| 1. |
- Krishna Vadivel, Chella, et al.
(författare)
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Staphylococcus aureus induce drug resistance in cancer T cells in Sézary Syndrome
- 2024
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Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 143:15, s. 1496-1512
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Tidskriftsartikel (refereegranskat)abstract
- Key Points Enterotoxins from Staphylococcus aureus bacteria induce drug resistance in primary malignant T cells in Sézary syndrome. Targeting bacteria, their toxins, and downstream signaling pathways in malignant T cells abrogate the induction of drug resistance. Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T cell lymphoma (CTCL), are prone to Staphylococcus aureus (S. aureus) infections and have a poor prognosis due to treatment-resistance. Here, we report that S. aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T-cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S. aureus and recombinant SE significantly inhibit cell death induced by HDAC inhibitor romidepsin in primary malignant T-cells from SS patients. Bacterial killing by engineered, bacteriophage-derived, S. aureus-specific endolysin (XZ.700) abrogates the effect of S. aureus supernatant. Likewise, mutations in MHC Class II binding sites of SE type-A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates TCR, NFB, and JAK/STAT signaling pathways (previously associated with drug-resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein Kinase C (upstream of NFB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by proteasome/NFB inhibitor bortezomib. Inhibition of JAK/STAT only blocks SE-induced rescue of malignant T-cells in some but not all patients, suggesting two distinct ways SE can induce drug resistance. In conclusion, we show that S. aureus enterotoxins induce drug-resistance in primary malignant T-cells. These findings suggest that S. aureus enterotoxins cause clinical treatment-resistance in SS patients and that anti-bacterial measures may improve the outcome of cancer-directed therapy in patients harboring S. aureus
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| 2. |
- von Beek, Christopher, et al.
(författare)
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A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells localize to mucosal tissues and contribute to innate immune defense against infection. How mast cells sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other related enterobacteria, here we show that mast cells can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and mast cells colocalize in the mouse gut during acute Salmonella infection. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure lipopolysaccharide, causes a modest induction of cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human mast cells triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to drive the full-blown mast cell response. Supernatants from S.Tm-infected mast cells boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that mast cells can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.
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| 3. |
- von Beek, Christopher, et al.
(författare)
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A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells localize to mucosal tissues and contribute to innate immune defense against infection. How mast cells sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other related enterobacteria, here we show that mast cells can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and mast cells colocalize in the mouse gut during acute Salmonella infection. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure lipopolysaccharide, causes a modest induction of cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human mast cells triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to drive the full-blown mast cell response. Supernatants from S.Tm-infected mast cells boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that mast cells can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.
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| 4. |
- Ögmundsdóttir Michelsen, Halldóra, et al.
(författare)
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The effect of audit and feedback and implementation support on guideline adherence and patient outcomes in cardiac rehabilitation : a study protocol for an open-label cluster-randomized effectiveness-implementation hybrid trial
- 2024
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Ingår i: Implementation Science. - : BioMed Central (BMC). - 1748-5908. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundProviding secondary prevention through structured and comprehensive cardiac rehabilitation programmes to patients after a myocardial infarction (MI) reduces mortality and morbidity and improves health-related quality of life. Cardiac rehabilitation has the highest recommendation in current guidelines. While treatment target attainment rates at Swedish cardiac rehabilitation centres is among the highest in Europe, there are considerable differences in service delivery and variations in patient-level outcomes between centres. In this trial, we aim to study whether centre-level guideline adherence and patient-level outcomes across Swedish cardiac rehabilitation centres can be improved through a) regular audit and feedback of cardiac rehabilitation structure and processes through a national quality registry and b) supporting cardiac rehabilitation centres in implementing guidelines on secondary prevention. Furthermore, we aim to evaluate the implementation process and costs.MethodsThe study is an open-label cluster-randomized effectiveness-implementation hybrid trial including all 78 cardiac rehabilitation centres (attending to approximately 10 000 MI patients/year) that report to the SWEDEHEART registry. The centres will be randomized 1:1:1 to three clusters: 1) reporting cardiac rehabilitation structure and process variables to SWEDEHEART every six months (audit intervention) and being offered implementation support to implement guidelines on secondary prevention (implementation support intervention); 2) audit intervention only; or 3) no intervention offered. Baseline cardiac rehabilitation structure and process variables will be collected. The primary outcome is an adherence score measuring centre-level adherence to secondary prevention guidelines. Secondary outcomes include patient-level secondary prevention risk factor goal attainment at one-year after MI and major adverse coronary outcomes for up to five-years post-MI. Implementation outcomes include barriers and facilitators to guideline adherence evaluated using semi-structured focus-group interviews and relevant questionnaires, as well as costs and cost-effectiveness assessed by a comparative health economic evaluation.DiscussionOptimizing cardiac rehabilitation centres’ delivery of services to meet standards set in guidelines may lead to improvement in cardiovascular risk factors, including lifestyle factors, and ultimately a decrease in morbidity and mortality after MI.
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| 5. |
- Areskoug, Mats, et al.
(författare)
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Naturvetenskapens bärande idéer : för lärare F-6
- 2020. - 3
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Att undervisa i de naturvetenskapliga ämnena (NO) i de tidiga skolåren är ett utmanande, spännande och roligt uppdrag. Dessa ämnen spänner dock över stora innehållsområden och därför kan det vara svårt att få en överblick och välja ett innehåll som är lämpligt för åldersgruppen.Den här boken hjälper läraren att få grepp om det viktigaste innehållet i de naturvetenskapliga ämnena. Naturvetenskapens grundläggande och bärande idéer förklaras detaljerat och belyses med en rad konkreta och vardagliga exempel. Innehållet diskuteras i förhållande till Läroplan för grundskolan, förskoleklassen och fritidshemmet (Lgr 11).Boken kan, gärna i kombination med boken Naturvetenskapens bärande idéer i praktiken, användas både som kurslitteratur för blivande lärare och som ämnesfördjupning för verksamma lärare.Den 3:e upplagan har reviderats i förhållande till ändringarna i kursplanerna 2020.
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| 6. |
- Areskoug, Mats, et al.
(författare)
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Naturvetenskapens bärande idéer : för lärare F-6
- 2020
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Att undervisa i de naturvetenskapliga ämnena (NO) i de tidiga skolåren är ett utmanande, spännande och roligt uppdrag. Dessa ämnen spänner dock över stora innehållsområden och därför kan det vara svårt att få en överblick och välja ett innehåll som är lämpligt för åldersgruppen. Den här boken hjälper läraren att få grepp om det viktigaste innehållet i de naturvetenskapliga ämnena. Naturvetenskapens grundläggande och bärande idéer förklaras detaljerat och belyses med en rad konkreta och vardagliga exempel. Innehållet diskuteras i förhållande till Läroplan för grundskolan, förskoleklassen och fritidshemmet (Lgr 11). Boken kan, gärna i kombination med boken Naturvetenskapens bärande idéer i praktiken, användas både som kurslitteratur för blivande lärare och som ämnesfördjupning för verksamma lärare. Den 3:e upplagan har reviderats i förhållande till ändringarna i kursplanerna 2020.
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| 7. |
- Berger, Karin, et al.
(författare)
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Xylooligosaccharides Increase Bifidobacteria and Lachnospiraceae in Mice on a High-Fat Diet, with a Concomitant Increase in Short-Chain Fatty Acids, Especially Butyric Acid
- 2021
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Ingår i: Journal of Agricultural and Food Chemistry. - : American Chemical Society (ACS). - 0021-8561 .- 1520-5118. ; 69:12, s. 3617-3625
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Tidskriftsartikel (refereegranskat)abstract
- Effects of xylooligosaccharides (XOSs) as well as a mixture of XOS, inulin, oligofructose, and partially hydrolyzed guar gum (MIX) in mice fed a high-fat diet (HFD) were studied. Control groups were fed an HFD or a low-fat diet. Special attention was paid to the cecal composition of the gut microbiota and formation of short-chain fatty acids, but metabolic parameters were also documented. The XOS group had significantly higher cecum levels of acetic, propionic, and butyric acids than the HFD group, and the butyric acid content was higher in the XOS than in the MIX group. The cecum microbiota of the XOS group contained more Bifidobacteria, Lachnospiraceae, and S24-7 bacteria than the HFD group. A tendency of lower body weight gain was observed on comparing the XOS and HFD groups. In conclusion, the XOS was shown to be a promising prebiotic candidate. The fiber diversity in the MIX diet did not provide any advantages compared to the XOS diet.
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| 8. |
- Bima, Paolo, et al.
(författare)
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Chest Pain in Cancer Patients Prevalence of Myocardial Infarction and Performance of High-Sensitivity Cardiac Troponins
- 2023
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Ingår i: JACC: CARDIOONCOLOGY. - : Elsevier. - 2666-0873. ; 5:5, s. 591-609
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Little is known about patients with cancer presenting with acute chest discomfort to the emergency department (ED).OBJECTIVES The aim of this study was to assess the prevalence of acute myocardial infarction (AMI), outcomes, and the diagnostic utility of recommended diagnostic tools in this population.METHODS Patients presenting with chest pain to the ED were prospectively enrolled in an international multicenter diagnostic study with central adjudication. Cancer status was assessed prospectively and additional cancer details retrospectively. Findings were externally validated in an independent multicenter cohort.RESULTS Among 8,267 patients, 711 (8.6%) had cancer. Patients with cancer had a higher burden of cardiovascular risk factors and pre-existing cardiac disease. Total length of stay in the ED (5.2 hours vs 4.3 hours) and hospitalization rate (49.8% vs 34.3%) were both increased in patients with cancer (P < 0.001 for both). Among 8,093 patients eligible for the AMI analyses, those with cancer more often had final diagnoses of AMI (184 of 686 with cancer [26.8%] vs 1,561 of 7,407 without cancer [21.1%]; P < 0.001). In patients with cancer, high-sensitivity cardiac troponin T (hs-cTnT) but not high sensitivity cardiac troponin I (hs-cTnI) concentration had lower diagnostic accuracy for non-ST-segment elevation myocardial infarction (for hs-cTnT, area under the curve: 0.89 [95% CI: 0.86-0.92] vs 0.94 [95% CI: 0.93-0.94] [P < 0.001]; for hs-cTnI, area under the curve: 0.93 [95% CI: 0.91-0.95] vs 0.95 [95% CI: 0.94-0.95] [P 1/4 0.10]). In patients with cancer, the European Society of Cardiology 0/1-hour hs-cTnT and hs-cTnI algorithms maintained very high safety but had lower efficacy, with twice the number of patients remaining in the observe zone. Similar findings were obtained in the external validation cohort.CONCLUSIONS Patients with cancer have a substantially higher prevalence of AMI as the cause of chest pain. Length of ED stay and hospitalization rates are increased. The diagnostic performance of hs-cTnT and the efficacy of both the European Society of Cardiology 0/1-hour hs-cTnT and hs-cTnI algorithms is reduced. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] Study; NCT00470587) (J Am Coll Cardiol CardioOnc 2023;5:591-609) (c) 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 9. |
- Bäck, Maria, 1978, et al.
(författare)
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The SWEDEHEART secondary prevention and cardiac rehabilitation registry (SWEDEHEART CR registry)
- 2021
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Ingår i: European Heart Journal-Quality of Care and Clinical Outcomes. - : Oxford University Press (OUP). - 2058-5225 .- 2058-1742. ; 7:5, s. 431-437
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Tidskriftsartikel (refereegranskat)abstract
- Aims The quality registry SWEDEHEART covers data across the patient pathway after an acute myocardial infarction (MI), from hospital care to secondary prevention. Although cardiac rehabilitation (CR) is strongly recommended after an MI, there is still heterogeneity regarding standards, uptake, and adherence rates. The aim of the SWEDEHEART-CR registry is to provide continuous information on secondary prevention and CR performance to support the audit and development of evidence-based practice. To facilitate quality improvement and research initiatives, a description of the characteristics and development of the SWEDEHEART-CR registry is needed. Methods and results The SWEDEHEART-CR registry starts with data obtained during hospital care and then collects data at out-patient visits 2 months and 1-year after discharge, and at start and end of an exercise-based CR programme. The registry data covers comorbidities, biochemistry, blood pressure, anthropometric variables, medication, psychosocial- and lifestyle variables, readmissions, patient-reported outcome measures, attendance in CR-related programmes, and physical fitness variables. Over 100 000 patients with MI have been included in the SWEDEHEART-CR registry since its start in 2005. From initially covering 35 centres (47%) and 2200 patients annually (27%), SWEDEHEART-CR has developed to a nation-wide registry with 75 centres (100%) and 8800 patients annually (80%) in 2020. Conclusion The SWEDEHEART-CR registry includes a high proportion of the national MI population entering a CR programme and is a powerful tool for quality audit, improvement, and research. The registry provides insights into the characteristics, treatment, and outcomes of evidence-based secondary preventive practice, ultimately leading to better cardiovascular health.
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| 10. |
- Cederlöf, Elin, et al.
(författare)
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Pregnancy Complications and Risk of Cardiovascular Disease Later in Life : A Nationwide Cohort Study
- 2022
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Ingår i: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate the associations between pregnancy complications and cardiovascular mortality and hospitalizations of cardiovascular disease (CVD) after adjustment for major confounding.Methods and Results: In a nationwide register‐based cohort study, women with singleton births between 1973 and 2014 were included from the Swedish Medical Birth Register. Outcomes of mortality and hospitalizations of CVD were collected from the Cause of Death Register and the National Inpatient Register. The cohort was followed from the date of the first delivery until death or end of follow‐up, whichever occurred first. The pregnancy complications studied were preeclampsia or eclampsia, gestational hypertension, gestational diabetes, preterm birth, small for gestational age, and stillbirth. Among the 2 134 239 women (mean age at first pregnancy, 27.0 [SD, 5.1] and mean parity 1.96 [SD, 0.9]), 19.1% (N=407 597) had 1 of the studied pregnancy complications. All pregnancy complications were associated with all‐cause and cardiovascular mortality and hospitalization for CVD (ischemic heart disease, ischemic stroke, and peripheral artery disease) after adjustment for major confounding in a Cox proportional hazard regression model. The adjusted hazard ratio for cardiovascular mortality was 1.84 (95% CI, 1.38–2.44) for preterm birth and 3.14 (95% CI, 1.81–5.44) for stillbirth.Conclusions: In this large cohort study, pregnancy complications were associated with all‐cause mortality, cardiovascular mortality, and hospitalizations for CVD, also after adjusting for confounding, including overweight, smoking, and comorbidities. The study highlights that less established pregnancy complications such as preterm birth and stillbirth are also associated with cardiovascular mortality and CVD.
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| 11. |
- Davila-Rodriguez, Maria Jose, et al.
(författare)
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Is breaking of a hydrogen bond enough to lead to drug resistance?
- 2020
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Ingår i: Chemical Communications. - : Royal Society of Chemistry. - 1359-7345 .- 1364-548X. ; 56:49, s. 6727-6730
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Tidskriftsartikel (refereegranskat)abstract
- Drug resistance is a serious problem in cancer, viral, bacterial, fungal and parasitic diseases. Examination of crystal structures of protein-drug complexes is often not enough to explain why a certain mutation leads to drug resistance. As an example, the crystal structure of the kinase inhibitor dasatinib bound to the Abl1 kinase shows a hydrogen bond between the drug and residue Thr(315)and very few contacts between the drug and residues Val(299)and Phe(317), yet mutations in those residues lead to drug resistance. In the first case, it is tempting to suggest that the loss of a hydrogen bond leads to drug resistance, whereas in the other two cases it is not known why mutations lead to drug resistance in the first place. We carried out extensive molecular dynamics (MD) simulations and free energy calculations to explain drug resistance to dasatinib from a molecular point of view and show that resistance is due to a multitude of subtle effects. Importantly, our calculations could reproduce the experimental values for the binding energies upon mutations in all three cases and shed light on their origin.
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| 12. |
- Faticov, Maria, et al.
(författare)
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Climate warming dominates over plant genotype in shaping the seasonal trajectory of foliar fungal communities on oak
- 2021
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 231:5, s. 1770-1783
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Tidskriftsartikel (refereegranskat)abstract
- Leaves interact with a wealth of microorganisms. Among these, fungi are highly diverse and are known to contribute to plant health, leaf senescence and early decomposition. However, patterns and drivers of the seasonal dynamics of foliar fungal communities are poorly understood. We used a multifactorial experiment to investigate the influence of warming and tree genotype on the foliar fungal community on the pedunculate oak Quercus robur across one growing season. Fungal species richness increased, evenness tended to decrease, and community composition strongly shifted during the growing season. Yeasts increased in relative abundance as the season progressed, while putative fungal pathogens decreased. Warming decreased species richness, reduced evenness and changed community composition, especially at the end of the growing season. Warming also negatively affected putative fungal pathogens. We only detected a minor imprint of tree genotype and warming x genotype interactions on species richness and community composition. Overall, our findings demonstrate that warming plays a larger role than plant genotype in shaping the seasonal dynamics of the foliar fungal community on oak. These warming-induced shifts in the foliar fungal community may have a pronounced impact on plant health, plant-fungal interactions and ecosystem functions.
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| 13. |
- Gluud, Maria, et al.
(författare)
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MicroRNAs in the Pathogenesis, Diagnosis, Prognosis and Targeted Treatment of Cutaneous T-Cell Lymphomas
- 2020
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:5
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Forskningsöversikt (refereegranskat)abstract
- Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL.
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| 14. |
- Gossen, Jonas, et al.
(författare)
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A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics
- 2021
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Ingår i: ACS Pharmacology & Translational Science. - : American Chemical Society (ACS). - 2575-9108. ; 4:3, s. 1079-1095
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Tidskriftsartikel (refereegranskat)abstract
- The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of similar to 30 000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing similar to 200 virtual screenings of compound libraries on selected protein structures, we redefine the protein's druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites.
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| 15. |
- Gubat, Johannes, 1986-
(författare)
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Identifying Essential Deubiquitinase Interactions and Targeting Protein Ubiquitination in Cancer
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is the second leading cause of death globally and is one of the most pressing health issues today. While significant advances have been made in cancer treatment, drug resistance and toxicity remain formidable obstacles to successful therapy. Thus, there is a need to find novel targets that pave the way for new cancer therapeutics. Ubiquitination, the process of tagging substrate proteins with ubiquitin molecules, regulates many of the pathways that underlie cancer progression. This thesis aims to explore innovative strategies for combating cancer by focusing on crucial elements within the ubiquitination machinery, specifically the Ubiquitin-Proteasome System (UPS) and deubiquitinases (DUBs). In Paper I, we employed the Connectivity Map to discern UPS inhibitors by analyzing the gene expression patterns of various compounds in comparison to those induced by proteasome perturbation. In Paper II, we employed orthogonal methods to identify the primary mechanism for the cytotoxicity of b-AP15. Here, we showed that pharmacologic doses of b-AP15 resulted in strong proteasome inhibition and that cytotoxicity is mediated through the mitochondria and influenced by the proteasome-associated DUB, USP14. In Paper III, we explored the role of USP14 in colorectal cancer cells and evaluated its potential as a cancer target. We found that the genetic deletion of USP14 confers a quiescent phenotype to cancer cells. In Paper IV, we used CRISPR-based screens to search for new deubiquitinase targets. We identified deubiquitinase interactions essential for cancer and explored the possibility of combinatorial deubiquitinase targeting. We pinpointed highly-networked deubiquitinases (PSMD14, USP9X, USP39, and USP7) and deubiquitinase pairs represent promising drug targets. This thesis underscores the importance of the ubiquitination process in the search for novel cancer therapeutics and provides new avenues to explore in developing therapies based on the inhibition of deubiquitinases.
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| 16. |
- Leosdottir, Margret, et al.
(författare)
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Cohort profile: Data standards for cardiac rehabilitation structure and processes for the SWEDEHEART cardiac rehabilitation (SWEDEHEART-CR) registry
- 2023
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 18:11
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Tidskriftsartikel (refereegranskat)abstract
- Data standards for quality registries should be evidence-based and follow guideline recommendations. To optimally monitor quality of care, not only patient-level variables, but also centre-level variables need to be included. Here we describe the development of variables to audit the structure and processes in cardiac rehabilitation for patients after myocardial infarction, and the resulting data standards to be implemented in the Swedish quality registry for cardiac disease, SWEDEHEART. The methodology used for the development of international clinical data standards for the European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) was followed. Based on national guidelines for secondary prevention, candidate variables were prepared, after which a multiprofessional expert group on cardiac rehabilitation selected key variables and assured face validity. An external reference group had the role of peer reviewing, ascertaining content validity and test-retest reliability. The process has resulted in 30 data standards to be introduced into the SWEDEHEART cardiac rehabilitation registry and administered on centre-level biannually. The data standards include measures of human resources, centre requirements and process-based metrics. Including registry variables which audit centre-level structure and processes is essential to improve benchmarking and standardize monitoring of quality of care, covering both services provided and patient outcomes.
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| 17. |
- Leosdottir, Margret, et al.
(författare)
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Temporal trends in cardiovascular risk factors, lifestyle and secondary preventive medication for patients with myocardial infarction attending cardiac rehabilitation in Sweden 2006-2019 : a registry-based cohort study
- 2023
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Registries have been highlighted as means to improve quality of care. Here, we describe temporal trends in risk factors, lifestyle and preventive medication for patients after myocardial infarction (MI) registered in the quality registry Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART).Design: A registry-based cohort study.Setting: All coronary care units and cardiac rehabilitation (CR) centres in Sweden.Participants: Patients attending a CR visit at 1-year post-MI 2006-2019 were included (n=81 363, 18-74 years, 74.7% men).Outcome measures: Outcome measures at 1-year follow-up included blood pressure (BP) <140/90 mm Hg, low-density lipoprotein-cholesterol (LDL-C)<1.8 mmol/L, persistent smoking, overweight/obesity, central obesity, diabetes prevalence, inadequate physical activity, and prescription of secondary preventive medication. Descriptive statistics and testing for trends were applied.Results: The proportion of patients attaining the targets for BP<140/90 mmHg increased from 65.2% (2006) to 86.0% (2019), and LDL-C<1.8 mmol/L from 29.8% (2006) to 66.9% (2019, p<0.0001 both). While smoking at the time of MI decreased (32.0% to 26.5%, p<0.0001), persistent smoking at 1 year was unchanged (42.8% to 43.2%, p=0.672) as was the prevalence of overweight/obesity (71.9% to 72.9%, p=0.559). Central obesity (50.5% to 57.0%), diabetes (18.2% to 27.2%) and patients reporting inadequate levels of physical activity (57.0% to 61.5%) increased (p<0.0001 for all). From 2007, >90.0% of patients were prescribed statins and approximately 98% antiplatelet and/or anticoagulant therapy. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescription increased from 68.7% (2006) to 80.2% (2019, p<0.0001).Conclusions: While little change was observed for persistent smoking and overweight/obesity, large improvements were observed for LDL-C and BP target achievements and prescription of preventive medication for Swedish patients after MI 2006-2019. Compared with published results from patients with coronary artery disease in Europe during the same period, these improvements were considerably larger. Continuous auditing and open comparisons of CR outcomes might possibly explain some of the observed improvements and differences.
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| 18. |
- Lindahl, Bernt, et al.
(författare)
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Health literacy is independently and inversely associated with carotid artery plaques and cardiovascular risk
- 2020
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Ingår i: European Journal of Preventive Cardiology. - : Sage Publications. - 2047-4873 .- 2047-4881. ; 27:2, s. 209-215
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Health literacy, the degree to which individuals understand and act upon health information, may have a pivotal role in the prevention of cardiovascular disease (CVD), with low health literacy potentially explaining poorer adherence to prevention guidelines. We investigated the associations between health literacy, ultrasound-detected carotid atherosclerosis and cardiovascular risk factors.Methods: Baseline data (cross-sectional analysis) from a randomized controlled trial, integrated within the Västerbotten Intervention Program, Northern Sweden, was used. We included 3459 individuals, aged 40 or 50 years with ≥1 conventional risk factor or aged 60 years old. The participants underwent clinical examination, blood sampling, carotid ultrasound assessment of intima-media wall thickness (CIMT) and plaque formation, and answered a questionnaire on health literacy – the Brief Health Literacy Screen. The European Systematic Coronary Risk Evaluation and Framingham Risk Score were calculated.Results: About 20% of the participants had low health literacy. Low health literacy was independently associated with the presence of ultrasound-detected carotid artery plaques after adjustment for age and education, odds ratio (95% confidence interval) 1.54 (1.28–1.85), demonstrating a similar level of risk as for smoking. Health literacy was associated with CIMT in men. Low health literacy was associated with higher CVD risk scores. Sensitivity analyses with low health literacy set to 9% or 30% of the study sample, respectively, yielded essentially the same results.Conclusions: Low health literacy was independently associated with carotid artery plaques and a high level of CVD risk scores. Presenting health information in a fashion that is understood by all patients may improve preventive efforts.
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| 19. |
- Lindahl Rajala, Elisabeth, et al.
(författare)
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How can agricultural research translation projects targeting smallholder production systems be strengthened by using Theory of Change?
- 2021
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Ingår i: Global Food Security. - : Elsevier BV. - 2211-9124. ; 28
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Tidskriftsartikel (refereegranskat)abstract
- Sustainable development of smallholder agriculture production in low and lower middle-income countries are crucial for improving food security. To accommodate this science based evidence needs to bridge with agricultural practices and policy development, which requires coordinated actions and long term strategies involving multiple stakeholders. This paper argues that using a Theory of Change (ToC) approach, with strong emphasis on communication and stakeholder engagement, science based knowledge can be more effectively integrated in agricultural development, but also in policy development. Three projects addressing different challenges within livestock production are used to illustrate the use of and challenges with using a ToC framework. A key for reaching outcome was early involvement of relevant stakeholders in implementing teams and using the flexibility included in the ToC approach from design to implementation.
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| 20. |
- Lopez-Ayala, Pedro, et al.
(författare)
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Novel Criteria for the Observe-Zone of the ESC 0/1 h-hs-cTnT Algorithm
- 2021
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 144:10, s. 773-787
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The non-ST-segment-elevation myocardial infarction (NSTEMI) guidelines of the European Society of Cardiology (ESC) recommend a 3h cardiac troponin determination in patients triaged to the observe-zone of the ESC 0/1h-algorithm; however, no specific cutoff for further triage is endorsed. Recently, a specific cutoff for 0/3h high-sensitivity cardiac troponin T (hs-cTnT) change (7 ng/L) was proposed, warranting external validation. METHODS: Patients presenting with acute chest discomfort to the emergency department were prospectively enrolled into an international multicenter diagnostic study. Final diagnoses were centrally adjudicated by 2 independent cardiologists applying the fourth universal definition of myocardial infarction, on the basis of complete cardiac workup, cardiac imaging, and serial hs-cTnT. Hs-cTnT concentrations were measured at presentation, after 1 hour, and after 3 hours. The objective was to externally validate the proposed cutoff, and if necessary, derive and internally as well as externally validate novel 0/3h-criteria for the observe-zone of the ESC 0/1h-hs-cTnT-algorithm in an independent multicenter cohort. RESULTS: Among 2076 eligible patients, application of the ESC 0/1h-hs-cTnT-algorithm triaged 1512 patients (72.8%) to either rule out or rule in NSTEMI, leaving 564 patients (27.2%) in the observe-zone (adjudicated NSTEMI prevalence, 120/564 patients, 21.3%). The suggested 0/3h-hs-cTnT-change of <7 ng/L triaged 517 patients (91.7%) toward rule-out, resulting in a sensitivity of 33.3% (95% CI, 25.5-42.2), missing 80 patients with NSTEMI, and >= 7 ng/L triaged 47 patients toward rule-in (8.3%), resulting in a specificity of 98.4% (95% CI, 96.8-99.2). Novel derived 0/3h-criteria for the observe-zone patients ruled out NSTEMI with a 3h hs-cTnT concentration <15 ng/L and a 0/3h-hs-cTnT absolute change <4 ng/L, triaging 138 patients (25%) toward rule-out, resulting in a sensitivity of 99.2% (95% CI, 96.0-99.9), missing 1 patient with NSTEMI. A 0/3h-hs-cTnT absolute change >= 6 ng/L triaged 63 patients (11.2%) toward rule-in, resulting in a specificity of 98% (95% CI, 96.2-98.9) Thereby, the novel 0/3h-criteria reduced the number of patients in the observe zone by 36%s and the number of type 1 myocardial infarction by 50%. Findings were confirmed in both internal and external validation. CONCLUSIONS: A combination of a 3h-hs-cTnT concentration (<15 ng/L) and a 0/3h absolute change (<4 ng/L) is necessary to safely rule out NSTEMI in patients remaining in the observe-zone of the ESC 0/1h-hs-cTnT-algorithm.
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| 21. |
- Löfgren, Maria, et al.
(författare)
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Conditioned serum in vitro treatment of chondrocyte pellets and osteoarthritic explants
- 2023
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Ingår i: Equine Veterinary Journal. - : Wiley. - 0425-1644 .- 2042-3306. ; 55:2, s. 325-335
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Tidskriftsartikel (refereegranskat)abstract
- Background: Autologous conditioned serum (ACS) is used to treat osteoarthritis in horses, although its effects are not fully investigated. Objectives: To investigate the effects of equine serum and conditioned serum on chondrocytes stimulated with interleukin (IL)-1 beta and cartilage explants with mild osteoarthritis. Study design: In vitro experimental study. Methods: The effect of three different serum preparations (unincubated control [PS], serum incubated 24 h [PS24h] and serum incubated 24 h in ACS containers [PCS]) pooled from lame horses were tested in two in vitro models. IL-1 beta and IL-1 receptor antagonist (IL-1Ra) concentrations were measured in all sera. In model 1, chondrocyte pellet cultures were stimulated with IL-1 beta prior to treatment with the serum preparations for 2 and 48 h. Microarray, polymerase chain reaction, and matrix metallopeptidase-13 analyses were performed. In model 2, cartilage explants from horses with structural osteoarthritis were treated with PS or PCS on days 0, 6 and 12, or left untreated, and evaluated at day 24 using the OARSI grading scale for histological evaluation of articular cartilage. Results: The IL-1Ra concentration in PS24h and PCS was significantly higher than in PS. In model 1, inflammation- and cartilage matrix degradation-related genes were upregulated after 48 h in all treatment groups versus untreated controls. Cartilage matrix molecules, aggrecan and collagens, were downregulated in PS24h- and PCS-treated pellets versus untreated controls. Growth factor signalling genes were upregulated-FGF7 in all treatment groups, BMP2 in PS24h-, and INHBA in PCS-treated-compared with untreated controls. In model 2, the OARSI score at day 24 was not significantly different between treatment groups. Main limitations: Results from in vitro models cannot be directly translated to in vivo situations. Conclusions: In vitro treatment with conditioned serum did not alleviate IL-1 beta-induced responses in chondrocyte pellets or lead to morphological improvement in osteoarthritic cartilage explants.
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| 22. |
- Matthews, Anthony A, et al.
(författare)
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Benchmarking Observational Analyses Before Using Them to Address Questions Trials Do Not Answer : An Application to Coronary Thrombus Aspiration.
- 2022
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 191:9, s. 1652-1665
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Tidskriftsartikel (refereegranskat)abstract
- To increase confidence in the use of observational analyses when addressing effectiveness questions beyond those addressed by randomized trials, one can first benchmark the observational analyses against existing trial results. We used Swedish registry data to emulate a target trial similar to the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) randomized trial, which found no difference in the risk of death or myocardial infarction by 1 year with or without thrombus aspiration among individuals with ST-elevation myocardial infarction. We benchmarked the emulation against the trial at 1 year and then extended the emulation's follow-up to 3 years and estimated effects in subpopulations underrepresented in the trial. As in the TASTE trial, the observational analysis found no differences in risk of outcomes by 1 year between groups (risk difference = 0.7 (confidence interval, -0.7, 2.0) and -0.2 (confidence interval, -1.3, 1.0) for death and myocardial infarction, respectively), so benchmarking was considered successful. We additionally showed no difference in risk of death or myocardial infarction by 3 years, or within subpopulations by 1 year. Benchmarking against an index trial before using observational analyses to answer questions beyond those the trial could address allowed us to explore whether the observational data can be trusted to deliver valid estimates of treatment effects.
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| 23. |
- Matthews, Anthony A., et al.
(författare)
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Comparing Effect Estimates in Randomized Trials and Observational Studies From the Same Population : An Application to Percutaneous Coronary Intervention
- 2021
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Ingår i: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 10:11, s. 020357-020357
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Tidskriftsartikel (refereegranskat)abstract
- Background To understand when results from observational studies and randomized trials are comparable, we performed an observational emulation of a target trial designed to ask similar questions as the VALIDATE (Bivalirudin Versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy) randomized trial. The VALIDATE trial compared the effect of bivalirudin and heparin during percutaneous coronary intervention on the risk of death, myocardial infarction, and bleeding across Sweden. Methods and Results We specified the protocol of a target trial similar to the VALIDATE trial, then emulated the target trial in the period before the VALIDATE trial took place using data from the SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry-the same registry in which the trial was undertaken. The target trial emulation and the VALIDATE trial both estimated little or no effect of bivalirudin versus heparin on the risk of death or myocardial infarction by 180 days (target trial emulation risk ratio for death, 1.21 [95% CI, 0.88 - 1.54]; VALIDATE trial hazard ratio for death, 1.05 [95% CI, 0.78 - 1.41]). The observational data, however, could not capture less severe cases of bleeding, resulting in an inability to define a bleeding outcome like the trial, and could not accurately estimate the comparative risk of death by 14 days, which may be the result of intractable confounding early in follow-up or the inability to precisely emulate the trial's eligibility criteria. Conclusions Using real-world data to emulate a target trial can deliver accurate effect estimates. Yet, even with rich observational data, it is not always possible to estimate the short-term effect of interventions or the effect on outcomes for which data are not routinely collected.
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| 24. |
- Matthews, Anthony, et al.
(författare)
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Extending treatment effects from a randomized trial using observational data
- 2022
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Ingår i: Pharmacoepidemiology and Drug Safety. - : John Wiley & Sons. - 1053-8569 .- 1099-1557. ; 31:Suppl. 2, s. 211-211
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: To increase confidence in the use of observational data for extending inferences from randomized trials, one can first benchmark. That is, demonstrate the observational analysis can replicate an index trial's findings, before using the observational data to estimate what the trial could not.Objectives: To benchmark an observational study designed to ask the questions to the TASTE trial against results from the TASTE trial itself. Then, if benchmarking is successful, use the observational data to extend the inferences made in the trial.Methods: We use Swedish registry data to emulate a target trial similar to the TASTE randomized trial, which found no difference in the risk of death or myocardial infarction by 1 year with or without thrombus aspiration among individuals with ST-elevation myocardial infarction. We benchmark the emulation against the trial at 1 year, then extend the emulation's follow-up to 3 years and estimate effects in subpopulations underrepresented in the trial.Results: Like TASTE, the observational analysis found no differences in risk of outcomes by 1 year between groups (risk difference 0.7 (0.7, 2.0) and0.2 (1.3, 1.0) for death and myocardial infarction respectively), so benchmarking was considered successful. We additionally show no difference in risk of death or myocardial infarction by 3 years, or within subpopulations by 1 year.Conclusions: Benchmarking before using observational data to extend treatment effects from a randomized trial allows us to understand if the observational data can be trusted to deliver valid estimates of treatment effects.
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| 25. |
- Nordin, Steven, 1960-, et al.
(författare)
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Associations between emotional support and cardiovascular risk factors and subclinical atherosclerosis in middle-age
- 2023
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Ingår i: Psychology and Health. - : Routledge. - 0887-0446 .- 1476-8321.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To test the hypothesis of low emotional support being associated with lifestyle and biomedical cardiovascular disease (CVD) risk factors, estimated risk of CVD morbidity and mortality, and subclinical atherosclerosis in middle-aged healthy adults.Methods and measures: Cross-sectional data were obtained from participants aged 40–60 years who had one or more conventional CVD risk factor. They underwent assessment based on questionnaires, clinical examination, blood sampling, and carotid ultrasound of plaque formation and carotid intima-media wall thickness (cIMT). Based on the Interview Schedule for Social Interaction, the participants were categorised as either low in emotional support (n = 884) or as a referent (n = 2570). Logistic regression analyses were conducted to study the associations.Results: Logistic regression analyses showed that low emotional support was significantly associated with smoking, alcohol consumption and physical inactivity (OR = 1.53 − 1.94), estimated risk of CVD morbidity and mortality (OR = 1.56 − 1.68), and plaque formation (OR = 1.39). No significant associations were found regarding biomedical CVD risk factors or cIMT.Conclusion: The findings suggest that low social support is associated with lifestyle CVD risk factors, estimated risk of CVD morbidity and mortality, and subclinical atherosclerosis in middle-aged healthy adults, encouraging causal evaluation with longitudinal data investigating an impact of emotional support on mechanisms underlying CVD.
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| 26. |
- Nåbo, Arne, 1958-, et al.
(författare)
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Battery-Swapping for Heavy Duty Vehicles : A Feasibility Study on Up-Scaling in Sweden
- 2024
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Rapporten fokuserar på den kommersiella genomförbarheten av ett batteribytessystem för tunga lastbilar i Sverige. Genom att studera affärsmodeller, kompatibilitet med svenska regelverk och integration i transportverksamheten har vi utforskat hur disruptiva teknologier, ekosystemeffekter och cirkularitet skulle kunna möjliggöra en snabb introduktion och uppskalning av ett batteribytessystem. Ett särskilt fokus har legat på Kina för att analysera statusen för batteribyten och de processer som har lett till den snabba utvecklingen och uppskalningen där. I Kina krävde batteribyte en ny affärsmodell där aktörer såsom energiproducenter, batteritillverkare och maskinindustri går i spetsen för utvecklingen och spridningen av batteribyten. Batteribyte är nu den dominerande tekniken för eldrivna lastbilar i Kina.Exempel på fördelar med batteribyte som förespråkas är att det bara tar några minuter att byta batteri, minskad investering för lastbilsägare, låg påverkan på det lokala elnätet och att fordons- och batterilivscykler separeras. En simuleringsstudie om batteribyte för tunga lastbilar i hamnverksamhet visar i denna rapport på tydliga fördelar jämfört med kabelladdning. Det finns dock ett par utmaningar med att införa batteribyte i Sverige. För det första finns det inga tydliga förespråkare för batteribyte inom industrin. Till exempel är de svenska och europeiska fordonstillverkarna tveksamma eftersom det utmanar deras nuvarande affärsmodell och att de kan ta rollen som grindvakter. För det andra omfattar inte de nuvarande standarderna och regelverken för fordon och energisystem i Sverige och i EU batteribyte. Rapporten tar också upp behovet av kunskap och utbildning av personer vid batteribytesstationer, samt vikten av social hållbarhet vid elektrifiering av tunga transporter.
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| 27. |
- Pérez-Izquierdo, Leticia, et al.
(författare)
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Fire severity as a key determinant of aboveground and belowground biological community recovery in managed even-aged boreal forests
- 2023
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Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Changes in fire regime of boreal forests in response to climate warming are expected to impact postfire recovery. However, quantitative data on how managed forests sustain and recover from recent fire disturbance are limited.Two years after a large wildfire in managed even-aged boreal forests in Sweden, we investigated how recovery of aboveground and belowground communities, that is, understory vegetation and soil microbial and faunal communities, responded to variation in the severity of soil (i.e., consumption of soil organic matter) and canopy fires (i.e., tree mortality).While fire overall enhanced diversity of understory vegetation through colonization of fire adapted plant species, it reduced the abundance and diversity of soil biota. We observed contrasting effects of tree- and soil-related fire severity on survival and recovery of understory vegetation and soil biological communities. Severe fires that killed overstory Pinus sylvestris promoted a successional stage dominated by the mosses Ceratodon purpureus and Polytrichum juniperinum, but reduced regeneration of tree seedlings and disfavored the ericaceous dwarf-shrub Vaccinium vitis-idaea and the grass Deschampsia flexuosa. Moreover, high tree mortality from fire reduced fungal biomass and changed fungal community composition, in particular that of ectomycorrhizal fungi, and reduced the fungivorous soil Oribatida. In contrast, soil-related fire severity had little impact on vegetation composition, fungal communities, and soil animals. Bacterial communities responded to both tree- and soil-related fire severity.Synthesis: Our results 2 years postfire suggest that a change in fire regime from a historically low-severity ground fire regime, with fires that mainly burns into the soil organic layer, to a stand-replacing fire regime with a high degree of tree mortality, as may be expected with climate change, is likely to impact the short-term recovery of stand structure and above- and belowground species composition of even-aged P. sylvestris boreal forests.
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| 28. |
- Rørvang, Maria, et al.
(författare)
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An added aroma changes the behaviour of domestic pigs in a novel situation aimed for stunning
- 2024
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Ingår i: Applied Animal Behaviour Science. - : Elsevier B.V.. - 0168-1591 .- 1872-9045. ; 270
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Tidskriftsartikel (refereegranskat)abstract
- The currently most widespread stunning method for pigs is high concentration of carbon dioxide (CO2), but this method is under scrutiny due to animal welfare deficits. One alternative method currently under development with potential to replace CO2 is nitrogen (N2) filled high expansion foam. While N2 does not elicit the same aversive behaviour as CO2, it is currently not known if the high expansion foam itself may be frightening to the pigs. Means to alleviate fear reactions to foam could consist of diverting pigs’ attention using aromas (an odour in combination with taste) of interest to them. The current study aimed to investigate if an added aroma (vanilla aroma) affected pigs’ avoidance and exploratory behaviour when exposed to air-filled high expansion foam in a foam box. The study included 50 pigs (30 females, 20 males) of 14–16 weeks of age, of different crosses between Yorkshire, Hampshire and Duroc. The pigs were randomly assigned to either the treatment with air-filled foam with added aroma or the control treatment with no added aroma, which they were exposed to in a foam box. The results showed that pigs with the aromatised foam expressed significantly more exploration behaviour directed towards the foam and box walls, but not towards the floor or the lid. The aromatised foam also resulted in a higher activity level of the pigs. In contrast to the hypotheses, pigs with aromatised foam expressed more avoidance behaviour, and escape attempts were exclusively observed when pigs were exposed to aromatised foam. Slipping events and frequency of vocalisations did not differ between pigs with and without aroma added to the foam. This study shows that an added aroma (taste and odour in combination) increased pigs’ exploration behaviour towards the foam, and thus could serve as a distraction for the pigs when inside a confined foam box. The results emphasise the importance of taking foam aroma into consideration in the further development of the N2-filled high expansion as a stunning method. The potential anxiety- or stress-reducing effect of any added aroma needs further investigation, and future studies should focus on assessing various types of aromas, and/or odours, as well as different concentrations of the compounds to determine which solution is most efficient in alleviating pig stress and anxiety.
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| 29. |
- Seidel, Pia, et al.
(författare)
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Drug information sources in professional work-a questionnaire study on physicians' usage and preferences (the drug information study)
- 2023
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Nature. - 0031-6970 .- 1432-1041. ; 79, s. 767-774
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThis study aimed to explore physicians' use of drug information in professional work, with special focus on those working in primary care, and also in relation to personal characteristics of physicians.MethodsA web-based questionnaire was distributed by e-mail to physicians in five regions in Sweden. The questions concerned drug-related queries at issue when searching for information, sources used, and factors of importance for the choice of source, as well as responder characteristics.ResultsA total of 3254 (85%) out of 3814 responding physicians stated that they searched for drug information every week. For physicians working in primary health care, the corresponding number was 585 (96%). The most common drug-related issues searched for by 76% of physicians every week concerned pharmacotherapeutic aspects (e.g., dosing), followed by adverse drug reactions (63%). For 3349 (88%) physicians, credibility was the most important factor for the choice of sources of drug information, followed by easy access online (n = 3127, 82%). Further analyses among physicians in primary care showed that some personal characteristics, like seniority, sex, and country of education, as well as research experience, were associated with usage and preferences of drug information sources.ConclusionsThis study confirms that physicians often use drug information sources in professional work, in particular those who work in primary health care. Credibility and easy access are key factors for usage. Among physicians in primary care, personal factors influenced the choice of drug information sources.
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| 30. |
- Szummer, Karolina, et al.
(författare)
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Comparison Between Ticagrelor and Clopidogrel in Elderly Patients With an Acute Coronary Syndrome : Insights From the SWEDEHEART Registry
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 1524-4539 .- 0009-7322. ; 142:18, s. 1700-1708
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The comparative efficacy and safety of ticagrelor versus clopidogrel in older patients with myocardial infarction (MI) has received limited study. METHODS: We performed an observational analysis of all patients ≥80 years (n=14 005) who were discharged alive with aspirin combined with either clopidogrel (60.2%) or ticagrelor (39.8%) after a MI between 2010 and 2017 registered in the national registry SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies). Inverse probability treatment weighting was used in Cox regression models to adjust for differences in demographics, in-hospital therapies, and medications. The primary ischemic outcome (death, MI, or stroke), and bleeding were obtained from national registries at 1 year. A sensitivity analysis in <80-year-old patients was performed. RESULTS: In patients ≥80 years, the incidence of the primary ischemic outcome (hazard ratio [HR], 0.97 [95% CI, 0.88-1.06]) was similar for ticagrelor- and clopidogrel-treated patients. Ticagrelor was associated with a 17% and 48% higher risk of death (HR, 1.17 [95% CI, 1.03-1.32]) and bleeding (HR, 1.48 [95% CI, 1.25-1.76]), but a lower risk of MI (HR, 0.80 [95% CI, 0.70-0.92]) and stroke (HR, 0.72 [95% CI, 0.56-0.93]). In <80-year-old patients, the incidence of the primary ischemic outcome was 17% (HR, 0.83 [95% CI, 0.77-0.89]) lower with ticagrelor. Ticagrelor was associated with 15% (HR, 0.85 [95% CI, 0.76-0.96]) lower risk of death, 32% higher risk of bleeding (HR, 1.32 [95% CI, 1.18-1.47]), but lower risk of MI (HR, 0.82 [95% CI, 0.75-0.91]) and stroke (HR, 0.82 [95% CI, 0.69-0.98]). CONCLUSIONS: Ticagrelor use among elderly patients with MI was associated with higher risk of bleeding and death compared with clopidogrel. A randomized study of ticagrelor versus clopidogrel in the elderly is needed.
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| 31. |
- Säll, Johanna, et al.
(författare)
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Salt-inducible kinases are required for glucose uptake and insulin signaling in human adipocytes
- 2023
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Ingår i: Obesity. - 1930-739X. ; 31:10, s. 2515-2529
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Salt-inducible kinase 2 (SIK2) is abundantly expressed in adipocytes and downregulated in adipose tissue from individuals with obesity or insulin resistance. The main aims of this work were to investigate the involvement of SIKs in the regulation of glucose uptake in primary mature human adipocytes and to identify mechanisms underlying this regulation.METHODS: Primary mature adipocytes were isolated from human, rat, or mouse adipose tissue and treated with pan-SIK inhibitors. Adipocytes isolated from wild type, ob/ob, and SIK2 knockout mice were also used. Glucose uptake was examined by glucose tracer assay. The insulin signaling pathway was monitored by Western blotting, co-immunoprecipitation, and total internal reflection fluorescence microscopy.RESULTS: This study demonstrates that SIK2 is downregulated in obese ob/ob mice and that SIK activity is required for intact glucose uptake in primary human and mouse adipocytes. The underlying mechanism involves direct effects on the insulin signaling pathway, likely at the level of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) generation or breakdown. Moreover, lack of SIK2 alone is sufficient to attenuate glucose uptake in mouse adipocytes.CONCLUSIONS: SIK2 is required for insulin action in human adipocytes, and the mechanism includes direct effects on the insulin signaling pathway.
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| 32. |
- Täufer Cederlöf, Elin
(författare)
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Pregnancy Complications and Cardiovascular Disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Women with a history of pregnancy complications have an increased risk of cardiovascular disease (CVD) later in life. The overall aims were to investigate pregnancy complications as cardiovascular risk factors; whether they have predictive value for the spread of atherosclerosis in older women, whether they are associated with atherosclerotic CVD after adjusting for major confounders, both at the population-level and in women with structural heart disease; and to investigate cardiovascular biomarkers in women with spontaneous preterm birth.Among 307 postmenopausal women with and without CVD, the self-reported frequency of pregnancy complications was assessed, and three vascular beds were examined (peripheral, carotid and coronary arteries). The self-reported complications were evaluated as possible predictors of spreading atherosclerosis. Exposures to pregnancy complications of a population-based cohort, including 2 134 239 women from the national Medical Birth Register from 1973 to 2014, were evaluated as a risk factor for atherosclerotic cardiovascular outcomes (hospitalizations and mortality) after adjustment for major confounders. The associations were further analyzed in 2554 women from the same cohort identified as having structural heart disease, and also for hospitalizations for heart failure and arrhythmias.A first screening phase used comparative mass spectrometry to examine differences in protein expression in mid-pregnancy plasma samples, from the Uppsala Biobank for Pregnant Women, from a subset of women with spontaneous preterm birth in first pregnancy and controls. Seven protein biomarkers differed significantly between cases and controls. In a second validation phase, plasma samples and data on cardiovascular risk factors were collected from 65 women who agreed to participate in a follow-up visit 4–15 years after pregnancy. Concentrations of the selected biomarkers were analyzed, as well as lipid profiles from samples from both pregnancy (Biobank) and follow-up.In conclusion, an association between pregnancy complications and the spread of atherosclerosis in older women was not found. Pregnancy complications were associated with an increased risk of atherosclerotic cardiovascular outcomes, both at the population level and in women with structural heart disease, after adjustment for major confounding factors. Compared with women without preterm birth, those with spontaneous preterm birth had higher concentrations of fibrinogen and triglycerides, both at mid-pregnancy and a decade after pregnancy.
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| 33. |
- Westin, Johan, 1965, et al.
(författare)
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Management of hepatitis B virus infection, updated Swedish guidelines
- 2020
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Ingår i: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 52:1, s. 1-22
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Tidskriftsartikel (refereegranskat)abstract
- Despite access to effective antiviral drugs and vaccines, hepatitis B virus (HBV) infection remains a major health issue worldwide. HBV is highly infectious and may cause chronic infection, progressive liver damage, hepatocellular cancer (HCC) and death. Early diagnosis, proper management and timing of treatment are crucial. The Swedish Reference group for Antiviral Treatment (RAV) here provides updated evidence-based guidelines for treatment and management of HBV infection which may be applicable also in other countries. Tenofovir alafenamide (TAF) has been introduced as a novel treatment option and new principles regarding indication and duration of treatment and characterization of hepatitis B have been gradually introduced which justifies an update of the previous guidelines from 2007. Updated guidelines on HCC surveillance in HBV-infected patients, treatment and prophylaxis for patients undergoing liver transplantation as well as management of pregnant women and children with HBV infection are also provided.
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| 34. |
- Öberg Westin, Maria, et al.
(författare)
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Laying the Groundwork: A Pilot Study Exploring Improved Endometriosis Management Strategies in Primary Healthcare.
- 2024
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Ingår i: International journal of general medicine. - 1178-7074. ; 17, s. 1325-1333
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate if a brief educational intervention for primary health care staff regarding endometriosis gives sustainable knowledge of endometriosis symptoms and if a brief questionnaire for women seeking care for common symptoms is feasible in the Swedish primary care context.Pilot study.3 primary care centres (PCCs) in Sweden. Exploring knowledge among staff about endometriosis at baseline and 3 months after an information workshop. Evaluation of feasibility of a brief questionnaire for women seeking care for common symptoms For PCC personnel: knowledge about endometriosis at baseline and after 3 months. For patient questionnaire: whether adequate, understandable, acceptable, and feasible.Females in primary care centre waiting room, and staff members at participating PCCs.The knowledge level of endometriosis was improved or sustained after 3 months compared to baseline among staff at PCCs. Over 90% of the patients stated that the questionnaire was adequate, understandable, acceptable, and feasible.We found that an educational programme improved the staff's knowledge about endometriosis. The programme together with the patient questionnaire could be a way to enhance knowledge about endometriosis among PCCs. This combined effort might facilitate earlier detection and treatment of women with endometriosis.
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