| 61. |
- Shoamanesh, Ashkan, et al.
(författare)
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Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke) : an international, randomised, double-blind, placebo-controlled, phase 2b trial
- 2022
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Ingår i: The Lancet. - 0140-6736. ; 400:10357, s. 997-1007
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown. Methods: In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26–52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose–response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete. Findings: Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0–4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79–1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93–1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85–1·32]; t statistic –0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91–2·71]). Interpretation: In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke. Funding: Bayer AG.
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| 62. |
- Walker, Anthony P., et al.
(författare)
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Integrating the evidence for a terrestrial carbon sink caused by increasing atmospheric CO2
- 2021
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Ingår i: New Phytologist. - : John Wiley & Sons. - 0028-646X .- 1469-8137. ; 229:5, s. 2413-2445
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric carbon dioxide concentration ([CO2]) is increasing, which increases leaf‐scale photosynthesis and intrinsic water‐use efficiency. These direct responses have the potential to increase plant growth, vegetation biomass, and soil organic matter; transferring carbon from the atmosphere into terrestrial ecosystems (a carbon sink). A substantial global terrestrial carbon sink would slow the rate of [CO2] increase and thus climate change. However, ecosystem CO2 responses are complex or confounded by concurrent changes in multiple agents of global change and evidence for a [CO2]‐driven terrestrial carbon sink can appear contradictory. Here we synthesize theory and broad, multidisciplinary evidence for the effects of increasing [CO2] (iCO2) on the global terrestrial carbon sink. Evidence suggests a substantial increase in global photosynthesis since pre‐industrial times. Established theory, supported by experiments, indicates that iCO2 is likely responsible for about half of the increase. Global carbon budgeting, atmospheric data, and forest inventories indicate a historical carbon sink, and these apparent iCO2 responses are high in comparison to experiments and predictions from theory. Plant mortality and soil carbon iCO2 responses are highly uncertain. In conclusion, a range of evidence supports a positive terrestrial carbon sink in response to iCO2, albeit with uncertain magnitude and strong suggestion of a role for additional agents of global change.
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| 63. |
- Caron, Patrick, et al.
(författare)
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Food systems for sustainable development : proposals for a profound four-part transformation
- 2018
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Ingår i: Agronomy for Sustainable Development. - : Springer Science and Business Media LLC. - 1774-0746 .- 1773-0155. ; 38:4
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Forskningsöversikt (refereegranskat)abstract
- Evidence shows the importance of food systems for sustainable development: they are at the nexus that links food security, nutrition, and human health, the viability of ecosystems, climate change, and social justice. However, agricultural policies tend to focus on food supply, and sometimes, on mechanisms to address negative externalities. We propose an alternative. Our starting point is that agriculture and food systems' policies should be aligned to the 2030 Agenda for Sustainable Development. This calls for deep changes in comparison with the paradigms that prevailed when steering the agricultural change in the XXth century. We identify the comprehensive food systems transformation that is needed. It has four parts: first, food systems should enable all people to benefit from nutritious and healthy food. Second, they should reflect sustainable agricultural production and food value chains. Third, they should mitigate climate change and build resilience. Fourth, they should encourage a renaissance of rural territories. The implementation of the transformation relies on (i) suitable metrics to aid decision-making, (ii) synergy of policies through convergence of local and global priorities, and (iii) enhancement of development approaches that focus on territories. We build on the work of the Milano Group, an informal group of experts convened by the UN Secretary General in Milan in 2015. Backed by a literature review, what emerges is a strategic narrative linking climate, agriculture and food, and calling for a deep transformation of food systems at scale. This is critical for achieving the Sustainable Development Goals and the Paris Agreement. The narrative highlights the needed consistency between global actions for sustainable development and numerous local-level innovations. It emphasizes the challenge of designing differentiated paths for food systems transformation responding to local and national expectations. Scientific and operational challenges are associated with the alignment and arbitration of local action within the context of global priorities.
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| 64. |
- Kowalec, Kaarina, et al.
(författare)
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Characteristics associated with drug-induced liver injury from interferon beta in multiple sclerosis patients
- 2014
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Ingår i: Expert Opinion on Drug Safety. - : Informa Healthcare. - 1474-0338 .- 1744-764X. ; 13:10, s. 1305-1317
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Forskningsöversikt (refereegranskat)abstract
- Objective: To identify and characterize drug-induced liver injury (DILI) associated with IFN-beta in multiple sclerosis (MS) using recommended criteria. Methods: This retrospective, mixed methods design included a cohort of IFN-beta exposed MS patients from British Columbia (BC), Canada and a series of DILI cases from other Canadian provinces and two adverse drug reaction (ADR) networks (USA and Sweden). Associations between sex, age and IFN-beta product, and DILI were explored in BC cohort using Cox proportional hazard analyses. Characteristics, including the time to DILI, were compared between sites. Results: In BC, 18/942 (1.9%) of IFN-beta exposed MS patients met criteria for DILI, with a trend toward an increased risk for women and those exposed to IFN-beta-1a SC (44 mcg 3 x weekly) (adjusted Hazard Ratios: 3.15; 95% CI: 0.72 - 13.72, p = 0.13 and 6.26; 95% CI: 0.78 - 50.39, p = 0.08, respectively). Twenty-four additional cases were identified from other sites; the median time to DILI was comparable between BC and other Canadian cases (105 and 90 days, respectively), but longer for the ADR network cases (590 days, p = 0.006). Conclusions: Approximately 1 in 50 IFN-beta exposed patients developed DILI in BC, Canada. Identification of DILI cases from diverse sources highlighted that this reaction occurs even after years of exposure.
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| 65. |
- Kowalec, Kaarina, et al.
(författare)
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Common variation near IRF6 is associated with IFN-beta-induced liver injury in multiple sclerosis
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:8, s. 1081-
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10–8, odds ratio = 8.3, 95% confidence interval = 3.6–19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10–5) and alkaline phosphatase (P = 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use.
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| 66. |
- Loeffen, Erik A. H., et al.
(författare)
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Reducing pain in children with cancer : Methodology for the development of a clinical practice guideline
- 2019
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 66:6
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Tidskriftsartikel (refereegranskat)abstract
- Although pain is one of the most prevalent and bothersome symptoms children with cancer experience, evidence-based guidance regarding assessment and management is lacking. With 44 international, multidisciplinary healthcare professionals and nine patient representatives, we aimed to develop a clinical practice guideline (following GRADE methodology), addressing assessment and pharmacological, psychological, and physical management of tumor-, treatment-, and procedure-related pain in children with cancer. In this paper, we present our thorough methodology for this development, including the challenges we faced and how we approached these. This lays the foundation for our clinical practice guideline, for which there is a high clinical demand.
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| 67. |
- Rist, Lucy, et al.
(författare)
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Adaptive management : where are we now?
- 2013
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Ingår i: Environmental Conservation. - : Cambridge University Press. - 0376-8929 .- 1469-4387. ; 40:1, s. 5-18
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Tidskriftsartikel (refereegranskat)abstract
- Adaptive management (AM) emerged in the literature in the mid-1970s in response both to a realization of the extent of uncertainty involved in management, and a frustration with attempts to use modelling to integrate knowledge and make predictions. The term has since become increasingly widely used in scientific articles, policy documents and management plans, but both understanding and application of the concept is mixed. This paper reviews recent literature from conservation and natural resource management journals to assess diversity in how the term is used, highlight ambiguities and consider how the concept might be further assessed. AM is currently being used to describe many different management contexts, scales and locations. Few authors define the term explicitly or describe how it offers a means to improve management outcomes in their specific management context. Many do not adhere to the idea as it was originally conceived, despite citing seminal work. Significant confusion exists over the distinction between active and passive approaches. Over half of the studies reporting to implement AM claimed to have done so successfully, yet none quantified specific benefits, or costs, in relation to possible alternatives. Similarly those studies reporting to assess the approach did so only in relation to specific models and their parameterizations; none assessed the benefits or costs of AM in the field. AM is regarded by some as an effective and well-established framework to support the management of natural resources, yet by others as a concept difficult to realize and fraught with implementation challenges; neither of these observations is wholly accurate. From a scientific and technical perspective many practical questions remain; in particular real-world assessments of the value of experimentation within a management framework, as well as of identified challenges and pathologies, are needed. Further discussion and systematic assessment of the approach is required, together with greater attention to its definition and description, enabling the assessment of new approaches to managing uncertainty, and AM itself.
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| 68. |
- Sako, Masao, et al.
(författare)
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The Data Release of the Sloan Digital Sky Survey-II Supernova Survey
- 2018
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Ingår i: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 130:988
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes the data release of the Sloan Digital Sky Survey-II (SDSS-II) Supernova Survey conducted between 2005 and 2007. Light curves, spectra, classifications, and ancillary data are presented for 10,258 variable and transient sources discovered through repeat ugriz imaging of SDSS Stripe 82, a 300 deg(2) area along the celestial equator. This data release is comprised of all transient sources brighter than r similar or equal to 22.5 mag with no history of variability prior to 2004. Dedicated spectroscopic observations were performed on a subset of 889 transients, as well as spectra for thousands of transient host galaxies using the SDSS-III BOSS spectrographs. Photometric classifications are provided for the candidates with good multi-color light curves that were not observed spectroscopically, using host galaxy redshift information when available. From these observations, 4607 transients are either spectroscopically confirmed, or likely to be, supernovae, making this the largest sample of supernova candidates ever compiled. We present a new method for SN host-galaxy identification and derive host-galaxy properties including stellar masses, star formation rates, and the average stellar population ages from our SDSS multi-band photometry. We derive SALT2 distance moduli for a total of 1364 SN. Ia with spectroscopic redshifts as well as photometric redshifts for a further 624 purely photometric SN. Ia candidates. Using the spectroscopically confirmed subset of the three-year SDSS-II SN. Ia sample and assuming a flat.CDM cosmology, we determine Omega(M) = 0.315 +/- 0.093 (statistical error only) and detect a non-zero cosmological constant at 5.7 sigma.
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| 69. |
- Smith, Mathew, et al.
(författare)
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THE EFFECT OF WEAK LENSING ON DISTANCE ESTIMATES FROM SUPERNOVAE
- 2014
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 780:1, s. Art.nr.-UNSP 24
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Tidskriftsartikel (refereegranskat)abstract
- Using a sample of 608 Type Ia supernovae from the SDSS-II and BOSS surveys, combined with a sample of foreground galaxies from SDSS-II, we estimate the weak lensing convergence for each supernova line of sight. We find that the correlation between this measurement and the Hubble residuals is consistent with the prediction from lensing (at a significance of 1.7 sigma). Strong correlations are also found between the residuals and supernova nuisance parameters after a linear correction is applied. When these other correlations are taken into account, the lensing signal is detected at 1.4 sigma. We show, for the first time, that distance estimates from supernovae can be improved when lensing is incorporated, by including a new parameter in the SALT2 methodology for determining distance moduli. The recovered value of the new parameter is consistent with the lensing prediction. Using cosmic microwave background data from WMAP7, H-0 data from Hubble Space Telescope and Sloan Digital Sky Survey (SDSS) Baryon acoustic oscillations measurements, we find the best-fit value of the new lensing parameter and show that the central values and uncertainties on Omega m and w are unaffected. The lensing of supernovae, while only seen at marginal significance in this low-redshift sample, will be of vital importance for the next generation of surveys, such as DES and LSST, which will be systematics-dominated.
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