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- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 2. |
- Franzén, Lovisa, et al.
(författare)
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Spatially resolved transcriptomics of human and mouse fibrotic lung
- 2022
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 60
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive and irreversible scarring of the lung tissue. Development of new efficacious and safe treatments is hampered by limited understanding of disease pathogenesis, lack of predictive preclinical models, and narrow therapeutic index of candidate drugs targeting complex biologies. Here, we tackle these aspects by generating spatially resolved transcriptomic maps of fibrotic lungs from clinical samples and a preclinical mouse model. We utilized the Visium platform to study parenchyma biopsies from four healthy lungs and regions of varying fibrotic severity from four IPF patient lungs. By mapping single cell RNA-seq data spatially, we were able to detect distinct fibroblast populations in different regions of the lesioned IPF lung, as well as the presence of various immune cell populations. To study lung fibrosis preclinically in vivo, the bleomycin mouse model is the most widely used alternative, although its translatability to human disease is disputed. Visium data from mouse lungs collected at two time points following bleomycin administration were generated, which allowed us to characterize the fibrotic lesions and inflammatory areas in their spatiotemporal context. In addition, mass spectrometry imaging was performed on adjacent tissue sections to provide paired spatial metabolomics. Herein, we have generated spatial maps of the lung fibrosis transcriptome from IPF lung biopsies and bleomycin-injured mouse lungs, providing an extensive resource to probe disease pathogenesis and animal model translatability.
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| 3. |
- Geser, F, et al.
(författare)
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The European Multiple System Atrophy-Study Group (EMSA-SG)
- 2005
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Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 112:12, s. 1677-1686
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.
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| 4. |
- Holtslag, A. A. M., et al.
(författare)
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STABLE ATMOSPHERIC BOUNDARY LAYERS AND DIURNAL CYCLES : Challenges for Weather and Climate Models
- 2013
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 94:11, s. 1691-1706
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Tidskriftsartikel (refereegranskat)abstract
- The representation of the atmospheric boundary layer is an important part of weather and climate models and impacts many applications such as air quality and wind energy. Over the years, the performance in modeling 2-m temperature and 10-m wind speed has improved but errors are still significant. This is in particular the case under clear skies and low wind speed conditions at night as well as during winter in stably stratified conditions over land and ice. In this paper, the authors review these issues and provide an overview of the current understanding and model performance. Results from weather forecast and climate models are used to illustrate the state of the art as well as findings and recommendations from three intercomparison studies held within the Global Energy and Water Exchanges (GEWEX) Atmospheric Boundary Layer Study (GABLS). Within GABLS, the focus has been on the examination of the representation of the stable boundary layer and the diurnal cycle over land in clear-sky conditions. For this purpose, single-column versions of weather and climate models have been compared with observations, research models, and large-eddy simulations. The intercomparison cases are based on observations taken in the Arctic, Kansas, and Cabauw in the Netherlands. From these studies, we find that even for the noncloudy boundary layer important parameterization challenges remain.
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| 9. |
- Widner, H, et al.
(författare)
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Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
- 1992
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 327:22, s. 63-1556
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism.METHODS: We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation.RESULTS: Both patients had substantial, sustained improvement in motor function and became much more independent. Postoperatively, the second patient's maintenance dose of levodopa was decreased to 150 mg daily, which was 30 percent of the original dose. Striatal uptake of fluorodopa was unchanged 5 to 6 months postoperatively but was markedly and bilaterally increased at 12 to 13 and 22 to 24 months in both patients, closely paralleling the patients' clinical improvement. There were no serious complications.CONCLUSIONS: Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum. The results in these patients resemble those obtained in MPTP-treated primates and suggest that this will be a useful model for the assessment of transplantation therapies in Parkinson's disease.
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