| 1. |
- Mercuri, E., et al.
(författare)
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Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study
- 2020
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Ingår i: Journal of Comparative Effectiveness Research. - : Becaris Publishing Limited. - 2042-6305 .- 2042-6313. ; 9:5, s. 341-360
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype-phenotype/-ataluren benefit correlations and ataluren safety. Patients & methods: Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion: Kaplan-Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p <= 0.05). There were no DMD genotype-phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier: NCT02369731. ClinicalTrials.gov identifier: NCT02369731.
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| 2. |
- Bushby, Katharine, et al.
(författare)
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Ataluren treatment of patients with nonsense mutation dystrophinopathy.
- 2014
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Ingår i: Muscle & nerve. - : Wiley. - 1097-4598 .- 0148-639X. ; 50:4, s. 477-87
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Tidskriftsartikel (refereegranskat)abstract
- Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders.
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| 3. |
- Forslund, Kristoffer, et al.
(författare)
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Domain tree-based analysis of protein architecture evolution
- 2008
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 25:2, s. 254-264
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the dynamics behind domain architecture evolution is of great importance to unravel the functions of proteins. Complex architectures have been created throughout evolution by rearrangement and duplication events. An interesting question is how many times a particular architecture has been created, a form of convergent evolution or domain architecture reinvention. Previous studies have approached this issue by comparing architectures found in different species. We wanted to achieve a finer-grained analysis by reconstructing protein architectures on complete domain trees. The prevalence of domain architecture reinvention in 96 genomes was investigated with a novel domain tree-based method that uses maximum parsimony for inferring ancestral protein architectures. Domain architectures were taken from Pfam. To ensure robustness, we applied the method to bootstrap trees and only considered results with strong statistical support. We detected multiple origins for 12.4% of the scored architectures. In a much smaller data set, the subset of completely domain-assigned proteins, the figure was 5.6%. These results indicate that domain architecture reinvention is a much more common phenomenon than previously thought. We also determined which domains are most frequent in multiply created architectures and assessed whether specific functions could be attributed to them. However, no strong functional bias was found in architectures with multiple origins.
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| 4. |
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| 5. |
- Henricson, Anna, et al.
(författare)
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Orthology confers intron position conservation
- 2010
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 11:412
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Tidskriftsartikel (refereegranskat)abstract
- Background: With the wealth of genomic data available it has become increasingly important to assign putative protein function through functional transfer between orthologs. Therefore, correct elucidation of the evolutionary relationships among genes is a critical task, and attempts should be made to further improve the phylogenetic inference by adding relevant discriminating features. It has been shown that introns can maintain their position over long evolutionary timescales. For this reason, it could be possible to use conservation of intron positions as a discriminating factor when assigning orthology. Therefore, we wanted to investigate whether orthologs have a higher degree of intron position conservation (IPC) compared to non-orthologous sequences that are equally similar in sequence. Results: To this end, we developed a new score for IPC and applied it to ortholog groups between human and six other species. For comparison, we also gathered the closest non-orthologs, meaning sequences close in sequence space, yet falling just outside the ortholog cluster. We found that ortholog-ortholog gene pairs on average have a significantly higher degree of IPC compared to ortholog-closest non-ortholog pairs. Also pairs of inparalogs were found to have a higher IPC score than inparalog-closest non-inparalog pairs. We verified that these differences can not simply be attributed to the generally higher sequence identity of the ortholog-ortholog and the inparalog-inparalog pairs. Furthermore, we analyzed the agreement between IPC score and the ortholog score assigned by the InParanoid algorithm, and found that it was consistently high for all species comparisons. In a minority of cases, the IPC and InParanoid score ranked inparalogs differently. These represent cases where sequence and intron position divergence are discordant. We further analyzed the discordant clusters to identify any possible preference for protein functions by looking for enriched GO terms and Pfam protein domains. They were enriched for functions important for multicellularity, which implies a connection between shifts in intronic structure and the origin of multicellularity. Conclusions: We conclude that orthologous genes tend to have more conserved intron positions compared to non-orthologous genes. As a consequence, our IPC score is useful as an additional discriminating factor when assigning orthology.
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| 6. |
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| 7. |
- Egerod, I., et al.
(författare)
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The patient experience of intensive care: A meta-synthesis of Nordic studies
- 2015
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Ingår i: International Journal of Nursing Studies. - : Elsevier BV. - 0020-7489 .- 1873-491X. ; 52:8, s. 1354-1361
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sedation practices in the intensive care unit have evolved from deep sedation and paralysis toward lighter sedation and better pain management. The new paradigm of sedation has enabled early mobilization and optimized mechanical ventilator weaning. Intensive care units in the Nordic countries have been particularly close to goals of lighter or no sedation and a more humane approach to intensive care. Objectives: The aim of our study was to systematically review and reinterpret newer Nordic studies of the patient experience of intensive care to obtain a contemporary description of human suffering during life-threatening illness. Design: We conducted a meta-synthesis in which we collected, assessed, and analyzed published qualitative studies with the goal of synthesizing these findings into a new whole. Analysis was based on the scientific approach of Gadamerian hermeneutics. Methods: We performed a literature search of qualitative studies of the patient experience of intensive care based on Nordic publications in 2000-2013. We searched the following databases: PubMed, CINAHL, Scopus, and PsycINFO. Each original paper was assessed by all authors using the Critical Appraisal Skills Program instrument for qualitative research. We included 22 studies, all of which provided direct patient quotes. Results: The overarching theme was identified as: The patient experience when existence itself is at stake. We constructed an organizing framework for analysis using the main perspectives represented in the included studies: body, mind, relationships, and ICU-environment. Final analysis and interpretation resulted in the unfolding of four themes: existing in liminality, existing in unboundedness, existing in mystery, and existing on the threshold. Conclusions: Our main finding was that human suffering during intensive care is still evident although sedation is lighter and the environment is more humane. Our interpretation suggested that patients with life-threatening illness descend into a liminal state, where they face the choice of life or death. Caring nurses and family members play an important role in assisting the patient to transition back to life. (C) 2015 Elsevier Ltd. All rights reserved.
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| 8. |
- Haridass, Isha N., et al.
(författare)
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Cellular metabolism and pore lifetime of human skin following microprojection array mediation
- 2019
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Ingår i: Journal of Controlled Release. - : ELSEVIER SCIENCE BV. - 0168-3659 .- 1873-4995. ; 306, s. 59-68
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Tidskriftsartikel (refereegranskat)abstract
- Skin-targeting microscale medical devices are becoming popular for therapeutic delivery and diagnosis. We used cryo-SEM, fluorescence lifetime imaging microscopy (FLIM), autofluorescence imaging microscopy and inflammatory response to study the puncturing and recovery of human skin ex vivo and in vivo after discretised puncturing by a microneedle array (Nanopatch (R)). Pores induced by the microprojections were found to close by similar to 25% in diameter within the first 30 min, and almost completely close by similar to 6 h. FLIM images of ex vivo viable epidermis showed a stable fluorescence lifetime for unpatched areas of similar to 1000 ps up to 24 h. Only the cells in the immediate puncture zones (in direct contact with projections) showed a reduction in the observed fluorescence lifetimes to between similar to 518-583 ps. The ratio of free-bound NAD(P)H (alpha 1/alpha 2) in unaffected areas of the viable epidermis was similar to 2.5-3.0, whereas the ratio at puncture holes was almost double at similar to 4.2-4.6. An exploratory pilot in vivo study also suggested similar closure rate with histamine administration to the forearms of human volunteers after Nanopatch (R) treatment, although a prolonged inflammation was observed with Tissue Viability Imaging. Overall, this work shows that the pores created by the microneedle-type medical device, Nanopatch (R), are transient, with the skin recovering rapidly within 1-2 days in the epidermis after application.
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| 9. |
- Karlsson, L., et al.
(författare)
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The meaning of caring touch for healthcare professionals in an intensive care unit : A qualitative interview study
- 2022
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Ingår i: Intensive & Critical Care Nursing. - : Elsevier. - 0964-3397 .- 1532-4036. ; 68
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Tidskriftsartikel (refereegranskat)abstract
- Background: The way health care professionals touch patients and relatives in the intensive care unit plays a significant role. A negative feeling can be caused by being touched in the wrong way, this is why a holistic approach with respect for the patient is important for the ability to make the patient and their relatives feel secure, avoiding unnecessary suffering.Aim: The aim of the study was to describe the meaning of caring touch that is given in the ICU from the health care professionals perspective.Method: Qualitative interview study with health care professionals in the intensive care unit, analysed using inductive content analysis, resulting in two themes and four main categories.Findings: Two themes emerged: Imperative touch and emotional touch and four main categories: touch as a natural tool, create a prerequisite for touch, empathetic touch and conversant touch.Conclusion: Caring touch can be used as a natural tool in the daily work in order to bring comfort and calm to the patient in the intensive care unit.
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| 10. |
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| 11. |
- Mercuri, E., et al.
(författare)
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Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015-2022): 2022 interim analysis
- 2023
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Ingår i: Journal of Neurology. - 0340-5354. ; 270, s. 3896-3913
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveStrategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS).MethodsPatients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression.ResultsAs of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan-Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone.ConclusionLong-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015.
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