| 1. |
- Alassaad, Anna, 1977-
(författare)
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Improving the Quality and Safety of Drug Use in Hospitalized Elderly : Assessing the Effects of Clinical Pharmacist Interventions and Identifying Patients at Risk of Drug-related Morbidity and Mortality
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Older people admitted to hospital are at high risk of rehospitalization and medication errors. We have demonstrated, in a randomized controlled trial, that a clinical pharmacist intervention reduces the incidence of revisits to hospital for patients aged 80 years or older admitted to an acute internal medicine ward. The aims of this thesis were to further study the effects of the intervention and to investigate possibilities of targeting the intervention by identifying predictors of treatment response or adverse health outcomes.The effect of the pharmacist intervention on the appropriateness of prescribing was assessed, by using three validated tools. This study showed that the quality of prescribing was improved for the patients in the intervention group but not for those in the control group. However, no association between the appropriateness of prescribing at discharge and revisits to hospital was observed.Subgroup analyses explored whether the clinical pharmacist intervention was equally effective in preventing emergency department visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing on admission. The intervention appeared to be most effective in patients taking fewer drugs, but the treatment effect was not altered by appropriateness of prescribing.The most relevant risk factors for rehospitalization and mortality were identified for the same study population, and a score for risk-estimation was constructed and internally validated (the 80+ score). Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid and being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked with a lower risk. These variables made up the components of the 80+ score. Pending external validation, this score has potential to aid identification of high-risk patients.The last study investigated the occurrence of prescription errors when patients with multi-dose dispensed (MDD) drugs were discharged from hospital. Twenty-five percent of the MDD orders contained at least one medication prescription error. Almost half of the errors were of moderate or major severity, with potential to cause increased health-care utilization.
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| 2. |
- Earle, Timothy K., et al.
(författare)
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The Political Economy and Metal Trade in Bronze Age Europe: Understanding Regional Variability in Terms of Comparative Advantages and Articulations
- 2015
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Ingår i: European Journal of Archaeology. - 1461-9571 .- 1741-2722. ; 18:4, s. 633-657
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Tidskriftsartikel (refereegranskat)abstract
- In the second millennium cal BC, a new metal conquered Europe: the alloy of copper and tin that improved the quality of tools and weapons. This development, we argue, initiated a framework for a new political economy. We explore how a political economy approach may help understand the European Bronze Age by focussing on regional comparative advantages in long-distance trade and resulting bottlenecks in commodity flows. Links existed in commodity chains, where obligated labour and ownership of resources helped mobilize surpluses, thus creating potential for social segments to control the production and flows of critical goods. The political economy of Bronze Age Europe would thus represent a transformation in how would-be leaders mobilized resources to support their political ends. The long-distance trade in metals and other commodities created a shift from local group ownership towards increasingly individual strategies to obtain wealth from macro-regional trade. We construct our argument to make sense of available data, but recognize that our model's primary purpose is to structure future research to test the model. Au cours du 2e millénaire av. J.-C. un nouveau métal conquérait l'Europe: l'alliage du cuivre et de l’étain, qui améliorait la qualité des outils et des armes. Nous soutenons ici que ce développement instaurait un cadre pour une nouvelle économie politique et nous examinons comment une approche fondée sur l’économie politique peut nous permettre de mieux comprendre l’Âge du Bronze européen, en mettant l'accent sur les avantages comparatifs régionaux lors des échanges à longue distance et sur les goulets d’étranglement des flux de marchandises qui en résultent. Il existait des liens dans les filières des produits de base, où le travail forcé et la possession des ressources aidaient à réaliser des excédents, permettant ainsi à des segments de la société de contrôler la production et les flux de produits essentiels. L’économie politique de l'Europe pendant l’Âge du Bronze décrirait donc un changement dans la manière avec laquelle des leaders potentiels mobilisaient des ressources pour soutenir leurs fins politiques. Les échanges à longue distance de métaux et autres marchandises ont déclenché un changement allant de la propriété collective locale vers des stratégies de plus en plus individuelles afin de produire de la richesse à partir du commerce macro-régional. Avec nos arguments nous cherchons à interpréter les données disponibles, mais nous admettons que le principal objectif de notre modèle est de structurer la recherche future afin de pouvoir le mettre à l’épreuve. Translation by Isabelle Gerges Im zweiten Jahrtausend v. Chr. trat ein neues Metall seinen Siegeszug durch Europa an: die Legierung von Kupfer und Zinn, die die Qualität von Werkzeugen und Waffen verbesserte. Diese Entwicklung, so vermuten wir, stieß die Entwicklung eines Netzwerkes für eine neue politische Ökonomie an. Wir untersuchen, wie der Ansatz der politischen Ökonomie dabei helfen kann, unter besonderer Berücksichtigung regionaler vergleichender Nutzeffekte beim Fernhandel und daraus resultierender Engpässe bei Warenströmen die europäische Bronzezeit zu verstehen. Es existierten Verbindungen bei den Güterketten, bei denen Arbeitsverpflichtungen und Eigentum an den Ressourcen dabei halfen, Überschuss zu erwirtschaften – und dadurch ein Potential für soziale Segmentierung schufen, das die Kontrolle der Produktion und Verteilung von wesentlichen Gütern gewährleistete. Die politische Ökonomie der europäischen Bronzezeit spiegelt demnach einen Übergang wider, bei dem die angehenden Oberhäupter Ressourcen mobilisierten, um ihre politischen Ziele zu unterstützen. Der Fernhandel von Metallen und anderen Waren ermöglichte einen Sprung vom lokalen Gruppenbesitz hin zu vermehrt individuellen Strategien, um aus dem makroregionalen Handel Reichtum zu erzielen. Wir entwickeln unsere Beweisführung, um bereits vorhandene Daten deuten zu können, sind uns jedoch bewusst, dass das vorrangige Ziel unseres Modells die Struktur zukünftiger Forschung ist, um seine Gültigkeit zu testen.Translation by Heiner Schwarzberg
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| 3. |
- Ehn, Mattias, 1972-
(författare)
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Life Strategies, Work and Health in People with Usher Syndrome
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: People with Usher syndrome (USH) have an inherited disorder causing congenital deafness or hearing loss combined with progressive vision loss and, in some cases, balance problems. Previous research has shown that people with USH have poor physical and psychological health. Research has, however, demonstrated that there are in-group health differences that have not yet been explored and that there is a lack of studies on life strategies as well as health in relation to working life.Aim: The aim was to explore the relationship between work and health in people with USH1 and 2 and to explore the experiences of life strategies in people with USH 2.Methods: A quantitative and a qualitative explorative design was employed comprising two cross-sectional studies of the relationship between work and health in people with USH2 (n=67) and USH1 (n=47). The third study, of life strategies, comprised focus group interviews with people with USH2a (n=14) analyzed by content analysis. The fourth study explored the lived experiences of working life by interviewing people with USH2 (n=7) using an interpretative phenomenological approach.Results: Study 1 and 2 demonstrated significant differences in health between working and nonworking people. Nonworking people showed significantly poorer health. In study 3, a variety of strategies to prevent and resolve challenges in life, as well as to comfort oneself was identified. The lived experiences of working life in people with USH2 (study 4) disclosed feelings of satisfaction, striving towards a work life balance. Work also disclosed feelings of limitations and uncertainty about the future.Conclusion: The results, which are discussed in relation to the Meikirsh model of health, demonstrated a complexity. Individual life strategies, psychological flexibility and environmental aspects, such as social determinants have to be considered to receive a comprehensive picture of the relationship between work and health in people with USH. This thesis provides new insights into the health of people with USH.
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| 4. |
- Gersing, Sarah K., et al.
(författare)
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Mapping the degradation pathway of a disease-linked aspartoacylase variant
- 2021
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:4
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Tidskriftsartikel (refereegranskat)abstract
- Canavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we use ASPA C152W as a model to investigate the degradation pathway of a disease-causing protein variant. When we expressed ASPA C152W in Saccharomyces cerevisiae, we found a decreased steady state compared to wild-type ASPA as a result of increased proteasomal degradation. However, molecular dynamics simulations of ASPA C152W did not substantially deviate from wild-type ASPA, indicating that the native state is structurally preserved. Instead, we suggest that the C152W substitution interferes with the de novo folding pathway resulting in increased proteasomal degradation before reaching its stable conformation. Systematic mapping of the protein quality control components acting on misfolded and aggregation-prone species of C152W, revealed that the degradation is highly dependent on the molecular chaperone Hsp70, its co-chaperone Hsp110 as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. In addition, the disaggregase Hsp104 facilitated refolding of aggregated ASPA C152W, while Cdc48 mediated degradation of insoluble ASPA protein. In human cells, ASPA C152W displayed increased proteasomal turnover that was similarly dependent on Hsp70 and Hsp110. Our findings underscore the use of yeast to determine the protein quality control components involved in the degradation of human pathogenic variants in order to identify potential therapeutic targets. Author summary Canavan disease is a fatal neurodegenerative disorder which is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene. Although the molecular mechanism of most disease-causing substitutions remains to be examined, some variants have been suggested to cause the loss-of-function phenotype by perturbing the structural stability of ASPA. So far the cellular fate of these variants have not been examined. Here we examine the stability and degradation pathways of the disease-causing ASPA variant C152W. In yeast cells, ASPA C152W showed decreased steady-state protein levels as a result of increased proteasomal turnover. Our molecular dynamics simulations showed that the C152W substitution did not globally perturb the native structure of ASPA. Instead we propose that ASPA C152W is targeted by the protein quality control system during de novo folding. Specifically, we found that the molecular chaperone Hsp70, its co-chaperone Hsp110, and the E3 ubiquitin-protein ligase Ubr1 promote degradation of ASPA C152W. When we expressed ASPA C152W in cultured human cells, we found that Hsp70 and Hsp110 similarly mediated degradation. Therefore, we propose that Hsp110 should be further examined as a potential therapeutic target in Canavan disease and other protein misfolding diseases.
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| 5. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 6. |
- Vande Vyvere, Thijs, et al.
(författare)
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Central versus Local Radiological Reading of Acute Computed Tomography Characteristics in Multi-Center Traumatic Brain Injury Research
- 2019
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 36:7, s. 1080-1092
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Tidskriftsartikel (refereegranskat)abstract
- Observer variability in local radiological reading is a major concern in large-scale multi-center traumatic brain injury (TBI) studies. A central review process has been advocated to minimize this variability. The aim of this study is to compare central with local reading of TBI imaging datasets and to investigate the added value of central review. A total of 2050 admission computed tomography (CT) scans from subjects enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were analyzed for seven main CT characteristics. Kappa statistics were used to calculate agreement between central and local evaluations and a center-specific analysis was performed. The McNemar test was used to detect whether discordances were significant. Central interobserver and intra-observer agreement was calculated in a subset of patients. Good agreement was found between central and local assessment for the presence or absence of structural pathology (CT+, CT-, κ = 0.73) and most CT characteristics (κ = 0.62 to 0.71), except for traumatic axonal injury lesions (κ = 0.37). Despite good kappa values, discordances were significant in four of seven CT characteristics (i.e., midline shift, contusion, traumatic subarachnoid hemorrhage, and cisternal compression; p = 0.0005). Central reviewers showed substantial to excellent interobserver and intra-observer agreement (κ = 0.73 to κ = 0.96), contrasted by considerable variability in local radiological reading. Compared with local evaluation, a central review process offers a more consistent radiological reading of acute CT characteristics in TBI. It generates reliable, reproducible data and should be recommended for use in multi-center TBI studies.
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