| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Landén, Mikael, 1966, et al.
(författare)
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Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 5124-5139
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Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18–75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen’s d = 0.14, 95% CI: 0.08–0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates. © 2020, The Author(s).
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| 7. |
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| 8. |
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| 9. |
- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 10. |
- Aoyama, T., et al.
(författare)
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The anomalous magnetic moment of the muon in the Standard Model
- 2020
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Ingår i: Physics reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 887, s. 1-166
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Forskningsöversikt (refereegranskat)abstract
- We review the present status of the Standard Model calculation of the anomalous magnetic moment of the muon. This is performed in a perturbative expansion in the fine-structure constant α and is broken down into pure QED, electroweak, and hadronic contributions. The pure QED contribution is by far the largest and has been evaluated up to and including O(α5) with negligible numerical uncertainty. The electroweak contribution is suppressed by (mμ/MW)2 and only shows up at the level of the seventh significant digit. It has been evaluated up to two loops and is known to better than one percent. Hadronic contributions are the most difficult to calculate and are responsible for almost all of the theoretical uncertainty. The leading hadronic contribution appears at O(α2) and is due to hadronic vacuum polarization, whereas at O(α3) the hadronic light-by-light scattering contribution appears. Given the low characteristic scale of this observable, these contributions have to be calculated with nonperturbative methods, in particular, dispersion relations and the lattice approach to QCD. The largest part of this review is dedicated to a detailed account of recent efforts to improve the calculation of these two contributions with either a data-driven, dispersive approach, or a first-principle, lattice-QCD approach. The final result reads aμSM = 116 591 810(43) x 10-11 and is smaller than the Brookhaven measurement by 3.7 σ. The experimental uncertainty will soon be reduced by up to a factor four by the new experiment currently running at Fermilab, and also by the future J-PARC experiment. This and the prospects to further reduce the theoretical uncertainty in the near future - which are also discussed here - make this quantity one of the most promising places to look for evidence of new physics.
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| 11. |
- Ge, R, et al.
(författare)
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Normative Modeling of Brain Morphometry Across the Lifespan Using CentileBrain: Algorithm Benchmarking and Model Optimization
- 2023
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Ingår i: bioRxiv : the preprint server for biology. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Normative modeling is a statistical approach to quantify the degree to which a particular individual-level measure deviates from the pattern observed in a normative reference population. When applied to human brain morphometric measures it has the potential to inform about the significance of normative deviations for health and disease. Normative models can be implemented using a variety of algorithms that have not been systematically appraised. Methods: To address this gap, eight algorithms were compared in terms of performance and computational efficiency using brain regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) collated from 87 international MRI datasets. Performance was assessed with the mean absolute error (MAE) and computational efficiency was inferred from central processing unit (CPU) time. The algorithms evaluated were Ordinary Least Squares Regression (OLSR), Bayesian Linear Regression (BLR), Generalized Additive Models for Location, Scale, and Shape (GAMLSS), Parametric Lambda, Mu, Sigma (LMS), Gaussian Process Regression (GPR), Warped Bayesian Linear Regression (WBLG), Hierarchical Bayesian Regression (HBR), and Multivariable Fractional Polynomial Regression (MFPR). Model optimization involved testing nine covariate combinations pertaining to acquisition features, parcellation software versions, and global neuroimaging measures (i.e., total intracranial volume, mean cortical thickness, and mean cortical surface area). Findings: Statistical comparisons across models at PFDR<0.05 indicated that the MFPR-derived sex- and region-specific models with nonlinear polynomials for age and linear effects of global measures had superior predictive accuracy; the range of the MAE of the models of regional subcortical volumes was 70-520 mm3 and the corresponding ranges for regional cortical thickness and regional cortical surface area were 0.09-0.26 mm and 24-560 mm2, respectively. The MFPR-derived models were also computationally more efficient with a CPU time below one second compared to a range of 2 seconds to 60 minutes for the other algorithms. The performance of all sex- and region-specific MFPR models plateaued at sample sizes exceeding 3,000 and showed comparable MAEs across distinct 10-year age-bins covering the human lifespan. Interpretation: These results provide an empirically benchmarked framework for normative modeling of brain morphometry that is useful for interpreting prior literature and supporting future study designs. The model and tools described here are freely available through CentileBrain (https://centilebrain.org/), a user-friendly web platform.
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| 12. |
- Shao, Z., et al.
(författare)
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Cytochrome P450 2C8 omega 3-Long-Chain Polyunsaturated Fatty Acid Metabolites Increase Mouse Retinal Pathologic Neovascularization-Brief Report
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 34:3, s. 581-586
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Tidskriftsartikel (refereegranskat)abstract
- Objective Regulation of angiogenesis is critical for many diseases. Specifically, pathological retinal neovascularization, a major cause of blindness, is suppressed with dietary 3-long-chain polyunsaturated fatty acids (3LCPUFAs) through antiangiogenic metabolites of cyclooxygenase and lipoxygenase. Cytochrome P450 epoxygenases (CYP2C8) also metabolize LCPUFAs, producing bioactive epoxides, which are inactivated by soluble epoxide hydrolase (sEH) to transdihydrodiols. The effect of these enzymes and their metabolites on neovascularization is unknown. Approach and Results The mouse model of oxygen-induced retinopathy was used to investigate retinal neovascularization. We found that CYP2C (localized in wild-type monocytes/macrophages) is upregulated in oxygen-induced retinopathy, whereas sEH is suppressed, resulting in an increased retinal epoxide:diol ratio. With a 3LCPUFA-enriched diet, retinal neovascularization increases in Tie2-driven human-CYP2C8-overexpressing mice (Tie2-CYP2C8-Tg), associated with increased plasma 19,20-epoxydocosapentaenoic acid and retinal epoxide:diol ratio. 19,20-Epoxydocosapentaenoic acids and the epoxide:diol ratio are decreased with overexpression of sEH (Tie2-sEH-Tg). Overexpression of CYP2C8 or sEH in mice does not change normal retinal vascular development compared with their wild-type littermate controls. The proangiogenic role in retina of CYP2C8 with both 3LCPUFA and 6LCPUFA and antiangiogenic role of sEH in 3LCPUFA metabolism were corroborated in aortic ring assays. Conclusions Our results suggest that CYP2C 3LCPUFA metabolites promote retinal pathological angiogenesis. CYP2C8 is part of a novel lipid metabolic pathway influencing retinal neovascularization.
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| 13. |
- Thompson, PM, et al.
(författare)
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ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries
- 2020
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1, s. 100-
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Tidskriftsartikel (refereegranskat)abstract
- This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
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| 14. |
- Wierenga, Lara M., et al.
(författare)
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Greater male than female variability in regional brain structure across the lifespan
- 2022
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Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 470-499
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Tidskriftsartikel (refereegranskat)abstract
- For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
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| 15. |
- Dima, Danai, et al.
(författare)
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Subcortical volumes across the lifespan : Data from 18,605 healthy individuals aged 3-90 years.
- 2022
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Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 43:1, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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| 16. |
- Frangou, Sophia, et al.
(författare)
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Cortical thickness across the lifespan : Data from 17,075 healthy individuals aged 3-90 years
- 2022
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Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 431-451
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Tidskriftsartikel (refereegranskat)abstract
- Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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| 17. |
- Ring, A., et al.
(författare)
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Bridging The Age Gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer
- 2021
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 125, s. 209-219
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. Methods: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. Results: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19–0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20–0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08–0.49];BCSS: HR 0.12 [95% CI 0.03–0.44]).Transient negative quality-of-life impacts were observed. Conclusions: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. Trial Registration: ISRCTN 46099296. © 2021, The Author(s).
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| 18. |
- Chen, J., et al.
(författare)
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Propranolol inhibition of beta-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy
- 2012
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404. ; 53:6, s. 2968-77
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective beta-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects. METHODS: Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups. RESULTS: None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor. CONCLUSIONS: Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of beta-adrenergic receptors is an appropriate therapeutic approach for treating ROP.
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| 19. |
- Wilkins, S. B., et al.
(författare)
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Resonant soft x-ray scattering investigation of orbital and magnetic ordering in La0.5Sr1.5MnO4
- 2005
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 71:24, s. 245102-
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Tidskriftsartikel (refereegranskat)abstract
- We report resonant x-ray scattering data of the orbital and magnetic ordering at low temperatures at the Mn L-2,L-3 edges in La0.5Sr1.5MnO4. The orderings display complex energy features close to the Mn absorption edges. Systematic modeling with atomic multiplet crystal field calculations was used to extract meaningful information regarding the interplay of spin, orbital, and Jahn-Teller order. These calculations provide a good general agreement with the observed energy dependence of the scattered intensity for a dominant orbital ordering of the d(x)(2)-z(2)/d(y)(2)-z(2) type. In addition, the origins of various spectral features are identified. The temperature dependence of the orbital and magnetic ordering was measured and suggests a strong interplay between the magnetic and orbital order parameters.
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| 20. |
- Barretina, Jordi, et al.
(författare)
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Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:8, s. 715-21
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Tidskriftsartikel (refereegranskat)abstract
- Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.
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| 21. |
- Battisti, N. M. L., et al.
(författare)
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Observational cohort study in older women with early breast cancer: Use of radiation therapy and impact on health-related quality of life and mortality
- 2021
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140. ; 161, s. 166-176
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Tidskriftsartikel (refereegranskat)abstract
- Background: Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL). Methods: A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires. Results: In 2013–2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months. Conclusion: Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient. © 2021 Elsevier B.V.
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| 22. |
- Burdett, Heidi L., et al.
(författare)
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Coralline algae as a globally significant pool of marine dimethylated sulfur
- 2015
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Ingår i: Global Biogeochemical Cycles. - : Blackwell Publishing. - 0886-6236 .- 1944-9224. ; 29:10, s. 1845-1853
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Tidskriftsartikel (refereegranskat)abstract
- Marine algae are key sources of the biogenic sulfur compound dimethylsulphoniopropionate (DMSP), a vital component of the marine sulfur cycle. Autotrophic ecosystem engineers such as red coralline algae support highly diverse and biogeochemically active ecosystems and are known to be high DMSP producers, but their importance in the global marine sulfur cycle has not yet been appreciated. Using a global sampling approach, we show that red coralline algae are a globally significant pool of DMSP in the oceans, estimated to be similar to 110x10(12) moles worldwide during the summer months. Latitude was a major driver of observed regional-scale variations, with peaks in polar and tropical climate regimes, reflecting the varied cellular functions for DMSP (e.g., as a cryoprotectant and antioxidant). A temperate coralline algal bed was investigated in more detail to also identify local-scale temporal variations. Here, water column DMSP was driven by water temperature, and to a lesser extent, cloud cover; two factors which are also vital in controlling coralline algal growth. This study demonstrates that coralline algae harbor a large pool of dimethylated sulfur, thereby playing a significant role in both the sulfur and carbon marine biogeochemical cycles. However, coralline algal habitats are severely threatened by projected climate change; a loss of this habitat may thus detrimentally impact oceanic sulfur and carbon biogeochemical cycling.
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| 23. |
- Burdett, Heidi L., et al.
(författare)
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Dynamic photoinhibition exhibited by red coralline algae in the red sea
- 2014
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Ingår i: BMC Plant Biology. - : BioMed Central. - 1471-2229. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Red coralline algae are critical components of tropical reef systems, and their success and development is, at least in part, dependent on photosynthesis. However, natural variability in the photosynthetic characteristics of red coralline algae is poorly understood. This study investigated diurnal variability in encrusting Porolithon sp. and free-living Lithophyllum kotschyanum. Measured parameters included: photosynthetic characteristics, pigment composition, thallus reflectance and intracellular concentrations of dimethylsulphoniopropionate (DMSP), an algal antioxidant that is derived from methionine, an indirect product of photosynthesis. L. kotschyanum thalli were characterised by a bleached topside and a pigmented underside.Results: Minimum saturation intensity and intracellular DMSP concentrations in Porolithon sp. were characterised by significant diurnal patterns in response to the high-light regime. A smaller diurnal pattern in minimum saturation intensity in the topside of L. kotschyanum was also evident. The overall reflectance of the topside of L. kotschyanum also exhibited a diurnal pattern, becoming increasingly reflective with increasing ambient irradiance. The underside of L. kotschyanum, which is shaded from ambient light exposure, exhibited a much smaller diurnal variability.Conclusions: This study highlights a number of dynamic photoinhibition strategies adopted by coralline algae, enabling them to tolerate, rather than be inhibited by, the naturally high irradiance of tropical reef systems; a factor that may become more important in the future under global change projections. In this context, this research has significant implications for tropical reef management planning and conservation monitoring, which, if natural variability is not taken into account, may become flawed. The information provided by this research may be used to inform future investigations into the contribution of coralline algae to reef accretion, ecosystem service provision and palaeoenvironmental reconstruction.
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| 24. |
- Burdett, Heidi L., et al.
(författare)
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Effects of reduced salinity on the photosynthetic characteristics and intracellular DMSP concentrations of the red coralline alga, Lithothamnion glaciale
- 2015
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Ingår i: Marine Biology. - : Springer. - 0025-3162 .- 1432-1793. ; 162:5, s. 1077-1085
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Tidskriftsartikel (refereegranskat)abstract
- Mid- to high-latitude fjordic coastal environments experience naturally variable salinity regimes. Climate projections suggest that freshwater input into the coastal ocean will increase in the future, exposing coastal organisms to further periods of reduced salinity. This study investigated the effect of low salinity on Lithothamnion glaciale, a red coralline alga found in mid- to high-latitude fjordic regions, during a 21-day experiment. Specific measurements included: the intracellular concentration of dimethylsulphoniopropionate (DMSP, an algal secondary metabolite and major precursor to the climatically active gas dimethylsulphide), pigment composition and photosynthetic characteristics. No significant difference in intracellular DMSP concentrations was observed between treatments, suggesting that the primary function for DMSP in L. glaciale is not as a compatible solute, perhaps favouring an antioxidant role . Photosynthetic parameters (including pigment composition) exhibited a mixed response, suggesting some degree of photosynthetic resilience to reduced salinity. This study provides evidence of intracellular mechanisms adopted by L. glaciale in response to reduced salinity. This has significant implications for the survival of L. glaciale under a projected freshening scenario and provides organism-level detail to ecosystem-level projected changes should lower-salinity conditions become more frequent and more intense in the future.
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| 25. |
- Burdett, Heidi L., et al.
(författare)
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Spatiotemporal Variability of Dimethylsulphoniopropionate on a Fringing Coral Reef : The Role of Reefal Carbonate Chemistry and Environmental Variability
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Oceanic pH is projected to decrease by up to 0.5 units by 2100 (a process known as ocean acidification, OA), reducing the calcium carbonate saturation state of the oceans. The coastal ocean is expected to experience periods of even lower carbonate saturation state because of the inherent natural variability of coastal habitats. Thus, in order to accurately project the impact of OA on the coastal ocean, we must first understand its natural variability. The production of dimethylsulphoniopropionate (DMSP) by marine algae and the release of DMSP's breakdown product dimethylsulphide (DMS) are often related to environmental stress. This study investigated the spatiotemporal response of tropical macroalgae (Padina sp., Amphiroa sp. and Turbinaria sp.) and the overlying water column to natural changes in reefal carbonate chemistry. We compared macroalgal intracellular DMSP and water column DMSP+DMS concentrations between the environmentally stable reef crest and environmentally variable reef flat of the fringing Suleman Reef, Egypt, over 45-hour sampling periods. Similar diel patterns were observed throughout: maximum intracellular DMSP and water column DMS/P concentrations were observed at night, coinciding with the time of lowest carbonate saturation state. Spatially, water column DMS/P concentrations were highest over areas dominated by seagrass and macroalgae (dissolved DMS/P) and phytoplankton (particulate DMS/P) rather than corals. This research suggests that macroalgae may use DMSP to maintain metabolic function during periods of low carbonate saturation state. In the reef system, seagrass and macroalgae may be more important benthic producers of dissolved DMS/P than corals. An increase in DMS/P concentrations during periods of low carbonate saturation state may become ecologically important in the future under an OA regime, impacting larval settlement and increasing atmospheric emissions of DMS.
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| 26. |
- Burdett, Heidi L., et al.
(författare)
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The effect of chronic and acute low pH on the intracellular DMSP production and epithelial cell morphology of red coralline algae
- 2012
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Ingår i: Marine Biology Research. - : Taylor & Francis. - 1745-1000 .- 1745-1019. ; 8:8, s. 756-763
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Tidskriftsartikel (refereegranskat)abstract
- The release of dimethylsulphoniopropionate (DMSP) by marine algae has major impacts on the global sulphur cycle and may influence local climate through the formation of dimethylsulphide (DMS). However, the effect of global change on DMSP/DMS (DMS(P)) production by algae is not well understood. This study examined the effect of low pH on DMS(P) production and epithelial cell morphology of the free-living red coralline alga Lithothamnion glaciale. Three pH treatments were used in the 80-day experiment: (1) current pH level (8.18, control), (2) low, chronic pH representing a 2100 ocean acidification (OA) scenario (7.70) and (3) low, acute pH (7.75, with a 3-day spike to 6.47), representing acute variable conditions that might be associated with leaks from carbon capture and storage infrastructure, at CO2 vent sites or in areas of upwelling. DMS(P) production was not significantly enhanced under low, stable pH conditions, indicating that red coralline algae may have some resilience to OA. However, intracellular and water column DMS(P) concentrations were significantly higher than the control when pH was acutely spiked. Cracks were observed between the cell walls of the algal skeleton in both low pH treatments. It is proposed that this structural change may cause membrane damage that allows DMS(P) to leak from the cells into the water column, with subsequent implications for the cycling of DMS(P) in coralline algae habitats.
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| 27. |
- Cederlund, Rio, 1971-
(författare)
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Social anxiety disorder in children and adolescents : assessment, maintaining factors, and treatment
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present dissertation consists of three empirical studies on social anxiety disorder (SAD) in a sample of Swedish children and adolescents. Based on findings made in a large behavior treatment study, the thesis contributes to the field of research on childhood SAD by investigating a factor that maintains the disorder, ways to measure and screen for diagnosis, and the treatment of the disorder. Study I investigated whether giving an educational course to the parents of socially anxious children would lead to a better outcome of a behavior-treatment study consisting of individual and group treatment components such as exposure in-vivo and social skills training, compared to a condition where only children were treated and the parents received no educational course. Another purpose of Study I was to investigate what influence, if any, co-morbidity has on treatment outcome. The results showed that there was no significant difference between the two treatment groups on any of the primary or secondary outcome measures. Further, the comorbid disorders did not impair the SAD treatment but was rather associated with further improvement, and despite the sole focus on SAD, there was significant improvement in the comorbid disorders. Study II tested the psychometric properties of the Social Phobia and Anxiety Inventory for Children in a sample of children with SAD. The results indicated that the instrument is a both valid and reliable measure. Further, a three-factor solution represented the three areas of SAD commonly found in adult studies, i.e. fear of performance, observation, and interaction situations. Study III explored threat perception and interpretation bias by means of an ambiguous stories task. The results showed that children with SAD deviated significantly from a non-anxious control peer group with regard to their interpretations. Post treatment the threat perception bias was altered in a normal direction, and one year after treatment termination, the SAD sample ratings were comparable to those of the non-anxious children.
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| 28. |
- Eisenhut, P., et al.
(författare)
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Systematic use of synthetic 5'-UTR RNA structures to tune protein translation improves yield and quality of complex proteins in mammalian cell factories
- 2020
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 48:20
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Tidskriftsartikel (refereegranskat)abstract
- Predictably regulating protein expression levels to improve recombinant protein production has become an important tool, but is still rarely applied to engineer mammalian cells. We therefore sought to set-up an easy-to-implement toolbox to facilitate fast and reliable regulation of protein expression in mammalian cells by introducing defined RNA hairpins, termed 'regulation elements (RgE)', in the 5'-untranslated region (UTR) to impact translation efficiency. RgEs varying in thermodynamic stability, GC-content and position were added to the 5'-UTR of a fluorescent reporter gene. Predictable translation dosage over two orders of magnitude in mammalian cell lines of hamster and human origin was confirmed by flow cytometry. Tuning heavy chain expression of an IgG with the RgEs to various levels eventually resulted in up to 3.5-fold increased titers and fewer IgG aggregates and fragments in CHO cells. Co-expression of a therapeutic Arylsulfatase-A with RgE-tuned levels of the required helper factor SUMF1 demonstrated that the maximum specific sulfatase activity was already attained at lower SUMF1 expression levels, while specific production rates steadily decreased with increasing helper expression. In summary, we show that defined 5'-UTR RNA-structures represent a valid tool to systematically tune protein expression levels in mammalian cells and eventually help to optimize recombinant protein expression.
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| 29. |
- Hatton, Fiona L., et al.
(författare)
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Grafting-from cellulose nanocrystals via photoinduced Cu-mediated reversible-deactivation radical polymerization
- 2017
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Ingår i: Carbohydrate Polymers. - : Elsevier. - 0144-8617 .- 1879-1344. ; 157, s. 1033-1040
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Tidskriftsartikel (refereegranskat)abstract
- In this work we describe the grafting of cellulose nanocrystals (CNCs) by surface-initiated photoinduced Cu-mediated reversible-deactivation radical polymerization (RDRP). Initially, CNCs obtained through sulfuric acid hydrolysis were functionalized with a tertiary bromo-ester moiety as an initiating group for the subsequent RDRP of methyl acrylate, targeting three different degrees of polymerization for the polymer grafts: 50, 300 and 600. The polymerizations proceeded in DMSO in the presence of CuBr2 and Me6TREN as the catalytic system utilizing a UV source (λmax ≈ 360 nm). The technique proved highly versatile for the modification of CNCs with poly(methyl acrylate), where considerably high grafting was achieved in short reaction times (90 min), with simple purification steps. CNC morphology was maintained and polymer grafts were evident through FT-IR spectroscopy, thermal analysis, contact angle measurements, X-ray photoelectron microscopy and x-ray diffraction.
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| 30. |
- Holmes, G. R., et al.
(författare)
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Cost-Effectiveness Modeling of Surgery Plus Adjuvant Endocrine Therapy Versus Primary Endocrine Therapy Alone in UK Women Aged 70 and Over With Early Breast Cancer
- 2021
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Ingår i: Value in Health. - : Elsevier BV. - 1098-3015. ; 24:6, s. 770-779
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Approximately 20% of UK women aged 70+ with early breast cancer receive primary endocrine therapy (PET) instead of surgery. PET reduces surgical morbidity but with some survival decrement. To complement and utilize a treatment dependent prognostic model, we investigated the cost-effectiveness of surgery plus adjuvant therapies versus PET for women with varying health and fitness, identifying subgroups for which each treatment is cost-effective. Methods: Survival outcomes from a statistical model, and published data on recurrence, were combined with data from a large, multicenter, prospective cohort study of over 3400 UK women aged 70+ with early breast cancer and median 52-month follow-up, to populate a probabilistic economic model. This model evaluated the cost-effectiveness of surgery plus adjuvant therapies relative to PET for 24 illustrative subgroups: Age {70, 80, 90} × Nodal status {FALSE (F), TRUE (T)} × Comorbidity score {0, 1, 2, 3+}. Results: For a 70-year-old with no lymph node involvement and no comorbidities (70, F, 0), surgery plus adjuvant therapies was cheaper and more effective than PET. For other subgroups, surgery plus adjuvant therapies was more effective but more expensive. Surgery plus adjuvant therapies was not cost-effective for 4 of the 24 subgroups: (90, F, 2), (90, F, 3), (90, T, 2), (90, T, 3). Conclusion: From a UK perspective, surgery plus adjuvant therapies is clinically effective and cost-effective for most women aged 70+ with early breast cancer. Cost-effectiveness reduces with age and comorbidities, and for women over 90 with multiple comorbidities, there is little cost benefit and a negative impact on quality of life. © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research
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| 31. |
- Kamenos, Nicholas A., et al.
(författare)
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Red coralline algae as a source of marine biogenic dimethylsulphoniopropionate
- 2008
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Ingår i: Marine Ecology Progress Series. - : Inter-Research. - 0171-8630 .- 1616-1599. ; 372, s. 61-66
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Tidskriftsartikel (refereegranskat)abstract
- The biogenic gas dimethylsulphide (DMS), derived from dimethylsulphoniopropionate (DMSP), plays an important role in the Earth's albedo, and thus climate regulation, through the formation of aerosols and cloud condensation nuclei. It is estimated that biogenic sources of DMS contribute 42% (mean) of the atmospheric sulphur burden and, significantly, > 90% of that contribution is derived from marine sources. Phytoplankton, macroalgae and corals are thought to be the main producers of marine biogenic DMSP. Red coralline algae (known as maerl or rhodoliths) cover extensive areas of seabed, yet despite their widespread global distribution, maerl-forming coralline algae have received little or no attention regarding their DMSP productivity. In the present study we report for the first time the occurrence of DMSP in 2 species of maerl. DMSP concentrations were found to average 1914 nmol g(-1) for soft tissue and estimated to be 637 mu mol m(-2) for maerl beds. In incubation experiments, maerl led to a dissolved DMSP (DMSPd) increase at a rate of 57.4 to 767.6 nmol m(-2) d(-1) in surrounding seawater, indicating that maerl contributes to DMSPd concentrations in the adjacent water column. Results show that maerl beds are a previously undiscovered source of DMSP in the marine environment. Further study is warranted to assess the significance of maerl as a source of DMSP and the role coralline algae may play in the biogenic sulphur cycle.
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| 32. |
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| 33. |
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| 34. |
- Moeser, G D, et al.
(författare)
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Structure of polymer-stabilized magnetic fluids: Small-angle neutron scattering and mean-field lattice modeling
- 2004
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 20:13, s. 5223-5234
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Tidskriftsartikel (refereegranskat)abstract
- Small-angle neutron scattering and mean-field lattice modeling were used to characterize a class of water-based magnetic fluids tailored specifically to extract soluble organic compounds from water. The fluids consist of a suspension of similar to7 nm magnetite (Fe3O4) nanoparticles coated with a bifunctional polymer layer comprised of an outer hydrophilic poly(ethylene oxide) (PEO) region for colloidal stability and an inner hydrophobic poly(propylene oxide) (PPO) region for solubilization of organic compounds. The inner region of the polymer shell is increasingly depleted of water as the fraction of PPO side chains increases. The incorporation of PPO side chains also leads to a small increase in interparticle attraction. The lattice model predicted a shell structure similar to that of a PEO-PPO-PEO triblock copolymer (Pluronic) micelle, with equivalent levels of hydration but with more PEO present in the PPO-rich regions, as the side chains grafted to the surface are less able to segregate than when in free micellar systems.
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| 35. |
- Sayer, Carl D., et al.
(författare)
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The application of palaeolimnology to evidence-based lake management and conservation: examples from UK lakes
- 2012
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Ingår i: Aquatic conservation. - : John Wiley & Sons, Ltd. - 1052-7613 .- 1099-0755. ; 22:2, s. 165-180
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Tidskriftsartikel (refereegranskat)abstract
- * To help meet the requirements of water legislation, palaeolimnology has been widely used to establish ‘reference conditions’ and restoration targets for lakes. However, its potential for assessing the necessity and appropriateness of different lake management activities has been less publicized. * With reference to selected case studies covering consultancy projects commissioned by UK conservation agencies, this study highlights the important applied role of palaeolimnology. Using varying combinations of diatom, plant macrofossil and cladoceran analysis, the degree, timing and in many cases the likely drivers of ecological change were inferred for several lake sites. * From this basis advice was given on a range of lake management issues, including the need for sediment removal to combat eutrophication and/or the necessity of other nutrient reduction measures (Case study 1), the depth of sediment to be removed to maximize restoration potential through exposure of dormant banks of characean oospores (Case study 2), the requirement for fish management (Case study 3), and advice regarding fish farm expansion and licensing (Case study 4). Where possible management responses to the recommendations are outlined including any major outcomes. * All case studies illustrate the advantages, for lake management and conservation decision-making, of placing current lake ecological conditions in the context of long-term change. Copyright © 2012 John Wiley & Sons, Ltd.
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| 36. |
- Wyld, L., et al.
(författare)
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Bridging the age gap in breast cancer: cluster randomized trial of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices
- 2021
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 108:5, s. 499-510
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice. METHODS: A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice. RESULTS: A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference -0.20, 95 per cent confidence interval (C.I.) -2.69 to 2.29; P=0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P=0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P=0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference -4.5 (C.I. -8.0 to 0) per cent; P=0.013). Survival was similar in both arms. CONCLUSION: The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com). © The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.
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| 37. |
- Wyld, L., et al.
(författare)
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Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life
- 2021
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049. ; 142, s. 48-62
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Tidskriftsartikel (refereegranskat)abstract
- Background: Age-related breast cancer treatment variance is widespread with many older women having primary endocrine therapy (PET), which may contribute to inferior survival and local control. This propensity-matched study determined if a subgroup of older women may safely be offered PET. Methods: Multicentre, prospective, UK, observational cohort study with propensity-matched analysis to determine optimal allocation of surgery plus ET (S+ET) or PET in women aged ≥70 with breast cancer. Data on fitness, frailty, cancer stage, grade, biotype, treatment and quality of life were collected. Propensity-matching (based on age, health status and cancer stage) adjusted for allocation bias when comparing S+ET with PET. Findings: A total of 3416 women (median age 77, range 69–102) were recruited from 56 breast units—2854 (88%) had ER+ breast cancer: 2354 had S+ET and 500 PET. Median follow-up was 52 months. Patients treated with PET were older and frailer than patients treated with S+ET. Unmatched overall survival was inferior in the PET group (hazard ratio, (HR) 0.27, 95% confidence interval (CI) 0.23–0.33, P < 0.001). Unmatched breast cancer–specific survival (BCSS) was also inferior in patients treated with PET (HR: 0.41, CI: 0.29–0.58, P < 0.001 for BCSS). In the matched analysis, PET was still associated with an inferior overall survival (HR = 0.72, 95% CI: 0.53–0.98, P = 0.04) but not BCSS (HR = 0.74, 95% CI: 0.40–1.37, P = 0.34) although at 4–5 years subtle divergence of the curves commenced in favor of surgery. Global health status diverged at certain time points between groups but over 24 months was similar when adjusted for baseline variance. Interpretation: For the majority of older women with early ER+ breast cancer, surgery is oncologically superior to PET. In less fit, older women, with characteristics similar to the matched cohort of this study (median age 81 with higher comorbidity and functional impairment burdens, the BCSS survival differential disappears at least out to 4–5 year follow-up, suggesting that for those with less than 5-year predicted life-expectancy (>90 years or >85 with comorbidities or frailty) individualised decision making regarding PET versus S+ET may be appropriate and safe to offer. The Age Gap online decision tool may support this decision-making process (https://agegap.shef.ac.uk/). Trial registration number: ISRCTN: 46099296. © 2020 The Authors
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| 38. |
- Wyld, L., et al.
(författare)
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Improving outcomes for women aged 70 years or above with early breast cancer: Research programme including a cluster RCT
- 2022
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Ingår i: Programme Grants for Applied Research. - 2050-4322. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: In breast cancer management, age-related practice variation is widespread, with older women having lower rates of surgery and chemotherapy than younger women, based on the premise of reduced treatment tolerance and benefit. This may contribute to inferior outcomes. There are currently no age-and fitness-stratified guidelines on which to base treatment recommendations. Aim: We aimed to optimise treatment choice and outcomes for older women (aged > 70 years) with operable breast cancer. Objectives: Our objectives were to (1) determine the age, comorbidity, frailty, disease stage and biology thresholds for endocrine therapy alone versus surgery plus adjuvant endocrine therapy, or adjuvant chemotherapy versus no chemotherapy, for older women with breast cancer; (2) optimise survival outcomes for older women by improving the quality of treatment decision-making; (3) develop and evaluate a decision support intervention to enhance shared decision-making; and (4) determine the degree and causes of treatment variation between UK breast units. Design: A prospective cohort study was used to determine age and fitness thresholds for treatment allocation. Mixed-methods research was used to determine the information needs of older women to develop a decision support intervention. A cluster-randomised trial was used to evaluate the impact of this decision support intervention on treatment choices and outcomes. Health economic analysis was used to evaluate the cost-benefit ratio of different treatment strategies according to age and fitness criteria. A mixed-methods study was used to determine the degree and causes of variation in treatment allocation. Main outcome measures: The main outcome measures were enhanced age-and fitness-specific decision support leading to improved quality-of-life outcomes in older women (aged > 70 years) with early breast cancer. Results: (1) Cohort study: The study recruited 3416 UK women aged > 70 years (median age 77 years). Follow-up was 52 months. (a) The surgery plus adjuvant endocrine therapy versus endocrine therapy alone comparison: 2854 out of 3416 (88%) women had oestrogen-receptor-positive breast cancer, 2354 of whom received surgery plus adjuvant endocrine therapy and 500 received endocrine therapy alone. Patients treated with endocrine therapy alone were older and frailer than patients treated with surgery plus adjuvant endocrine therapy. Unmatched overall survival and breast-cancer-specific survival were higher in the surgery plus adjuvant endocrine therapy group (overall survival: Hazard ratio 0.27, 95% confidence interval 0.23 to 0.33; p < 0.001; breast-cancer-specific survival: Hazard ratio 0.41, 95% confidence interval 0.29 to 0.58; p < 0.001) than in the endocrine therapy alone group. In matched analysis, surgery plus adjuvant endocrine therapy was still associated with better overall survival (hazard ratio 0.72, 95% confidence interval 0.53 to 0.98; p = 0.04) than endocrine therapy alone, but not with better breast-cancer-specific survival (hazard ratio 0.74, 95% confidence interval 0.40 to 1.37; p = 0.34) or progression-free-survival (hazard ratio 1.11, 95% confidence interval 0.55 to 2.26; p = 0.78). (b) The adjuvant chemotherapy versus no chemotherapy comparison: 2811 out of 3416 (82%) women received surgery plus adjuvant endocrine therapy, of whom 1520 (54%) had high-recurrence-risk breast cancer [grade 3, node positive, oestrogen receptor negative or human epidermal growth factor receptor-2 positive, or a high Oncotype DX® (Genomic Health, Inc., Redwood City, CA, USA) score of > 25]. In this high-risk population, there were no differences according to adjuvant chemotherapy use in overall survival or breast-cancer-specific survival after propensity matching. Adjuvant chemotherapy was associated with a lower risk of metastatic recurrence than no chemotherapy in the unmatched (adjusted hazard ratio 0.36, 95% confidence interval 0.19 to 0.68; p = 0.002) and propensity-matched patients (adjusted hazard ratio 0.43, 95% confidence interval 0.20 to 0.92; p = 0.03). Adjuva t chemotherapy improved the overall survival and breast-cancer-specific survival of patients with oestrogen-receptor-negative disease. (2) Mixed-methods research to develop a decision support intervention: An iterative process was used to develop two decision support interventions (each comprising a brief decision aid, a booklet and an online tool) specifically for older women facing treatment choices (endocrine therapy alone or surgery plus adjuvant endocrine therapy, and adjuvant chemotherapy or no chemotherapy) using several evidence sources (expert opinion, literature and patient interviews). The online tool was based on models developed using registry data from 23,842 patients and validated on an external data set of 14,526 patients. Mortality rates at 2 and 5 years differed by < 1% between predicted and observed values. (3) Cluster-randomised clinical trial of decision support tools: 46 UK breast units were randomised (intervention, n = 21; usual care, n = 25), recruiting 1339 women (intervention, n = 670; usual care, n = 669). There was no significant difference in global quality of life at 6 months post baseline (difference-0.20, 95% confidence interval-2.7 to 2.3; p = 0.90). In women offered a choice of endocrine therapy alone or surgery plus adjuvant endocrine therapy, knowledge about treatments was greater in the intervention arm than the usual care arm (94% vs. 74%; p = 0.003). Treatment choice was altered, with higher rates of endocrine therapy alone than of surgery in the intervention arm. Similarly, chemotherapy rates were lower in the intervention arm (endocrine therapy alone rate: Intervention sites 21% vs. usual-care sites 15%, difference 5.5%, 95% confidence interval 1.1% to 10.0%; p = 0.02; adjuvant chemotherapy rate: Intervention sites 10% vs. usual-care site 15%, difference 4.5%, 95% confidence interval 0.0% to 8.0%; p = 0.013). Survival was similar in both arms. (4) Health economic analysis: A probabilistic economic model was developed using registry and cohort study data. For most health and fitness strata, surgery plus adjuvant endocrine therapy had lower costs and returned more quality-adjusted life-years than endocrine therapy alone. However, for some women aged > 90 years, surgery plus adjuvant endocrine therapy was no longer cost-effective and generated fewer quality-adjusted life-years than endocrine therapy alone. The incremental benefit of surgery plus adjuvant endocrine therapy reduced with age and comorbidities. (5) Variation in practice: analysis of rates of surgery plus adjuvant endocrine therapy or endocrine therapy alone between the 56 breast units in the cohort study demonstrated significant variation in rates of endocrine therapy alone that persisted after adjustment for age, fitness and stage. Clinician preference was an important determinant of treatment choice. Conclusions: This study demonstrates that, for older women with oestrogen-receptor-positive breast cancer, there is a cohort of women with a life expectancy of < 4 years for whom surgery plus adjuvant endocrine therapy may offer little benefit and simply have a negative impact on quality of life. The Age Gap decision tool may help make this shared decision. Similarly, although adjuvant chemotherapy offers little benefit and has a negative impact on quality of life for the majority of older women with oestrogen-receptor-positive breast cancer, for women with oestrogen-receptor-negative breast cancer, adjuvant chemotherapy is beneficial. The negative impacts of adjuvant chemotherapy on quality of life, although significant, are transient. This implies that, for the majority of fitter women aged > 70 years, standard care should be offered. Limitations: As with any observational study, despite detailed propensity score matching, residual bias cannot be excluded. Follow-up was at median 52 months for the cohort analysis. Longer-term follow-up will be required to validate these findings owing to the slow time course of oestrogen-receptor-positive breast cancer. Future work: The online algorithm is now available (URL: Https://ag gap.shef.ac.uk/; accessed May 2022). There are plans to validate the tool and incorprate quality-of-life and 10-year survival outcomes.
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