142 resultados para minskad risk för våld


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The main purpose of revascularization procedures for critical limb ischaemia (CLI) is to preserve the leg and sustain the patient s ambulatory status. Other goals are ischaemic pain relief and healing of ischaemic ulcers. Patients with CLI are usually old and have several comorbidities affecting the outcome. Revascularization for CLI is meaningless unless both life and limb are preserved. Therefore, the knowledge of both patient- and bypass-related risk factors is of paramount importance in clinical decision-making, patient selection and resource allocation. The aim of this study was to identify patient- and graft-related predictors of impaired outcome after infrainguinal bypass for CLI. The purpose was to assess the outcome of high-risk patients undergoing infrainguinal bypass and to evaluate the usefulness of specific risk scoring methods. The results of bypasses in the absence of optimal vein graft material were also evaluated, and the feasibility of the new method of scaffolding suboptimal vein grafts was assessed. The results of this study showed that renal insufficiency - not only renal failure but also moderate impairment in renal function - seems to be a significant risk factor for both limb loss and death after infrainguinal bypass in patients with CLI. Low estimated GFR (PIENEMPI KUIN 30 ml/min/1.73 m2) is a strong independent marker of poor prognosis. Furthermore, estimated GFR is a more accurate predictor of survival and leg salvage after infrainguinal bypass in CLI patients than serum creatinine level alone. We also found out that the life expectancy of octogenarians with CLI is short. In this patient group endovascular revascularization is associated with a better outcome than bypass in terms of survival, leg salvage and amputation-free survival especially in presence of coronary artery disease. This study was the first one to demonstrate that Finnvasc and modified Prevent III risk scoring methods both predict the long-term outcome of patients undergoing both surgical and endovascular infrainguinal revascularization for CLI. Both risk scoring methods are easy to use and might be helpful in clinical practice as an aid in preoperative patient selection and decision-making. Similarly than in previous studies, we found out that a single-segment great saphenous vein graft is superior to any other autologous vein graft in terms of mid-term patency and leg salvage. However, if optimal vein graft is lacking, arm vein conduits are superior to prosthetic grafts especially in infrapopliteal bypasses for CLI. We studied also the new method of scaffolding suboptimal quality vein grafts and found out that this method may enable the use of vein grafts of compromised quality otherwise unsuitable for bypass grafting. The remarkable finding was that patients with the combination of high operative risk due to severe comorbidities and risk graft have extremely poor survival, suggesting that only relatively fit patients should undergo complex bypasses with risk grafts. The results of this study can be used in clinical practice as an aid in preoperative patient selection and decision-making. In the future, the need of vascular surgery will increase significantly as the elderly and diabetic population increases, which emphasises the importance of focusing on those patients that will gain benefit from infrainguinal bypass. Therefore, the individual risk of the patient, ambulatory status, outcome expectations, the risk of bypass procedure as well as technical factors such as the suitability of outflow anatomy and the available vein material should all be assessed and taken into consideration when deciding on the best revascularization strategy.

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Hostility is a multidimensional construct having wide effects on society. In its different forms, hostility is related to a large array of social and health problems, such as criminality, substance abuse, depression, and cardiovascular risks. Identifying and tackling early-life factors that contribute to hostility may have public health significance. Although the variance in hostility is estimated to be 18-50 percent heritable, there are significant gaps in knowledge regarding the molecular genetics of hostility. It is known that a cold and unsupportive home atmosphere in childhood predicts a child s later hostility. However, the long-term effects of care-giving quality on hostility in adulthood and the role of genes in this association are unclear. The present dissertation is part of the ongoing population-based prospective Young Finns study, which commenced in 1980 with 3596 3-18-year-old boys and girls who were followed for 27 years. The specific aims of the dissertation were first to study the antecedents of hostility by looking at 1) the genetic background, 2) the early environmental predictors, and 3) the gene environment interplay behind hostility. As a second aim, the thesis endeavored to examine 4) the association between hostility and cardiovascular risks, and 5) the moderating effect of demographic factors, such as gender and socioeconomic status, on this association. The study found potential gene polymorphisms from chromosomes 7, 14, 17, and 22 suggestively associated with hostility. Of early environmental influences, breastfeeding and early care-giving were found to predict hostility in adulthood. In addition, a serotonin receptor 2A polymorphism rs6313 moderated the effect of early care-giving on later hostile attitudes. Furthermore, hostility was shown to predict cardiovascular risks, such as metabolic syndrome and inflammation. Finally, parental socioeconomic status was found to moderate the association between anger and early atherosclerosis. The new genetic and early environmental antecedents of hostility identified in this research may help in understanding the development of hostility and its health risks, and in planning appropriate prevention. The significance of early influences on this development is stressed. Although the markers studied are individual- and family-related factors, these may be influenced at the societal level by giving accurate information to all individuals concerned and by improving the societal circumstances.

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Activation of midbrain dopamine systems is thought to be critically involved in the addictive properties of abused substances. Drugs of abuse increase dopamine release in the nucleus accumbens and dorsal striatum, which are the target areas of mesolimbic and nigrostriatal dopamine pathways, respectively. Dopamine release in the nucleus accumbens is thought to mediate the attribution of incentive salience to rewards, and dorsal striatal dopamine release is involved in habit formation. In addition, changes in the function of prefrontal cortex (PFC), the target area of mesocortical dopamine pathway, may skew information processing and memory formation such that the addict pays an abnormal amount of attention to drug-related cues. In this study, we wanted to explore how long-term forced oral nicotine exposure or the lack of catechol-O-methyltransferase (COMT), one of the dopamine metabolizing enzymes, would affect the functioning of these pathways. We also wanted to find out how the forced nicotine exposure or the lack of COMT would affect the consumption of nicotine, alcohol, or cocaine. First, we studied the effect of forced chronic nicotine exposure on the sensitivity of dopamine D2-like autoreceptors in microdialysis and locomotor activity experiments. We found that the sensitivity of these receptors was unchanged after forced oral nicotine exposure, although an increase in the sensitivity was observed in mice treated with intermittent nicotine injections twice daily for 10 days. Thus, the effect of nicotine treatment on dopamine autoreceptor sensitivity depends on the route, frequency, and time course of drug administration. Second, we investigated whether the forced oral nicotine exposure would affect the reinforcing properties of nicotine injections. The chronic nicotine exposure did not significantly affect the development of conditioned place preference to nicotine. In the intravenous self-administration paradigm, however, the nicotine-exposed animals self-administered nicotine at a lower unit dose than the control animals, indicating that their sensitivity to the reinforcing effects of nicotine was enhanced. Next, we wanted to study whether the Comt gene knock-out animals would be a suitable model to study alcohol and cocaine consumption or addiction. Although previous work had shown male Comt knock-out mice to be less sensitive to the locomotor-activating effects of cocaine, the present study found that the lack of COMT did not affect the consumption of cocaine solutions or the development of cocaine-induced place preference. However, the present work did find that male Comt knock-out mice, but not female knock-out mice, consumed ethanol more avidly than their wild-type littermates. This finding suggests that COMT may be one of the factors, albeit not a primary one, contributing to the risk of alcoholism. Last, we explored the effect of COMT deficiency on dorsal striatal, accumbal, and prefrontal cortical dopamine metabolism under no-net-flux conditions and under levodopa load in freely-moving mice. The lack of COMT did not affect the extracellular dopamine concentrations under baseline conditions in any of the brain areas studied. In the prefrontal cortex, the dopamine levels remained high for a prolonged time after levodopa treatment in male, but not female, Comt knock-out mice. COMT deficiency induced accumulation of 3,4-dihydroxyphenylacetic acid, which increased further under levodopa load. Homovanillic acid was not detectable in Comt knock-out animals either under baseline conditions or after levodopa treatment. Taken together, the present results show that although forced chronic oral nicotine exposure affects the reinforcing properties of self-administered nicotine, it is not an addiction model itself. COMT seems to play a minor role in dopamine metabolism and in the development of addiction under baseline conditions, indicating that dopamine function in the brain is well-protected from perturbation. However, the role of COMT becomes more important when the dopaminergic system is challenged, such as by pharmacological manipulation.

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Fluid bed granulation is a key pharmaceutical process which improves many of the powder properties for tablet compression. Dry mixing, wetting and drying phases are included in the fluid bed granulation process. Granules of high quality can be obtained by understanding and controlling the critical process parameters by timely measurements. Physical process measurements and particle size data of a fluid bed granulator that are analysed in an integrated manner are included in process analytical technologies (PAT). Recent regulatory guidelines strongly encourage the pharmaceutical industry to apply scientific and risk management approaches to the development of a product and its manufacturing process. The aim of this study was to utilise PAT tools to increase the process understanding of fluid bed granulation and drying. Inlet air humidity levels and granulation liquid feed affect powder moisture during fluid bed granulation. Moisture influences on many process, granule and tablet qualities. The approach in this thesis was to identify sources of variation that are mainly related to moisture. The aim was to determine correlations and relationships, and utilise the PAT and design space concepts for the fluid bed granulation and drying. Monitoring the material behaviour in a fluidised bed has traditionally relied on the observational ability and experience of an operator. There has been a lack of good criteria for characterising material behaviour during spraying and drying phases, even though the entire performance of a process and end product quality are dependent on it. The granules were produced in an instrumented bench-scale Glatt WSG5 fluid bed granulator. The effect of inlet air humidity and granulation liquid feed on the temperature measurements at different locations of a fluid bed granulator system were determined. This revealed dynamic changes in the measurements and enabled finding the most optimal sites for process control. The moisture originating from the granulation liquid and inlet air affected the temperature of the mass and pressure difference over granules. Moreover, the effects of inlet air humidity and granulation liquid feed rate on granule size were evaluated and compensatory techniques used to optimize particle size. Various end-point indication techniques of drying were compared. The ∆T method, which is based on thermodynamic principles, eliminated the effects of humidity variations and resulted in the most precise estimation of the drying end-point. The influence of fluidisation behaviour on drying end-point detection was determined. The feasibility of the ∆T method and thus the similarities of end-point moisture contents were found to be dependent on the variation in fluidisation between manufacturing batches. A novel parameter that describes behaviour of material in a fluid bed was developed. Flow rate of the process air and turbine fan speed were used to calculate this parameter and it was compared to the fluidisation behaviour and the particle size results. The design space process trajectories for smooth fluidisation based on the fluidisation parameters were determined. With this design space it is possible to avoid excessive fluidisation and improper fluidisation and bed collapse. Furthermore, various process phenomena and failure modes were observed with the in-line particle size analyser. Both rapid increase and a decrease in granule size could be monitored in a timely manner. The fluidisation parameter and the pressure difference over filters were also discovered to express particle size when the granules had been formed. The various physical parameters evaluated in this thesis give valuable information of fluid bed process performance and increase the process understanding.

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The study analyses the prevention or endorsing of the crime of infanticide in Finland 1702 1807, rather than the result. Also the impacts of the female body, biology of childbirth and experiences of pregnancy are examined, together with insights from modern medical research. Circumstances are reconstructed by a critical reading of judicial records on all levels of the judicial system. In all 269 cases of infanticide and 142 accessory crimes within the jurisdiction of the Turku court of appeal are studied, with particular focus on exceptionally well recorded cases of 83 accused women and 41 women and men accused of being party to the crime. Secondary sources are medical and jurisprudential writings, the public debate on infanticide, broadsheets and letters asking the King for pardon. Infanticide was considered murder by law. Unmarried women were predetermined as the main culprits. Nevertheless, deliberate infanticides were rare and committed mostly in accomplice. The majority of the infanticides studied were cases where inexperienced and unmarried women accidentally had given birth alone and usually to a dead child. Unaware that the pain they were experiencing was in fact a labour, the accused women instinctively sought solitude to push out the child. Some misunderstood the birth as an urgent need to defecate. The unexpected delivery ended in hiding the baby without remorse. This crime was promoted by several factors in Finnish rural culture, amongst others that also married women hid their pregnancy. The immediate household members did not necessarily know about the childbirth and failed to help the woman. This typical pattern in most cases of infanticide in 18th century Finland is also recorded in modern cases of unknown pregnancies. Fear of accountability prevented witnesses testifying to the actual course of events. The truth remained elusive. With only a few exceptions, the women were sentenced to death or imprisonment. The majority of those accused of accomplice were acquitted. However, too harsh sentences for accidents affected the reporting of the crime. Criminal politics failed to curtail infanticide as the crime was unsatisfactorily addressed by law, society and the judicial system.

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Jämställdhetslagen från 1995 kräver att både myndigheter och arbetsgivare med aktiva och målinriktade åtgärder främjar jämställdheten, och denna pro gradu-avhandling undersöker närmare hur denna lag implementerats i de finlandssvenska kommunerna (kommuner med majoritetsspråk svenska) under en 10årsperiod. I kommunerna jobbar 80% kvinnor, och 38% av alla kvinnliga arbetstagare hittas i arbeten inom den offentliga sektorn. Kommunens skyldighet att trygga dessa kvinnors lika villkor inom kommunorganisationen ingår både som en del i arbetsgivaransvaret, men även som del i statens demokratiska utövande genom myndighetsansvaret. De tre planer som ingår i mitt material innehåller en kartläggning av jämställdhetsområdet i olika omfattning, definierade mål och åtgärder och ingen av planerna har följts upp efter att de godkänts. Planerna varierar både i utformning och omfattning men också i ansvarsspecificering och åtgärdernas konkretisering, vilken ger en varierande kvalitet och därmed även varierande förutsättning att genomdrivas och därmed uppfylla lagens ålägganden. Två av kommunerna har eller har haft en jämställdhetskommitté. I de 26 inkomna svarsformulär görs en närläsning av hur begreppet jämställdhet används och hur jämställdhetslagen tolkas och orsakerna till frånvaron av jämställdhetsåtgärder. På frågan om varför jämställdhetsarbetet inte genomförts helt eller delvis utkristalliserade sig sex olika argumentationsteman: 1. Myten om den jämställda kommunen, innebär en hänvisning till att det inte förekommit några problem med jämställdheten. 2. Den naturligt integrerade jämställdheten, är kommunens policy och sker utan planer, men en liten kritik av problematiken med frånvaron av planer framförs av några kommuner. 3. Könens komplettering, utgår jämställdhetsbegreppet ifrån i några kommuner. 4. Den matematiska jämställdheten, är argument där man genom hänvisningar till kvinnor på olika högre positioner visar på att jämställdheten är uppnådd. 5.En fråga om resurser, används som ett argument till jämställdhetsarbetets frånvaro i kommunen. 6. Avsaknad av intresse, hos personalen och allmänheten är ett annat argument för ogenomförda jämställdhetsåtgärder. Det framkommer tydligt i materialet att kommunerna anser sig följa jämställdhetslagen, samtidigt som det blir tydligt att det råder en oklarhet om vad jämställdhetslagen från 1995 egentligen innehåller. En tydlig sammanblandning mellan den lagstadgade kvoteringen och skyldigheten att aktivt främja jämställdhet träder fram i materialet. Det ofullständiga jämställdhetsarbetet strandar på olika punkter, men en avgörande anser punkt är oförståelsen inför begreppet jämställdhet och därmed också lagens syfte och innehåll. Avhandlingens slutsats är att frånvaron av en könsmaktanalys försvårar förståelsen av ojämställdhetens komplexhet, dvs. dess orsaker, mångskiftande funktion och olika uttryck i organisationens strukturer och i de handlande aktörerna.

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The present research focused on motivational and personality traits measuring individual differences in the experience of negative affect, in reactivity to negative events, and in the tendency to avoid threats. In this thesis, such traits (i.e., neuroticism and dispositional avoidance motivation) are jointly referred to as trait avoidance motivation. The seven studies presented here examined the moderators of such traits in predicting risk judgments, negatively biased processing, and adjustment. Given that trait avoidance motivation encompasses reactivity to negative events and tendency to avoid threats, it can be considered surprising that this trait does not seem to be related to risk judgments and that it seems to be inconsistently related to negatively biased information processing. Previous work thus suggests that some variable(s) moderate these relations. Furthermore, recent research has suggested that despite the close connection between trait avoidance motivation and (mal)adjustment, measures of cognitive performance may moderate this connection. However, it is unclear whether this moderation is due to different response processes between individuals with different cognitive tendencies or abilities, or to the genuinely buffering effect of high cognitive ability against the negative consequences of high trait avoidance motivation. Studies 1-3 showed that there is a modest direct relation between trait avoidance motivation and risk judgments, but studies 2-3 demonstrated that state motivation moderates this relation. In particular, individuals in an avoidance state made high risk judgments regardless of their level of trait avoidance motivation. This result explained the disparity between the theoretical conceptualization of avoidance motivation and the results of previous studies suggesting that the relation between trait avoidance motivation and risk judgments is weak or nonexistent. Studies 5-6 examined threat identification tendency as a moderator for the relationship between trait avoidance motivation and negatively biased processing. However, no evidence for such moderation was found. Furthermore, in line with previous work, the results of studies 5-6 suggested that trait avoidance motivation is inconsistently related to negatively biased processing, implying that theories concerning traits and information processing may need refining. Study 7 examined cognitive ability as a moderator for the relation between trait avoidance motivation and adjustment, and demonstrated that cognitive ability moderates the relation between trait avoidance motivation and indicators of both self-reported and objectively measured adjustment. Thus, the results of Study 7 supported the buffer explanation for the moderating influence of cognitive performance. To summarize, the results showed that it is possible to find factors that consistently moderate the relations between traits and important outcomes (e.g. adjustment). Identifying such factors and studying their interplay with traits is one of the most important goals of current personality research. The present thesis contributed to this line of work in relation to trait avoidance motivation.

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The concept of vascular cognitive impairment (VCI) covers a wide spectrum of cognitive dysfunctions related to cerebrovascular disease. Among the pathophysiological determinants of VCI are cerebral stroke, white matter lesions and brain atrophy, which are known to be important risk factors for dementia. However, the specific mechanisms behind the brain abnormalities and cognitive decline are still poorly understood. The present study investigated the neuropsychological correlates of particular magnetic resonance imaging (MRI) findings, namely, medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH), general cortical atrophy and corpus callosum (CC) atrophy in subjects with cerebrovascular disease. Furthermore, the cognitive profile of subcortical ischaemic vascular disease (SIVD) was examined. This study was conducted as part of two large multidisciplinary study projects, the Helsinki Stroke Aging Memory (SAM) Study and the multinational Leukoaraiosis and Disability (LADIS) Study. The SAM cohort consisted of 486 patients, between 55 and 85 years old, with ischaemic stroke from the Helsinki University Hospital, Helsinki, Finland. The LADIS Study included a mixed sample of subjects (n=639) with age-related WMH, between 65 and 84 years old, gathered from 11 centres around Europe. Both studies included comprehensive clinical and neuropsychological assessments and detailed brain MRI. The relationships between the MRI findings and the neuropsychological test performance were analysed by controlling for relevant confounding factors such as age, education and other coexisting brain lesions. The results revealed that in elderly patients with ischaemic stroke, moderate to severe MTA was specifically related to impairment of memory and visuospatial functions, but mild MTA had no clinical relevance. Instead, WMH were primarily associated with executive deficits and mental slowing. These deficits mediated the relationship between WMH and other, secondary cognitive deficits. Cognitive decline was best predicted by the overall degree of WMH, whereas the independent contribution of regional WMH measures was low. Executive deficits were the most prominent cognitive characteristic in SIVD. Compared to other stroke patients, the patients with SIVD also presented more severe memory deficits, which were related to MTA. The cognitive decline in SIVD occurred independently of depressive symptoms and, relative to healthy control subjects, it was substantial in severity. In stroke patients, general cortical atrophy also turned out to be a strong predictor of cognitive decline in a wide range of cognitive domains. Moreover, in elderly subjects with WMH, overall CC atrophy was related to reduction in mental speed, while anterior CC atrophy was independently associated with frontal lobe-mediated executive functions and attention. The present study provides cross-sectional evidence for the involvement of WMH, MTA, general cortical atrophy and CC atrophy in VCI. The results suggest that there are multifaceted pathophysiological mechanisms behind VCI in the elderly, including both vascular ischaemic lesions and neurodegenerative changes. The different pathological changes are highly interrelated processes and together they may produce cumulative effects on cognitive decline.

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Occupational burnout and heath Occupational burnout is assumed to be a negative consequence of chronic work stress. In this study, it was explored in the framework of occupational health psychology, which focusses on psychologically mediated processes between work and health. The objectives were to examine the overlap between burnout and ill health in relation to mental disorders, musculoskeletal disorders, and cardiovascular diseases, which are the three commonest disease groups causing work disability in Finland; to study whether burnout can be distinguished from ill health by its relation to work characteristics and work disability; and to determine the socio-demographic correlates of burnout at the population level. A nationally representative sample of the Finnish working population aged 30 to 64 years (n = 3151-3424) from the multidisciplinary epidemiological Health 2000 Study was used. Burnout was measured with the Maslach Burnout Inventory - General Survey. The diagnoses of common mental disorders were based on the standardized mental health interview (the Composite International Diagnostic Interview), and physical illnesses were determined in a comprehensive clinical health examination by a research physician. Medically certified sickness absences exceeding 9 work days during a 2-year period were extracted from a register of The Social Insurance Institution of Finland. Work stress was operationalized according to the job strain model. Gender, age, education, occupational status, and marital status were recorded as socio-demographic factors. Occupational burnout was related to an increased prevalence of depressive and anxiety disorders and alcohol dependence among the men and women. Burnout was also related to musculoskeletal disorders among the women and cardiovascular diseases among the men independently of socio-demographic factors, physical strenuousness of work, health behaviour, and depressive symptoms. The odds of having at least one long, medically-certified sickness absence were higher for employees with burnout than for their colleagues without burnout. For severe burnout, this association was independent of co-occurring common mental disorders and physical illnesses for both genders, as was also the case for mild burnout among the women. In a subgroup of the men with absences, severe burnout was related to a greater number of absence days than among the women with absences. High job strain was associated with a higher occurrence of burnout and depressive disorders than low job strain was. Of these, the association between job strain and burnout was stronger, and it persisted after control for socio-demographic factors, health behaviour, physical illnesses, and various indicators of mental health. In contrast, job strain was not related to depressive disorders after burnout was accounted for. Among the working population over 30 years of age, burnout was positively associated with age. There was also a tendency towards higher levels of burnout among the women with low educational attainment and occupational status and among the unmarried men. In conclusion, a considerable overlap was found between burnout, mental disorders, and physical illnesses. Still, burnout did not seem to be totally redundant with respect to ill health. Burnout may be more strongly related to stressful work characteristics than depressive disorders are. In addition, burnout seems to be an independent risk factor for work disability, and it could possibly be used as a marker of health-impairing work stress. However, burnout may represent a different kind of risk factor for men and women, and this possibility needs to be taken into account in the promotion of occupational health.

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The success of entering work life, young people s psychological resources and self-reported well-being were studied in a longitudinal setting from a life-span developmental-contextual perspective in early adulthood. The aim was to analyse how psychosocial characteristics in early childhood and adolescence predict successful entrance into work life, how this is associated with well-being, and to assess the level of psychological resources such as dispositional optimism, personal meaning of work and coping in early adulthood. The role of these and social support, in the relationship between regional factors (such as place of residence and migration), self-reported health and life satisfaction was studied. The association between a specific coping strategy, i.e. eating and drinking in a stressful situation and eating habits, was studied to demonstrate how coping is associated with health behaviour. Multivariate methods, including binary logistic regression analyses and ANOVA, were used for statistical analyses. The subjects were members of the Northern Finland 1966 Birth Cohort, which consists of all women and men born in 1966 in the two northernmost provinces of Finland (n= 12,058). The most recent follow-up, at the age of 31 years when 11,637 subjects were alive, took place in 1997-1998. The results show, first, that social resources in the childhood family and adolescence school achievement predict entrance into the labour market. Secondly, psychosocial resources were found to mediate the relationship between migration from rural to urban areas, and subjective well-being. Thirdly, psychological resources at entrance into the labour market were found to develop from early infancy on. They are, however, influenced later by work history. Fourthly, stress-related eating and drinking, as a way of coping, was found to be directly associated with unhealthy eating habits and alcohol use. Gender differences were found in psychosocial resources predicting, and being associated with success in entering the labour market. For men, the role of attitudinal and psychological factors seems to be especially important in entrance into work life and in the development of psychological resources. For women, academic attainment was more important for successfully entering work life, and lack of emotional social support was a risk factor for stress-related eating only among women. Stress-related eating and drinking habits were predicted by a long history of unemployment as well as a low level of education among both genders, but not excluding an academic degree among men. The results emphasize the role of childhood psychosocial factors in preventing long-term unemployment and in enhancing psychological well-being in early adulthood. Success in entering work life, in terms of continuous work history, plays a crucial role for well-being and the amount of psychological resources in early adulthood. The results emphasize the crucial role of enhancing psychological resources for promoting positive health behaviour and diminishing regional differences in subjective well-being.