<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>

Background: Dental trauma occur in childhood and adolescence with consequences in time and costs for both patient and family. The scientific knowledge of these matters is scarce. For some individuals, dental trauma will result in long, time-consuming and costly treatments in childhood which will continue into adulthood. Aim: The thesis aimed to increase the knowledge of incidence, risk, treatment, time and costs spent on dental traumas to primary and permanent teeth in children and adolescents. Material and method: The material for the studies emanated from the county of Västmanland, Sweden, and the municipality of Copenhagen, Denmark, and from a Swedish nation-wide material (Folksam). The material was collected from accident reports, dental files, dental trauma forms, questionnaires and telephone interviews. Descriptive, prospective and analytical methods were used. A classification of uncomplicated and complicated dental traumas was presented. Results: The incidence of dental trauma to boys was higher, compared to girls, in the county of Västmanland in almost all age groups. For both sexes, the first years in life and the first years in school were the most accident prone periods with incidence twice as high as the average incidence for all children and adolescents in the county. Every third trauma was complicated with injuries to the pulp or periodontal ligaments. Every second patient with a dental trauma to permanent teeth suffered from multiple dental trauma episodes (MDTE) during a period of 12 years. In almost every second patient with MDTE, at least one of the affected teeth had sustained repeated trauma episodes. The risk of sustaining MDTE increased when the first trauma episode occurred in the age interval of 6-10, compared to 11-18 year olds. During a 12-year period, treatment times for complicated traumas were 2.0 and 2.7 times higher for primary and permanent teeth, respectively, compared to corresponding values for uncomplicated traumas. On average, direct time (treatment time) represented 11% and 16% of the total time, while the direct costs (health are service, transport, loss of personal property and medicine) represented 60% and 72% of the total costs of traumas to primary and permanent teeth, respectively, during a 2-year period for cases of a nation-wide material. Conclusion: Dental traumas are frequent and some individuals are injured several times. Besides treatment time, efforts from the family are substantial in time and costs. Parameters such as degree of severity, access to treatment and place of injury are of major importance to both patient and family and should be considered when calculating time and costs of dental trauma in children and adolescents.

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). 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. 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. 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.

Background: Idiopathic parkinsonism is a neurodegenerative syndrome of unknown cause and includes Parkinson’s disease (PD) and atypical parkinsonian disorders. The atypical parkinsonian disorders are: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The incidence rates of these diseases in Sweden are largely unknown. The diagnosis of each disease relies mainly on clinical examination although several imaging and laboratory parameters may show changes. A diagnosis based on clinical examination is especially difficult early in the course of each disease; diagnosis is easier later on when disease-charactersistic signs have evolved and become more prominent. However, even in later stages it is not uncommon that patients are misdiagnosed. PD can be divided into subgroups based on the main clinical symptoms, i. e. tremor dominant, postural instability and gait difficulty (PIGD), and indeterminate. The PIGD subtype has worse prognosis including higher risk of dementia. The aims were to study the incidence of idiopathic parkinsonism and the different specific parkinsonian disorders in the Umeåregion and to investigate the patients early in the course of the disease with brainmagnetic resonance tomography (MRI), external anal sphincterelectromyography (EAS-EMG) and oculomotor examination. Can these methods improve the differential diagnostic work-up and/or differentiate between the subtypes of PD? Methods: We examined all patients in our catchment area (142,000 inhabitants) who were referred to us due to a suspected parkinsonian syndrome. Our clinic is the only clinic in the area receiving referrals regarding movement disorders. During the period (January 1, 2004 through April 30,2009) 190 patients fulfilled the inclusion criteria and were included in the study. Healthy volunteers served as controls.  Results: Incidence: We found the highest incidences reported in the literature: PD (22.5/100,000/year), MSA(2.4/100,000/year), and PSP (1.2/100,000/year). No CBD patients were encountered. Brain MRI: Degenerative changes were common both in controls and PD. There were no differences between the PD subtypes. EAS-EMG: Pathological changes in EAS-EMG examination were common in PD, MSA and PSP. It was not possible to separate PD, MSA and PSP by the EAS-EMG examination. Oculomotor examination: Pathological results were common in all diagnosis groups compared to controls. It was not possible to separate PD, MSA and PSP or the PD subtypes with the help of oculomotor examination. Conclusions: The incidences of idiopathic parkinsonism, PD, MSA and PSP were higher than previously reported in the literature. It is not clear weather this is due to a true higher incidence in the Umeå region or a more effective casefinding than in other studies. MRI, EAS-EMG and oculomotor examination could not contribute to the differential diagnostic work-up between PD, MSA and PSP nor differentiate between PD subtypes early in the course of the disease.

<p> <p>&nbsp / </p> <p align="left">&nbsp / </p> </p> <p align="left">In addition to football and basketball, volleyball has become a very popular sport globally over the last 30 years. The International Federation of Volleyball represents about 150 million players in approximately 170 countries. While a large body of research has been conducted regarding the nature and prevalence of volleyball injuries internationally, very little has been done locally or on the African continent to assess the status of injuries incurred at professional or amateur levels. The aim of this study is to determine the prevalence of injuries sustained by professional volleyball players of a club in the WPVU in one season. An exploratory, descriptive, nonexperimental approach was used for this study on 42 volleyball players at the University of the Western Cape Volleyball Club. A self&ndash / administered questionnaire that was based on a questionnaire used in a Dutch national volleyball study was used in the present study. A response rate of 89.4% was obtained. The collected data were captured and analysed by means of the Statistical Package for Social Science version 14.0 (SPSS). The associations between variables were evaluated by means of the chi-square test and a 5% level of significance was used. The results were displayed using tables, bar chart, and pie chart. Most of the volleyball players sustained one or more injuries in the season, giving a prevalence rate of 88.1%. The incidence rate was 1.2 injuries per player. Injuries prevalence was higher among male players 54.1% than female players 45.9%. Among the injured players, ankle and knee injuries showed the highest injury prevalence with 25.5% for each followed by 19.6% for shoulder injuries. The study revealed 69.2% injury prevalence with a higher significance (p=0.04) that players who are injured in the ankle were in contact. Half of the injuries (50%), which occurred gradually, were prevalent in the shoulder, followed by the knee (28.6%), then the ankle and fingers (14.3%). Players in the left and right front row were significantly (p=0.008) more prone to be injured during spiking. Awareness programmes highlighting prevention strategies and physiotherapy intervention are required for coaches and players at the University of the Western Cape Volleyball Club to assist in the prevention of volleyball injuries.</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. 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 Survey for Eating Disorders is a reliable and valid self-report questionnaire for the screening of ED and case ascertainment. 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.

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 in vivo and in vitro. The effect of photoprotection by sunscreens was also evaluated. 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 in vivo and in vitro 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 in vitro culture of explanted skin provides an excellent alternative to in vivo experiments. 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.

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. 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. 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.

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. 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. 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.