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1.	Sønderby, Ida E., et al. (författare) 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans 2021 Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 11:1 Tidskriftsartikel (refereegranskat)abstract Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
2.	Allentoft, Morten E., et al. (författare) 100 ancient genomes show repeated population turnovers in Neolithic Denmark 2024 Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 329-337 Tidskriftsartikel (refereegranskat)abstract Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1–4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5–7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.
3.	Allentoft, Morten E., et al. (författare) Population genomics of post-glacial western Eurasia 2024 Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311 Tidskriftsartikel (refereegranskat)abstract Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
4.	Alzuhairi, Karam Sadoon, et al. (författare) Sub-acute cardiac magnetic resonance to predict irreversible reduction in left ventricular ejection fraction after ST-segment elevation myocardial infarction : A DANAMI-3 sub-study 2020 Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273. ; 301, s. 215-219 Tidskriftsartikel (refereegranskat)abstract Aims: To predict irreversible reduction in left ventricular ejection fraction (LVEF) during admission for ST-segment elevation myocardial infarction (STEMI) using cardiac magnetic resonance (CMR) in addition to classical clinical parameters. Irreversible reduction in LVEF is an important prognostic factor after STEMI which necessitates medical therapy and implantation of prophylactic implantable cardioverter defibrillator (ICD). Methods and results: A post-hoc analysis of DANAMI-3 trial program (Third DANish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction) which recruited 649 patients who had CMR performed during index hospitalization and after 3 months. Patients were divided into two groups according to CMR-LVEF at 3 months: Group 1 with LVEF≤35% and Group 2 with LVEF>35%. Group 1 included 15 patients (2.3%) while Group 2 included 634 patients (97.7%). A multivariate analysis showed that: Killip class >1 (OR 7.39; CI:1.47–36.21, P = 0.01), symptom onset-to-wire ≥6 h (OR 7.19; CI 1.07–50.91, P = 0.04), LVEF≤35% using index echocardiography (OR 7.11; CI: 1.27–47.43, P = 0.03), and infarct size ≥40% of LV on index CMR (OR 42.62; CI:7.83–328.29, P < 0.001) independently correlated with a final LVEF≤35%. Clinical models consisted of these parameters could identify 7 out of 15 patients in Group 1 with 100% positive predictive value. Conclusion: Together with other clinical measurements, the assessment of infarct size using late Gadolinium enhancement by CMR during hospitalization is a strong predictor of irreversible reduction in CMR_LVEF ≤35. That could potentially, after validation with future research, aids the selection and treatment of high-risk patients after STEMI, including implantation of prophylactic ICD during index hospitalization.
5.	Bennesved, Peter, 1986- (författare) Sheltered Society : Civilian Air raid shelters in Sweden — from idea to materiality, 1918-1940 and beyond 2020 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract In 2002, Sweden finally stopped producing air raid shelters for its population after over sixty years of continuous production since 1938. Judging from the Swedish Civil Contingencies Agency, MSB, the Swedish Air raid shelter registry contain about 65,000 air raid shelters registered as being in use. This figure reflect a huge security infrastructure which, today, is said to provide shelter for around 70% of the Swedish population. By studying the interwar period and the origins of civil defence in Swedish history, this dissertation sets out to explain the origins of the Swedish air raid shelter and provide an explanation of how Sweden eventually became a “Sheltered Society”.In order to achieve this, this dissertation will study the interwar period up until the first year of the Second World War, 1918 to 1940, which can be said to be the formative years for aerial protection politics and air raid shelters. As a theoretical inspiration, the dissertation uses LTS theory, intertwined with a Multi-Level Perspective on technological transitions. Through the close reading of reports and articles, newspapers and archival materials, written by fortification officers, engineers, architects, politicians and journalists during these years, the study shows how the originally military bunkers and air raid shelters were conceptually transferred to civilian use during the interwar years by authors concerned about the technological and strategic developments in aerial warfare.This process was enabled by a careful navigation between militaristic notions of aerial protection and the politically neutral civilian use of air raid shelters. Key factors for the successful implementation was framing the shelters as a simple technical matter through the concept of “Construction-Technical Aerial Protection”, as well as removing all military involvement in building and organizing them, making them seem “civilian” rather than military. This eventually led to the ratification of the Air raid shelter statute of 1940, which could be said to be the origin of the Swedish air raid shelter system. While politicians, engineers and fortification officers launched this image of the air raid shelter, the contemporary press discourse also provided a means of interpreting the10newly introduced shelters as being culturally compatible with Swedish urban modernity, thus making the radical urban change appear less frightening and a natural part of the development of the burgeoning Swedish welfare state.
6.	Bomholt, Tobias, et al. (författare) The Accuracy of Hemoglobin A1c and Fructosamine Evaluated by Long-Term Continuous Glucose Monitoring in Patients with Type 2 Diabetes Undergoing Hemodialysis 2022 Ingår i: Blood Purification. - : S. Karger. - 0253-5068 .- 1421-9735. ; 51:7, s. 608-616 Tidskriftsartikel (refereegranskat)abstract INTRODUCTION: The accuracy of hemoglobin A1c (HbA1c) as a glycemic marker in patients with type 2 diabetes (T2D) receiving hemodialysis (HD) remains unknown. To assess accuracy, we compared HbA1c and fructosamine levels with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with T2D receiving HD.METHODS: Thirty patients in the HD group and 36 patients in the control group (T2D and an estimated glomerular filtration rate >60 mL/min/1.73 m2) completed the study period of 17 weeks. CGM (Ipro2®, Medtronic) was performed 5 times for periods of up to 7 days (with 4-week intervals) during a 16-week period. HbA1c (mmol/mol), the estimated mean plasma glucose from HbA1c (eMPGA1c [mmol/L]) and fructosamine (μmol/L) was measured at week 17 and compared with mean sensor glucose levels from CGM.FINDINGS: In the HD group, mean sensor glucose was 1.4 mmol/L (95% confidence interval [CI]: 1.0-1.8) higher than the eMPGA1c, whereas the difference for controls was 0.1 mmol/L (95% CI: -0.1-[0.4]; p < 0.001). Adjusted for mean sensor glucose, HbA1c was lower in the HD group (-7.3 mmol/mol, 95% CI: -10.0-[-4.7]) than in the control group (p < 0.001), with no difference detected for fructosamine (p = 0.64).DISCUSSION: HbA1c evaluated by CGM underestimates plasma glucose levels in patients receiving HD. The underestimation represents a clinical challenge in optimizing glycemic control in the HD population. Fructosamine is unaffected by the factors affecting HbA1c and appears to be more accurate for glycemic monitoring. CGM or fructosamine could thus complement HbA1c in obtaining more accurate glycemic control in this patient group.
7.	Botteri, Edoardo, et al. (författare) Characteristics of non-participants in a randomized colorectal cancer screening trial comparing sigmoidoscopy and faecal immunochemical testing. 2022 Ingår i: International journal of cancer. - : Wiley. - 1097-0215 .- 0020-7136. ; 151:3, s. 361-371 Tidskriftsartikel (refereegranskat)abstract Public health systems should guarantee universal access to health care services, including cancer screening. We assessed whether certain population subgroups were underrepresented among participants in colorectal cancer screening with sigmoidoscopy and faecal immunochemical testing (FIT). Between 2012 and 2019, about 140,000 individuals aged 50-74years were randomly invited to once-only sigmoidoscopy or first round of FIT screening. This study included 46,919 individuals invited to sigmoidoscopy and 70,019 to FIT between 2012 and 2017. We used logistic regression models to evaluate if demographic and socioeconomic factors and use of certain drugs were associated with participation. 24,159 (51.5%) individuals attended sigmoidoscopy and 40,931 (58.5%) FIT screening. Male gender, young age, low education and income, being retired or unemployed, living alone, being an immigrant, long driving time to screening centre, and use of antidiabetic and psychotropic drugs were associated with low participation in both screening groups. Many of these factors also predicted low acceptance of colonoscopy after positive FIT. While male gender, young age and living alone were more strongly associated with non-participation in FIT than sigmoidoscopy, low education and income, being retired or immigrant and long driving time were more strongly associated with non-participation in sigmoidoscopy than FIT. In conclusion, participation was lower in sigmoidoscopy than FIT. Predictors of non-participation were similar between arms. However, low socioeconomic status, being an immigrant and long driving time affected participation more in sigmoidoscopy screening, suggesting that FIT may guarantee more equal access to screening services than sigmoidoscopy.
8.	Currie, Thomas E., et al. (författare) Integrating evolutionary theory and social–ecological systems research to address the sustainability challenges of the Anthropocene 2024 Ingår i: Philosophical Transactions of the Royal Society of London. Biological Sciences. - 0962-8436 .- 1471-2970. ; 379:1893 Forskningsöversikt (refereegranskat)abstract The rapid, human-induced changes in the Earth system during the Anthropocene present humanity with critical sustainability challenges. Social–ecological systems (SES) research provides multiple approaches for understanding the complex interactions between humans, social systems, and environments and how we might direct them towards healthier and more resilient futures. However, general theories of SES change have yet to be fully developed. Formal evolutionary theory has been applied as a dynamic theory of change of complex phenomena in biology and the social sciences, but rarely in SES research. In this paper, we explore the connections between both fields, hoping to foster collaboration. After sketching out the distinct intellectual traditions of SES research and evolutionary theory, we map some of their terminological and theoretical connections. We then provide examples of how evolutionary theory might be incorporated into SES research through the use of systems mapping to identify evolutionary processes in SES, the application of concepts from evolutionary developmental biology to understand the connections between systems changes and evolutionary changes, and how evolutionary thinking may help design interventions for beneficial change. Integrating evolutionary theory and SES research can lead to a better understanding of SES changes and positive interventions for a more sustainable Anthropocene.
9.	Dantoft, Thomas Meinertz, et al. (författare) Multiple chemical sensitivity described in the Danish general population : Cohort characteristics and the importance of screening for functional somatic syndrome comorbidity-The DanFunD study 2021 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 16:2 Tidskriftsartikel (refereegranskat)abstract Background: Multiple chemical sensitivity (MCS) is characterized by widespread symptoms attributed to exposure to airborne chemicals. MCS is categorized as a functional somatic syndrome (FSS), and MCS cases often meet the criteria for other types of FSS, e.g. fibromyalgia. The primary aim was to characterize MCS regarding symptom triggers, symptoms, lifestyle and describe demographics, socioeconomics and lifestyle factors associated with MCS. A secondary aim was to examine the implication of FSS comorbidity.Methods: Data were derived from a random sample of the Danish adult population enrolled in the Danish Study of Functional Disorders (DanFunD; n = 9,656). Questionnaire data comprised information used to delimit MCS and four additional types of FSS, as well as data on demographics, socioeconomics and lifestyle. MCS cases (n = 188) was stratified into subgroups; MCS only (n = 109) and MCS with comorbid FSS (n = 73). Information regarding FSS comorbidities were missing for six MCS cases. MCS subgroups and controls without FSS comorbidities (n = 7,791) were compared by means of logistic regression analyses, adjusted for age and sex.Results: MCS was associated with female sex, not being in occupation and low social status, but not with age or education. MCS cases reported normal dietary intake and smoking habits and lower alcohol consumption. Additional associations were found between MCS and low rate of cohabitation, sedentarism, daily physically limitations, and poor quality of sleep. However, subgroup analysis revealed that these findings were primarily associated with MCS with comorbid FSS.Conclusions: MCS was associated with lower socioeconomic status, physically inactivity and poor quality of sleep. Subgroup analysis revealed that several associations was explained by FSS comorbidity, i.e. MCS cases with no comorbid FSS showed normal rate of cohabitation and did not report physical limitations or difficulties sleeping. Overall, our findings emphasise the importance of screening MCS cases for FSS comorbidity both in epidemiological and clinical settings.
10.	Fenton, Thomas M., et al. (författare) Immune Profiling of Human Gut-Associated Lymphoid Tissue Identifies a Role for Isolated Lymphoid Follicles in Priming of Region-Specific Immunity 2020 Ingår i: Immunity. - : Elsevier BV. - 1074-7613. ; 52:3, s. 557-570 Tidskriftsartikel (refereegranskat)abstract The intestine contains some of the most diverse and complex immune compartments in the body. Here we describe a method for isolating human gut-associated lymphoid tissues (GALTs) that allows unprecedented profiling of the adaptive immune system in submucosal and mucosal isolated lymphoid follicles (SM-ILFs and M-ILFs, respectively) as well as in GALT-free intestinal lamina propria (LP). SM-ILF and M-ILF showed distinct patterns of distribution along the length of the intestine, were linked to the systemic circulation through MAdCAM-1+ high endothelial venules and efferent lymphatics, and had immune profiles consistent with immune-inductive sites. IgA sequencing analysis indicated that human ILFs are sites where intestinal adaptive immune responses are initiated in an anatomically restricted manner. Our findings position ILFs as key inductive hubs for regional immunity in the human intestine, and the methods presented will allow future assessment of these compartments in health and disease.
11.	Forslund, Sofia K., et al. (författare) Combinatorial, additive and dose-dependent drug–microbiome associations 2021 Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7889, s. 500-505 Tidskriftsartikel (refereegranskat)abstract During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1–5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
12.	Frederiksen, Line Elmerdahl, et al. (författare) Psychiatric disorders in childhood cancer survivors in Denmark, Finland, and Sweden : a register-based cohort study from the SALiCCS research programme 2022 Ingår i: The Lancet Psychiatry. - 2215-0366 .- 2215-0374. ; 69 Tidskriftsartikel (refereegranskat)abstract Background: A childhood cancer diagnosis and treatment-induced somatic late effects can affect the long-term mental health of survivors. We aimed to explore whether childhood cancer survivors are at higher risk of psychiatric disorders later in life than their siblings and the general population. Methods: In this register-based cohort study (part of the Socioeconomic Consequences in Adult Life after Childhood Cancer [SALiCCS] research programme), we included 5-year survivors of childhood cancer diagnosed before 20 years of age between Jan 1, 1974 and Dec 31, 2011, in Denmark, Finland, and Sweden. In Denmark and Sweden, 94·7% of individuals were born in a Nordic country (ie, Denmark, Finland, Iceland, Norway, or Sweden); similar information was not available in Finland. Data on ethnicity were not collected. Survivors were compared with their siblings and randomly selected individuals from the general population who were matched to the survivors by year of birth, sex, and geographical region. We followed up our study population from 5 years after the childhood cancer diagnosis or corresponding calendar date for matched individuals (the index date) until Aug 11, 2017, and assessed information on hospital contacts for any and specific psychiatric disorders. For siblings, the index date was defined as 5 years from the date on which they were of the same age as their sibling survivor when diagnosed with cancer. Findings: The study population included 18 621 childhood cancer survivors (9934 [53·3%] males and 8687 [46·7%] females), 24 775 siblings (12 594 [50·8%] males and 12 181 [49·2%] females), and 88 630 matched individuals (47 300 [53·4%] males and 41 330 [46·6%] females). The cumulative incidence proportion of having had a psychiatric hospital contact by 30 years of age between Jan 1, 1979, and Aug 11, 2017, was 15·9% (95% CI 15·3–16·5) for childhood cancer survivors, 14·0% (13·5–14·5) for siblings, and 12·7% (12·4–12·9) for matched individuals. Despite a small absolute difference, survivors were at higher relative risk of any psychiatric hospital contact than their siblings (1·39, 1·31–1·48) and matched individuals (hazard ratio 1·34, 95% CI 1·28–1·39). The higher risk persisted at the age of 50 years. Survivors had a higher burden of recurrent psychiatric hospital contacts and had more hospital contacts for different psychiatric disorders than their siblings and the matched individuals. Interpretation: Childhood cancer survivors are at higher long-term risk of psychiatric disorders than their siblings and matched individuals from the general population. To improve mental health and the overall quality of life after childhood cancer, survivorship care should include a focus on early signs of mental health problems, especially among high-risk groups of survivors. Funding: NordForsk, Aarhus University, Swedish Childhood Cancer Foundation, Danish Health Foundation, and Swiss National Science Foundation.
13.	Gonzalez-Franquesa, Alba, et al. (författare) Discovery of thymosin β4 as a human exerkine and growth factor 2021 Ingår i: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 321:5, s. 770-778 Tidskriftsartikel (refereegranskat)abstract Skeletal muscle is an endocrine organ secreting exercise-induced factors (exerkines), which play a pivotal role in interorgan cross talk. Using mass spectrometry (MS)-based proteomics, we characterized the secretome and identified thymosin b4 (TMSB4X) as the most upregulated secreted protein in the media of contracting C2C12 myotubes. TMSB4X was also acutely increased in the plasma of exercising humans irrespective of the insulin resistance condition or exercise mode. Treatment of mice with TMSB4X did not ameliorate the metabolic disruptions associated with diet induced-obesity, nor did it enhance muscle regeneration in vivo. However, TMSB4X increased osteoblast proliferation and neurite outgrowth, consistent with its WADA classification as a prohibited growth factor. Therefore, we report TMSB4X as a human exerkine with a potential role in cellular cross talk.
14.	Harborg, Sixten, et al. (författare) Statin use and breast cancer recurrence in postmenopausal women treated with adjuvant aromatase inhibitors : a Danish population-based cohort study 2020 Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 183:1, s. 153-160 Tidskriftsartikel (refereegranskat)abstract Purpose: To examine the association between statin use and risk of breast cancer recurrence in a national Danish cohort of postmenopausal breast cancer patients receiving aromatase inhibitors (AI) in the adjuvant setting. Patients and methods: We enrolled all postmenopausal patients diagnosed with stage I–III estrogen receptor positive breast cancer during the years 2007–2017, assigned adjuvant AI treatment, and registered in both the Danish Breast Cancer Group database and the Danish Cancer Registry. We ascertained incident statin exposure (≥ 1 prescription post-diagnosis) from the Danish National Prescription Registry and modeled statins as a time-varying exposure lagged by 6 months. Follow-up began 7 months after diagnosis and continued to the first event of recurrence, death, emigration, 5 years elapsed, or 25th September 2018. We estimated incidence rates of recurrence at 5 years and used Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI), comparing statin exposure with non-exposure. Results: We enrolled 14,773 eligible patients. During the 5 years of follow-up, there were 32 recurrences in 3163 person-years of follow-up among statin-exposed patients, and 612 recurrences in 45,655 person-years among unexposed patients (incidence rate per 1000 person-years: 10.12 [95% CI 6.92–14.28] and 13.40 [95% CI 12.36–14.51], respectively). In multivariable models, any statin exposure was associated with a reduced rate of 5-year breast cancer recurrence (adjusted HR 0.72 [95% CI 0.50–1.04]). Considering only lipophilic statins as exposure the results were similar (adjusted HR 0.70 [95% CI 0.48–1.02]). Conclusions: Statin use was associated with a reduced risk of breast cancer recurrence among postmenopausal patients diagnosed with early stage breast cancer who received adjuvant AI therapy.
15.	Jakobsen, Lasse H., et al. (författare) Minimal relapse risk and early normalization of survival for patients with Burkitt lymphoma treated with intensive immunochemotherapy : an international study of 264 real-world patients 2020 Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 189:4, s. 661-671 Tidskriftsartikel (refereegranskat)abstract Non-endemic Burkitt lymphoma (BL) is a rare germinal centre B-cell-derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic-based and population-based lymphoma registries from six countries were used to identify 264 real-world patients. The median age was 47 years and the majority had advanced-stage disease and elevated LDH. Treatment protocols were R-CODOX-M/IVAC (47%), R-hyper-CVAD (16%), DA-EPOCH-R (11%), R-BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two-year overall survival and event-free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two-year relapse risk was 6% but diminished to 0·6% for patients reaching 12 months of post-remission event-free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0·4 (95% CI: −0·7 to 2) months. In conclusion, real-world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow-up strategies with increased focus on survivorship and less focus on routine disease surveillance.
16.	Jørgensen, Bo Barker, et al. (författare) Sub-seafloor biogeochemical processes and microbial life in the Baltic Sea 2020 Ingår i: Environmental Microbiology. - : Society for Applied Microbiology. - 1462-2912 .- 1462-2920. ; 22:5, s. 1688-1706 Forskningsöversikt (refereegranskat)abstract The post-glacial Baltic Sea has experienced extreme changes that are archived today in the deep sediments. IODP Expedition 347 retrieved cores down to 100 m depth and studied the climate history and the deep biosphere. We here review the biogeochemical and microbiological highlights and integrate these with other studies from the Baltic seabed. Cell numbers, endospore abundance and organic matter mineralization rates are extremely high. A 100-fold drop in cell numbers with depth results from a small difference between growth and mortality in the ageing sediment. Evidence for growth derives from a D:L amino acid racemization model, while evidence for mortality derives from the abundance and potential activity of lytic viruses. The deep communities assemble at the bottom of the bioturbated zone from the founding surface community by selection of organisms suited for life under deep sediment conditions. The mean catabolic per-cell rate of microorganisms drops steeply with depth to a life in slow-motion, typical for the deep biosphere. The subsurface life under extreme energy limitation is facilitated by exploitation of recalcitrant substrates, by biochemical protection of nucleic acids and proteins, and by repair mechanisms for random mismatches in DNA or damaged amino acids in proteins. This article is protected by copyright. All rights reserved.
17.	Jørgensen, Peter B., et al. (författare) Identification, isolation and analysis of human gut-associated lymphoid tissues 2021 Ingår i: Nature Protocols. - : Springer Science and Business Media LLC. - 1754-2189 .- 1750-2799. ; 16:4, s. 2051-2067 Tidskriftsartikel (refereegranskat)abstract Gut-associated lymphoid tissues (GALTs) comprise key intestinal immune inductive sites, including the Peyer’s patches of the small intestine and different types of isolated lymphoid follicle (ILF) found along the length of the gut. Our understanding of human GALT is limited due to a lack of protocols for their isolation. Here we describe a technique that, uniquely among intestinal cell isolation protocols, allows identification and isolation of all human GALT, as well as GALT-free intestinal lamina propria (LP). The technique involves the mechanical separation of intestinal mucosa from the submucosa, allowing the identification and isolation of submucosal ILF (SM-ILF), LP-embedded mucosal ILF (M-ILF) and LP free of contaminating lymphoid tissue. Individual SM-ILF, M-ILF and Peyer’s patch follicles can be subsequently digested for downstream cellular and molecular characterization. The technique, which takes 4–10 h, will be useful for researchers interested in intestinal immune development and function in health and disease.
18.	Jørgensen, Peter B, et al. (författare) The porcine large intestine contains developmentally distinct submucosal lymphoid clusters and mucosal isolated lymphoid follicles 2022 Ingår i: Developmental and Comparative Immunology. - : Elsevier BV. - 0145-305X. ; 131 Tidskriftsartikel (refereegranskat)abstract Gut-associated lymphoid tissues (GALT) serve as key priming sites for intestinal adaptive immune responses. Most of our understanding of GALT function and development arises from studies in mice. However, the diversity, structure and cellular composition of GALT differs markedly between mammalian species and the developmental window in which distinct GALT structures develop in large mammals remains poorly understood. Given the importance of pigs as models of human disease, as well as their role in livestock production, we adapted a recently developed protocol for the isolation of human GALT to assess the diversity, development and immune composition of large intestinal GALT in neonatal and adult pigs. We demonstrate that the large intestine of adult pigs contains two major GALT types; multifollicular submucosal GALT that we term submucosal lymphoid clusters (SLC) which develop prenatally, and as yet undescribed mucosal isolated lymphoid follicles (M-ILF), which arise after birth. Using confocal laser microscopy and flow cytometry, we additionally assess the microanatomy and lymphocyte composition of SLC and M-ILF, compare them to jejunal Peyer's patches (PP), and describe the maturation of these structures. Collectively, our results provide a deeper understanding of the diversity and development of GALT within the porcine large intestine.
19.	Kristensen, Kristian K., et al. (författare) Unfolding of monomeric lipoprotein lipase by ANGPTL4 : Insight into the regulation of plasma triglyceride metabolism 2020 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:8, s. 4337-4346 Tidskriftsartikel (refereegranskat)abstract The binding of lipoprotein lipase (LPL) to GPIHBP1 focuses the intravascular hydrolysis of triglyceride-rich lipoproteins on the surface of capillary endothelial cells. This process provides essential lipid nutrients for vital tissues (e.g., heart, skeletal muscle, and adipose tissue). Deficiencies in either LPL or GPIHBP1 impair triglyceride hydrolysis, resulting in severe hypertriglyceridemia. The activity of LPL in tissues is regulated by angiopoietin-like proteins 3, 4, and 8 (ANGPTL). Dogma has held that these ANGPTLs inactivate LPL by converting LPL homodimers into monomers, rendering them highly susceptible to spontaneous unfolding and loss of enzymatic activity. Here, we show that binding of an LPL-specific monoclonal antibody (5D2) to the tryptophan-rich lipid-binding loop in the carboxyl terminus of LPL prevents homodimer formation and forces LPL into a monomeric state. Of note, 5D2-bound LPL monomers are as stable as LPL homodimers (i.e., they are not more prone to unfolding), but they remain highly susceptible to ANGPTL4-catalyzed unfolding and inactivation. Binding of GPIHBP1 to LPL alone or to 5D2-bound LPL counteracts ANGPTL4-mediated unfolding of LPL. In conclusion, ANGPTL4-mediated inactivation of LPL, accomplished by catalyzing the unfolding of LPL, does not require the conversion of LPL homodimers into monomers. Thus, our findings necessitate changes to long-standing dogma on mechanisms for LPL inactivation by ANGPTL proteins. At the same time, our findings align well with insights into LPL function from the recent crystal structure of the LPL•GPIHBP1 complex.
20.	Mörbe, Urs M, et al. (författare) Human gut-associated lymphoid tissues (GALT); diversity, structure, and function 2021 Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. Forskningsöversikt (refereegranskat)abstract Gut-associated lymphoid tissues (GALT) are the key antigen sampling and adaptive immune inductive sites within the intestinal wall. Human GALT includes the multi-follicular Peyer's patches of the ileum, the vermiform appendix, and the numerous isolated lymphoid follicles (ILF) which are distributed along the length of the intestine. Our current understanding of GALT diversity and function derives primarily from studies in mice, and the relevance of many of these findings to human GALT remains unclear. Here we review our current understanding of human GALT diversity, structure, and composition as well as their potential for regulating intestinal immune responses during homeostasis and inflammatory bowel disease (IBD). Finally, we outline some key remaining questions regarding human GALT, the answers to which will advance our understanding of intestinal immune responses and provide potential opportunities to improve the treatment of intestinal diseases.
21.	Nepper-Christensen, Lars, et al. (författare) Clinical outcome following late reperfusion with percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction 2021 Ingår i: European Heart Journal: Acute Cardiovascular Care. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 10:5, s. 523-531 Tidskriftsartikel (refereegranskat)abstract Background: Up to 40% of patients with ST-segment elevation myocardial infarction (STEMI) present later than 12 hours after symptom onset. However, data on clinical outcomes in STEMI patients treated with primary percutaneous coronary intervention (PCI) ≥12 hours after symptom onset are non-existent. We evaluated the association between primary PCI performed later than 12 hours after symptom onset and clinical outcomes in a large all-comer contemporary STEMI cohort. Methods: All STEMI patients treated with primary PCI in eastern Denmark from November 2009 to November 2016 were included and stratified by timing of the PCI. The combined clinical endpoint of all-cause mortality and hospitalisation for heart failure was identified from nationwide Danish registries. Results: We included 6674 patients: 6108 (92%) were treated <12 hours and 566 (8%) were treated ≥12 hours after symptom onset. During a median follow-up period of 3.8 (interquartile range 2.3-5.6) years, 30-day, one-year and long-term cumulative rates of the combined endpoint were 11%, 17% and 25% in patients treated <12 hours and 21%, 29% and 37% in patients treated ≥12 hours after symptom onset (P > 0.001 for all). Late presentation was independently associated with an increased risk of an adverse clinical outcome (hazard ratio 1.42, 95% confidence interval 1.22-1.66; P < 0.001). Conclusions: Increasing duration from symptom onset to primary PCI was associated with an increased risk of an adverse clinical outcome in patients with STEMI, especially when the delay exceeded 12 hours.
22.	Pasquier, Coralie, et al. (författare) Anisotropic protein-protein interactions in dilute and concentrated solutions 2023 Ingår i: Journal of Colloid and Interface Science. - : Elsevier BV. - 0021-9797. ; 629, s. 794-804 Tidskriftsartikel (refereegranskat)abstract Interactions between biomolecules are ubiquitous in nature and crucial to many applications including vaccine development; environmentally friendly textile detergents; and food formulation. Using small angle X-ray scattering and structure-based molecular simulations, we explore protein–protein interactions in dilute to semi-concentrated protein solutions. We address the pertinent question, whether interaction models developed at infinite dilution can be extrapolated to concentrated regimes? Our analysis is based on measured and simulated osmotic second virial coefficients and solution structure factors at varying protein concentration and for different variants of the protein Thermomyces Lanuginosus Lipase (TLL). We show that in order to span the dilute and semi-concentrated regime, any model must carefully capture the balance between spatial and orientational correlations as the protein concentration is elevated. This requires consideration of the protein surface morphology, including possible patch interactions. Experimental data for TLL is most accurately described when assuming a patchy interaction, leading to dimer formation. Our analysis supports that the dimeric proteins predominantly exist in their open conformation where the active site is exposed, thereby maximising hydrophobic attractions that promote inter-protein alignment.
23.	Sabbah, Muhammad, et al. (författare) Routine revascularization with percutaneous coronary intervention in patients with coronary artery disease undergoing transcatheter aortic valve implantation - the third Nordic Aortic Valve Intervention Trial - NOTION-3. 2022 Ingår i: American heart journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. Tidskriftsartikel (refereegranskat)abstract Coronary artery disease (CAD) frequently coexists with severe aortic valve stenosis (AS) in patients planned for transcatheter aortic valve implantation (TAVI). How to manage CAD in this patient population is still an unresolved question. In particular, it is still not known whether fractional flow reserve (FFR) guided revascularization with percutaneous coronary intervention (PCI) is superior to medical treatment for CAD in terms of clinical outcomes.The third Nordic Aortic Valve Intervention (NOTION-3) Trial is an open-label investigator-initiated, multicenter multinational trial planned to randomize 452 patients with severe AS and significant CAD to either FFR-guided PCI or medical treatment, in addition to TAVI. Patients are eligible for the study in the presence of at least one significant PCI-eligible coronary stenosis. A significant stenosis is defined as either FFR ≤0.80 and/or diameter stenosis >90%. The primary endpoint is a composite of first occurring all-cause mortality, myocardial infarction, or urgent revascularization (PCI or coronary artery bypass graft performed during unplanned hospital admission) until the last included patient have been followed for 1 year after the TAVI.NOTION-3 is a multicenter, multinational randomized trial aiming at comparing FFR-guided revascularization vs medical treatment of CAD in patients with severe AS planned for TAVI.
24.	Sabbah, Muhammad, et al. (författare) Routine revascularization with percutaneous coronary intervention in patients with coronary artery disease undergoing transcatheter aortic valve implantation – the third nordic aortic valve intervention trial – NOTION-3 2023 Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 255, s. 39-51 Tidskriftsartikel (refereegranskat)abstract Background: Coronary artery disease (CAD) frequently coexists with severe aortic valve stenosis (AS) in patients planned for transcatheter aortic valve implantation (TAVI). How to manage CAD in this patient population is still an unresolved question. In particular, it is still not known whether fractional flow reserve (FFR) guided revascularization with percutaneous coronary intervention (PCI) is superior to medical treatment for CAD in terms of clinical outcomes. Study design: The third Nordic Aortic Valve Intervention (NOTION-3) Trial is an open-label investigator-initiated, multicenter multinational trial planned to randomize 452 patients with severe AS and significant CAD to either FFR-guided PCI or medical treatment, in addition to TAVI. Patients are eligible for the study in the presence of at least 1 significant PCI-eligible coronary stenosis. A significant stenosis is defined as either FFR ≤0.80 and/or diameter stenosis >90%. The primary end point is a composite of first occurring all-cause mortality, myocardial infarction, or urgent revascularization (PCI or coronary artery bypass graft performed during unplanned hospital admission) until the last included patient have been followed for 1 year after the TAVI. NOTION-3 is a multicenter, multinational randomized trial aiming at comparing FFR-guided revascularization vs medical treatment of CAD in patients with severe AS planned for TAVI.
25.	Sahin, Cagla, et al. (författare) Structural Basis for Dityrosine-Mediated Inhibition of Î±-Synuclein Fibrillization 2022 Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 144:27, s. 11949-11954 Tidskriftsartikel (refereegranskat)abstract Î±-Synuclein (Î±-Syn) is an intrinsically disordered protein which self-assembles into highly organized Î²-sheet structures that accumulate in plaques in brains of Parkinsonâ€™s disease patients. Oxidative stress influences Î±-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric Î±-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the Î±-Syn monomer by a factor of âˆš2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation.
26.	Søgaard Jørgensen, Peter, et al. (författare) Evolution of the polycrisis : Anthropocene traps that challenge global sustainability 2023 Ingår i: Philosophical Transactions of the Royal Society of London. Biological Sciences. - 0962-8436 .- 1471-2970. ; 379:1893 Tidskriftsartikel (refereegranskat)abstract The Anthropocene is characterized by accelerating change and global challenges of increasing complexity. Inspired by what some have called a polycrisis, we explore whether the human trajectory of increasing complexity and influence on the Earth system could become a form of trap for humanity. Based on an adaptation of the evolutionary traps concept to a global human context, we present results from a participatory mapping. We identify 14 traps and categorize them as either global, technology or structural traps. An assessment reveals that 12 traps (86%) could be in an advanced phase of trapping with high risk of hard-to-reverse lock-ins and growing risks of negative impacts on human well-being. Ten traps (71%) currently see growing trends in their indicators. Revealing the systemic nature of the polycrisis, we assess that Anthropocene traps often interact reinforcingly (45% of pairwise interactions), and rarely in a dampening fashion (3%). We end by discussing capacities that will be important for navigating these systemic challenges in pursuit of global sustainability. Doing so, we introduce evolvability as a unifying concept for such research between the sustainability and evolutionary sciences.
27.	Wang, Mengwei, et al. (författare) Different or the same? exploring the physicochemical properties and molecular mobility of celecoxib amorphous forms 2024 Ingår i: International Journal of Pharmaceutics. - 0378-5173. ; 661 Tidskriftsartikel (refereegranskat)abstract The influence of different preparation methods on the physicochemical properties of amorphous solid forms have gained considerable attention, especially with recent publications on pharmaceutical polyamorphism. In the present study, we have investigated the possible occurrence of polyamorphism in the drug celecoxib (CEL) by investigating the thermal behavior, morphology, structure, molecular mobility and physical stability of amorphous CEL obtained by quench-cooling (QC), ball milling (BM) and spray drying (SD). Similar glass transition temperatures but different recrystallization behaviors were observed for CEL-QC, CEL-BM and CEL-SD using modulated differential scanning calorimetry analysis. A correlation between the different recrystallization behaviors of the three CEL amorphous forms and the respective distinct powder morphologies, was also found. Molecular dynamics simulations however, reveal that CEL presents similar molecular conformational distributions when subjected to QC and SD. Moreover, the obtained molecular conformational distributions of CEL are different from the ones found in its crystal structure and also from the ones found in the lowest-energy structure obtained by quantum mechanical calculations. The type and strength of CEL hydrogen bond interactions found in CEL-QC and CEL-SD systems are almost identical, though different from the ones presented in the crystal structure. Pair distribution function analyses and isothermal microcalorimetry show similar local structures and structural relaxation times, respectively, for CEL-QC, CEL-BM and CEL-SD. The present work shows that not only similar physicochemical properties (glass transition temperature, and structural relaxation time), but also similar molecular conformational distributions were observed for all prepared CEL amorphous systems. Hence, despite their different recrystallization behaviors, the three amorphous forms of CEL did not show any signs of polyamorphism.

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