| 1. |
- Breznau, Nate, et al.
(författare)
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Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:44
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Tidskriftsartikel (refereegranskat)abstract
- This study explores how researchers analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each teams workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.
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| 2. |
- Furukawa, Toshi A., et al.
(författare)
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Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression : a systematic review and component network meta-analysis using individual data
- 2021
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Ingår i: Lancet psychiatry. - London, United Kingdom : Elsevier. - 2215-0374 .- 2215-0366. ; 8:6, s. 500-511
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Forskningsöversikt (refereegranskat)abstract
- Findings We identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42.0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD -1.83 [95% credible interval (CrI) -2.90 to -0.80]) and that relaxation might be harmful (1.20 [95% CrI 0.17 to 2.27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0.32 [95% CrI 0.13 to 0.93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components. 511
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| 3. |
- George, Julie, et al.
(författare)
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Comprehensive genomic profiles of small cell lung cancer
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 524:7563, s. 47-U73
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Tidskriftsartikel (refereegranskat)abstract
- We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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| 4. |
- Aliramaji, Shamsa, et al.
(författare)
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Effect of Growth Temperature and Atmosphere Exposure Time on Impurity Incorporation in Sputtered Mg, Al, and Ca Thin Films
- 2023
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Ingår i: Materials. - : MDPI. - 1996-1944. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Impurities can be incorporated during thin film deposition, but also can originate from atmosphere exposure. As impurities can strongly affect the composition-structure-property relations in magnetron sputter deposited thin films, it is important to distinguish between both incorporation channels. Therefore, the impurity incorporation by atmosphere exposure into sputtered Mg, Al, and Ca thin films is systematically studied by a variation of the deposition temperatures and atmosphere exposure times. Deposition temperature variation results in morphological modifications explained by considering surface and bulk diffusion as well as grain boundary motion and evaporation. The film morphologies exhibiting the lowest oxygen concentrations, as measured by energy dispersive X-ray spectroscopy, are obtained at a homologous temperature of 0.4 for both Mg and Al thin films. For Ca, preventing atmosphere exposure is essential to hinder impurity incorporation: By comparing the impurity concentration in Al-capped and uncapped thin films, it is demonstrated that Ca thin films are locally protected by Al-capping, while Mg (and Al) form native passivation layers. Furthermore, it can be learned that the capping (or self-passivation) efficiency in terms of hindering further oxidation of the films in atmosphere is strongly dependent on the underlying morphology, which in turn is defined by the growth temperature.
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| 5. |
- Amare, Azmeraw T, et al.
(författare)
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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
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Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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| 6. |
- Beneitez Galan, Miguel
(författare)
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Nonlinear dynamics in transitional wall-bounded flows
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on numerical studies of subcritical transition to turbulence in shear flows. The thesis employs a framework based on nonlinear dynamics in the subsequent studies. The geometrical approach to subcritical transition pivots the concepts of edge manifold and edge state. Such concepts are explored in detail in the Blasius boundary layer. The identified edge trajectory is chaotic and presents a couple of high- and low-speed streaks akin to those identified in other shear flows. For long enough times the linear instability of the Blasiusboundary layer coexists with the bypass transition scenario. The edge is thus reinterpreted as a manifold separating both routes. On the edge manifold of the Blasius boundary layer, the fully localised minimal seed is identified. The minimal seed experiences a sequence of linear mechanisms: the Orr mechanism followed by the lift-up. The resulting perturbation approaches the same region in state space as identified from arbitrary perturbations.These insights from the edge trajectory identified in the Blasius boundary layer inspired a low-dimensional model. The model illustrates the e↵ect of the laminar attractor becoming linearly unstable and it agrees qualitatively withother recent studies in the literature.The edge has been identified as a hyperbolic Lagrangian coherent structure of infinite dimension. We show how two Lagrangian diagnostics can be used to locate the edge directly in state space. This allows us to revisit edge tracking as a method optimising a Lagrangian diagnostic instead of a binary algorithm.The two last studies of the thesis focus on the optimally time-dependent(OTD) modes as a basis for the linearised dynamics about a base flow with arbitrary time-dependence. The OTD modes are explored for a periodic flow in pulsating plane Poiseuille flow. The resulting OTD modes can be linked to thespectrum of the Orr-Sommerfeld operator. The results revealed perturbations which span more than one period of the base flow. Finally, the OTD frameworkis used on the edge trajectory starting from the minimal seed in the Blasiusboundary layer.
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| 7. |
- Daly, C. A., et al.
(författare)
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Secondary instability and tertiary states in rotating plane Couette flow
- 2014
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Ingår i: Journal of Fluid Mechanics. - : Cambridge University Press (CUP). - 0022-1120 .- 1469-7645. ; 761, s. 27-61
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Tidskriftsartikel (refereegranskat)abstract
- Recent experimental studies have shown rich transition behaviour in rotating plane Couette flow (RPCF). In this paper we study the transition in supercritical RPCF theoretically by determination of equilibrium and periodic orbit tertiary states via Floquet analysis on secondary Taylor vortex solutions. Two new tertiary states are discovered which we name oscillatory wavy vortex flow (oWVF) and skewed vortex flow (SVF). We present the bifurcation routes and stability properties of these new tertiary states and, in addition, we describe a bifurcation procedure whereby a set of defected wavy twist vortices is approached. Further to this, transition scenarios at flow parameters relevant to experimental works are investigated by computation of the set of stable attractors which exist on a large domain. The physically observed flow states are shown to share features with states in our set of attractors.
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| 8. |
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| 9. |
- Eichhorst, B., et al.
(författare)
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First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia.
- 2023
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Ingår i: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 388:19, s. 1739-1754
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Tidskriftsartikel (refereegranskat)abstract
- Background Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. Methods In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity,
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| 10. |
- Fischer, Benjamin M. C., et al.
(författare)
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Contributing sources to baseflow in pre-alpine headwaters using spatial snapshot sampling
- 2015
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Ingår i: Hydrological Processes. - : Wiley. - 0885-6087 .- 1099-1085. ; 29:26, s. 5321-5336
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Tidskriftsartikel (refereegranskat)abstract
- Mountainous headwaters consist of different landscape units including forests, meadows and wetlands. In these headwaters it is unclear which landscape units contribute what percentage to baseflow. In this study, we analysed spatiotemporal differences in baseflow isotope and hydrochemistry to identify catchment-scale runoff contribution. Three baseflow snapshot sampling campaigns were performed in the Swiss pre-alpine headwater catchment of the Zckentobel (4.25 km(2)) and six of its adjacent subcatchments. The spatial and temporal variability of delta H-2, Ca, DOC, AT, pH, SO4, Mg and H4SiO4 of streamflow, groundwater and spring water samples was analysed and related to catchment area and wetland percentage using bivariate and multivariate methods. Our study found that in the six subcatchments, with variable arrangements of landscape units, the inter-and intra catchment variability of isotopic and hydrochemical compositions was small and generally not significant. Stream samples were distinctly different from shallow groundwater. An upper spring zone located near the water divide above 1,400m and a larger wetland were identified by their distinct spatial isotopic and hydrochemical composition. The upstream wetland percentage was not correlated to the hydrochemical streamflow composition, suggesting that wetlands were less connected and act as passive features with a negligible contribution to baseflow runoff. The isotopic and hydrochemical composition of baseflow changed slightly from the upper spring zone towards the subcatchment outlets and corresponded to the signature of deep groundwater. Our results confirm the need and benefits of spatially distributed snapshot sampling to derive process understanding of heterogeneous headwaters during baseflow.
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