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- Abe, K., et al.
(författare)
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J-PARC Neutrino Beamline Upgrade Technical Design Report
- 2019
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Rapport (refereegranskat)abstract
- In this document, technical details of the upgrade plan of the J-PARC neutrino beamline for the extension of the T2K experiment are described. T2K has proposed to accumulate data corresponding to 2×1022 protons-on-target in the next decade, aiming at an initial observation of CP violation with 3σ or higher significance in the case of maximal CP violation. Methods to increase the neutrino beam intensity, which are necessary to achieve the proposed data increase, are described.
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| 4. |
- Tawil, Rabi, et al.
(författare)
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Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial
- 2024
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Ingår i: Lancet Neurology. - : ELSEVIER SCIENCE INC. - 1474-4422 .- 1474-4465. ; 23:5, s. 477-486
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Tidskriftsartikel (refereegranskat)abstract
- Background Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38 alpha MAPK, a regulator of DUX4 expression, and p38 beta MAPK) for the treatment of facioscapulohumeral muscular dystrophy. Methods We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. Findings Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45<middle dot>7 (SD 12<middle dot>5) years. Least squares mean changes from baseline in DUX4driven gene expression did not differ significantly between the losmapimod (0<middle dot>83 [SE 0<middle dot>61]) and placebo (0<middle dot>40 [0<middle dot>65]) groups (difference 0<middle dot>43 [SE 0<middle dot>56; 95% CI -1<middle dot>04 to 1<middle dot>89]; p=0<middle dot>56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drugrelated) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. Interpretation Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy.
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- Angelstam, Per, et al.
(författare)
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Meeting places and social capital supporting rural landscape stewardship : A Pan-European horizon scanning
- 2021
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Ingår i: Ecology and Society. - : Resilience Alliance. - 1708-3087. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Achieving sustainable development as an inclusive societal process in rural landscapes, and sustainability in terms of functional green infrastructures for biodiversity conservation and ecosystem services, are wicked challenges. Competing claims from various sectors call for evidence-based adaptive collaborative governance. Leveraging such approaches requires maintenance of several forms of social interactions and capitals. Focusing on Pan-European regions with different environmental histories and cultures, we estimate the state and trends of two groups of factors underpinning rural landscape stewardship, namely, (1) traditional rural landscape and novel face-to-face as well as virtual fora for social interaction, and (2) bonding, bridging, and linking forms of social capital. We applied horizon scanning to 16 local landscapes located in 18 countries, representing Pan-European social-ecological and cultural gradients. The resulting narratives, and rapid appraisal knowledge, were used to estimate portfolios of different fora for social interactions and forms of social capital supporting landscape stewardship. The portfolios of fora for social interactions were linked to societal cultures across the European continent: "self-expression and secular-rational values" in the northwest, "Catholic" in the south, and "survival and traditional authority values" in the East. This was explained by the role of traditional secular and religious local meeting places. Virtual internet-based fora were most widespread. Bonding social capitals were the strongest across the case study landscapes, and linking social capitals were the weakest. This applied to all three groups of fora. Pan-European social-ecological contexts can be divided into distinct clusters with respect to the portfolios of different fora supporting landscape stewardship, which draw mostly on bonding and bridging forms of social capital. This emphasizes the need for regionally and culturally adapted approaches to landscape stewardship, which are underpinned by evidence-based knowledge about how to sustain green infrastructures based on both forest naturalness and cultural landscape values. Sharing knowledge from comparative studies can strengthen linking social capital.
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- Pienkowski, Martin, et al.
(författare)
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A review of hyperacusis and future directions : part II. Measurement, mechanisms, and treatment.
- 2014
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Ingår i: American Journal of Audiology. - : American Speech-Language-Hearing Association. - 1059-0889 .- 1558-9137. ; 23:4, s. 420-436
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Forskningsöversikt (refereegranskat)abstract
- PURPOSE: Hyperacusis can be extremely debilitating, and at present, there is no cure. In this detailed review of the field, we consolidate present knowledge in the hope of facilitating future research.METHOD: We review and reference the literature on hyperacusis and related areas. This is the 2nd of a 2-part review.RESULTS: Hyperacusis encompasses a wide range of reactions to sounds, which can be grouped into the categories of excessive loudness, annoyance, fear, and pain. Reasonable approaches to assessing the different forms of hyperacusis are emerging, including brain-imaging studies. Researchers are only beginning to understand the many mechanisms at play, and valid animal models are still evolving. There are many counseling and sound-therapy approaches that some patients find helpful, but well-controlled studies are needed to measure their long-term efficacy and to test new approaches.CONCLUSIONS: Hyperacusis can make life difficult in this increasingly noisy world, forcing sufferers to dramatically alter their work and social habits. We believe this is an opportune time to explore approaches to better understand and treat hyperacusis.
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| 7. |
- Tyler, Richard S, et al.
(författare)
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A review of hyperacusis and future directions : part I. Definitions and manifestations.
- 2014
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Ingår i: American Journal of Audiology. - : American Speech-Language-Hearing Association. - 1059-0889 .- 1558-9137. ; 23:4, s. 402-19
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Forskningsöversikt (refereegranskat)abstract
- PURPOSE: Hyperacusis can be extremely debilitating, and at present, there is no cure. We provide an overview of the field, and possible related areas, in the hope of facilitating future research.METHOD: We review and reference literature on hyperacusis and related areas. We have divided the review into 2 articles. In Part I, we discuss definitions, epidemiology, different etiologies and subgroups, and how hyperacusis affects people. In Part II, we review measurements, models, mechanisms, and treatments, and we finish with some suggestions for further research.RESULTS: Hyperacusis encompasses a wide range of reactions to sound, which can be grouped into the categories of excessive loudness, annoyance, fear, and pain. Many different causes have been proposed, and it will be important to appreciate and quantify different subgroups. Reasonable approaches to assessing the different forms of hyperacusis are emerging, including psychoacoustical measures, questionnaires, and brain imaging.CONCLUSIONS: Hyperacusis can make life difficult for many, forcing sufferers to dramatically alter their work and social habits. We believe this is an opportune time to explore approaches to better understand and treat hyperacusis.
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