enrolled in 1997 as well as 1998 to study the annual wage earnings of 1999 and 2000 and data on attachment to branches of employment before and after program. Data on branches of employment indicate less mobility among the AEI participants. This is largely due to a stronger attachment to the public service sector. The analysis of wage earnings of the sample enrolled in 1997, indicate that the effects on wage earnings tended to be more advantageous for the AEI in 2000 rather than 1999, possibly implying a lag in the effects of the program.</p>

<p>Ultraviolet radiation (UVR) is a major risk factor for development of skin cancer. UVR-induced DNA damage and a dysfunctional p53 protein are important steps in the development of squamous cell carcinoman in human skin (SCC). The aim of the present investigation was to analyze incidence trends of SCC in Sweden, quantify the risk of second primary cancer after SCC and further analyze the effects of UVR and p53 protein in human skin <i>in vivo</i> and <i>in vitro</i>. The effect of photoprotection by sunscreens was also evaluated. </p><p>We found that the age-standardized incidence rate of SCC in Sweden increased substantially in both men and women during the period 1961-1995, especially in men and at chronically sun-exposed skin sites. Patients with SCC are also at increased risk of developing new primary cancers, especially in the skin, squamous cell epithelium, hematopoietic tissues and respiratory organs. In experimental studies <i>in vivo</i> and <i>in vitro</i> in human skin we observed that repair of UV-induced DNA damage appears to be more efficient in chronically sun-exposed skin despite a less uniform p53 response. Non-sun- exposed skin is more homogeneous with respect to the epidermal p53 response. Keratinocytes in skin exposed frequently to the sun may be prone to react more easily to cytotoxic stress. Two different modalities of photoprotection significantly reduced the amount of DNA damage and the number of p53-positive cells. In addition, we demonstrated that a well-defined system for <i>in vitro</i> culture of explanted skin provides an excellent alternative to <i>in vivo</i> experiments. </p><p>In conclusion, this study has increased our knowledge of SCC epidemiology in Sweden and of the effects of artificial and solar UVR and sunscreens on chronically sun-exposed and non-sun-exposed sites, respectively, of human skin.</p>

<p>Urinary incontinence is a prevalent condition; nevertheless few women seek professional help. One aim of this study was to investigate all women aged 18-70 years in a Swedish community regarding (a) the prevalence rate and risk factors of urine leakage and (b) the quality of life for women with and without urine leakage, for women with stress incontinence versus urge incontinence, and for women with urine leakage who had or had not sought help. A second aim was to study all women aged 18-46 years from the same population four years later regarding (a) the quality of life and natural history of urine leakage, (b) why some women with persistent urine leakage seek help and others do not, and (c) how they deal with their urine leakage.</p><p>Every fourth woman aged 18-70 years was found to have urine leakage. The number of women with urine leakage increased with increasing age, the number of deliveries, the presence of urinary tract infection, and the use of oestrogen substitutions. Women with urine leakage had a lower quality of life in all eight dimensions of the SF-36 as compared with women without urine leakage. Furthermore, in women with urge incontinence the quality of life was lower compared with women with stress incontinence in all dimensions of the SF-36. Women with urine leakage who had sought help had lower quality of life in seven of eight SF-36 dimensions as compared with women with urine leakage who had not sought help.</p><p>At the four-year follow-up the quality of life had deteriorated in five of eight SF-36 dimensions in women aged 18-46 years with persistent urine leakage as compared with women with persistent continence. The mean annual incidence and remission rates of urine leakage were on the same low level (4%). Most women with slight or moderate long-term urine leakage had not sought professional help, largely because they considered their leakage a minor problem. Pelvic floor exercises was the most commonly used management method for all participants.</p>

<p>Eating disorders (ED) constitute a significant source of psychiatric morbidity and are an important public health concern in Western societies. Knowledge about risk factors for ED is crucial for early detection and implementation of preventive interventions. The aim of the present thesis was to examine the prevalence, incidence, correlates, and the risk factors for ED among 1,157 young adult women in the general population. The studies in the thesis used a prospective design with the potential of addressing methodological limitations in earlier research.</p><p>In Study I, conducted in 1997, the lifetime and point prevalence of DSM-IV-based diagnoses of ED was, respectively, 7.85% and 2.59%. Participants with ED reported higher body dissatisfaction, lower perceived social support from the family, and lower self-esteem compared to participants with no ED. In Study II, it was shown that highest relative use of escape-avoidance coping was reported among participants with ED, followed by dieting participants with no ED, and least among those neither dieting nor with ED. In Study III, (i.e., the follow-up in 1999), the point prevalence of ED was 3.15% and the cumulative 2-year first time incidence was .0105 (n=8). The total incidence group (n=34), as compared to the participants with no ED (controls, n=643), reported significantly lower premorbid self-esteem, and perceived social support from the family and higher body dissatisfaction, higher relative use of escape-avoidance coping, and dieting. Furthermore, the incidence group reported a significant increase in body dissatisfaction and relative use of escape-avoidance coping, and a significant decrease in self-esteem as compared to controls from 1997 to 1999. In Study IV, it was shown that the <i>Survey for Eating Disorders</i> is a reliable and valid self-report questionnaire for the screening of ED and case ascertainment. </p><p>In conclusion, it is suggested that premorbid low self-esteem, perceived low social support, high body dissatisfaction, high relative use of escape-avoidance coping, and dieting be regarded as risk factors for a later development of ED among young adult women. It is also proposed that more attention be devoted to these factors both in designing prevention interventions and in refining current treatments. </p>

<p>Headache is the most frequently reported pain in children and is associated with missed schooldays, anxiety, depressive symptoms and various physical symptoms. A secular trend of increasing headache prevalence has been suggested. Few studies have focused on tension-type headache among children from the general population. </p><p>The aims of this thesis were to describe the prevalence, incidence and prognosis of tension-type headache, migraine and overall headache in schoolchildren, to identify medical, psychological and social factors associated with these headache types, and to determine whether the prevalence of headache has increased over the last decades.</p><p>In 1997, 1850 schoolchildren aged 7-15 years from the city of Uppsala participated in a questionnaire study and 1371 (74.1%) responded. Out of these, a randomly selected, stratified sample of 131 children and their parents were interviewed. Three years later, 122 children from the interview sample replied to an identical headache questionnaire.</p><p>Compared with a similar study in 1955, a significantly lower proportion of schoolchildren reported no headache. The prevalence of tension-type headache increased with age and was significantly higher in girls than boys after the age of twelve. Similar age and gender differences were obtained for migraine. A higher proportion of girls reported frequent headache than boys. Children with headache, especially those with migraine, as well as their first-degree relatives suffered from other pains and physical symptoms more frequently than headache-free children and their first-degree relatives. Although the likelihood of experiencing the same headache diagnosis and symptoms at follow-up was high, about one fifth of children with migraine developed tension-type headache and vice versa. Female gender was a predictor of migraine and frequent headache a predictor of overall headache at follow-up. The estimated annual incidence for tension-type headache, migraine and overall headache was 81, 65 and 131 per 1000 children, respectively. </p><p>In conclusion, the results indicate that headache has become increasingly common among schoolchildren over the last decades. Prevention and treatment of headache is particularly important for girls since they have high prevalence of headache, frequent headache episodes and a poor outcome. In children with headache, diagnoses and treatment should be reassessed regularly and other pains should be asked about and treated as well. </p>

<p>Spontaneous reporting systems (SRSs) for adverse drug reactions (ADRs) have been developed as a result of the thalidomide disaster, whereby thousands of children world-wide were born with birth defects. The Swedish Adverse Drug Reactions Advisory Committee was established in 1965. Since 1975, reporting has been compulsory for all suspected serious or new ADRs. International collaboration started in 1968 with countries contributing their ADR reports to an international database set up by the World Health Organization. </p><p>ADRs represent the negative side of the benefit-to-risk balance that in theory needs to be counteracted by perceived or established positive drug effects. All drugs are subject to preclinical and clinical testing prior to marketing authorization. However, these studies are insufficient to detect rare ADRs, ADRs that occur after long-term administration or with latency, ADRs that occur in special patient groups such as children, the elderly, patients with renal or hepatic insufficiency or patients on concomitant drug treatment, and ADRs that represent a modest increase in the risk of diseases (including mortality) that are prevalent in the study population. Postmarketing surveillance of drugs is therefore essential, and regulatory action may be needed on the basis of new ADR information. </p><p>SRSs are important sources of ADR information as exemplified here by the evaluation of peripheral sensory disturbances with fluoroquinolones, hyponatremia with antidepressants, blood dyscrasias with dipyrone, glucose intolerance with atypical antipsychotics, pulmonary embolism with combined oral contraceptives and extrapyramidal symptoms with selective serotonin reuptake inhibitors. SRSs can be used to study clinical manifestations of ADRs (that can give insights into potential ADR mechanisms), risk factors for the ADR or for specific outcomes of the ADR, and ADR reporting incidences when combined with sales data. Signals from SRSs may need to be studied further e.g., by use of large-scale epidemiologic studies based on record linkage between drug prescription databases and health databases. Owing to the rapid availability of information, however, SRSs are likely to remain of major importance for the post-marketing surveillance of drugs.</p>

<p>Wegener´s granulomatosis (WG) is an unusual, serious, systemic vasculitis with specific clinical findings. The studies in this thesis aim at broadening our understanding of the aetiology and outcome of WG.</p><p>Patients with WG were identified in the In-patient Register 1975-2001. During this time the incidence increased three-fold, and neither ANCA-related increased awareness, nor diagnostic drift, seem to fully explain this trend, but it is still unclear if a true rise in incidence exists. </p><p>Anti- neutrophil cytoplasmic antibodies (ANCA) have been presented as highly specific for vasculitis. In a series of consecutive cANCA/PR3-ANCA positive patients, we investigated the positive predictive value for ANCA, and the outcome of patients with a positive cANCA/PR3-ANCA but not vasculitis. These patients have a low future risk of developing vasculitis, possibly indicating that ANCA, in this setting, reflects neutrophil activating properties not specific to vasculitis.</p><p>By linkage of the WG-cohort, and randomly selected population controls, to the Multi-generation register, we identified all first-degree relatives and spouses of patients and controls, totally encompassing some 2,000 patients and 70,000 relatives. Familial aggregation of WG was the exception, with absolute risks of < 1 per 1000.However, relative risks in first-grade relatives amounted to 1.56 (95% CI 0.35-6.90) such that a moderate familial aggregation cannot be excluded.</p><p>In the WG-cohort, cancer occurrence and risk was compared to that of the general population. Patients with WG have an overall doubled risk of cancer, with particularly increased risks of bladder-cancer, haematopoietic cancers including lymphomas and squamous skin-cancer. In a case-control study nested within the WG-cohort, treatment with cyclophosphamide was compared among bladder-cancer patients and matched cancer-free controls. Absolute risk of bladder cancer as high as 10% some years after diagnosis were found, and this risk can partly be attributed to cyclophosphamide-treatment, with a dose-response relationship.</p>