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- Drouin-Ouellet, Janelle, et al.
(författare)
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REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways
- 2017
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 9:8, s. 1117-1131
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Tidskriftsartikel (refereegranskat)abstract
- Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease-specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient-derived material for large-scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts. Via functional experiments where we overexpress and knockdown the REST-controlled neuron-specific microRNAs miR-9 and miR-124, we show that the effect of REST inhibition is only partially mediated via microRNA up-regulation. Transcriptional analysis confirmed that REST knockdown activates an overlapping subset of neuronal genes as microRNA overexpression and also a distinct set of neuronal genes that are not activated via microRNA overexpression. Based on this, we developed an optimized one-step method to efficiently reprogram dermal fibroblasts from elderly individuals using a single-vector system and demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's, as well as Alzheimer's disease.
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| 2. |
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| 3. |
- Saha, Sanjib, et al.
(författare)
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Economic Evaluation of Interventions for Screening of Dementia
- 2018
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- OBJECTIVE: The objective is to systematically review the literature on economic evaluations of screening interventions for early diagnosis of dementia disorders. METHODS: A systematic search of published economic evaluation studies in English was conducted using specified key words in relevant databased and websites. Data extracted included methods and empirical evidence (costs, effects, incremental cost-effectiveness ratio) and we assessed if the conclusions made in terms of cost-effectiveness were supported by the reported evidence. The included studies were also assessed for reporting quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Fourteen studies were identified and broadly fell into two groups: screening without biomarkers and screening using biomarkers. There was a considerable heterogeneity in methodological approaches, target populations, study time frames, and perspectives as well as types of biomarkers used. The sensitivity and specificity of screening instruments are one of the important aspects in estimating the cost-effectiveness of the interventions. Cost-effectiveness of non-biomarker based interventions cannot be judged due to lack of information. The biomarkers based screening have the potential to be cost-effective but their effectiveness has to be established first. CONCLUSION: More economic evaluations studies as well as good quality effectiveness studies are required in screening strategies before these can be implemented in the clinical practice.
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| 4. |
- Saha, Sanjib, et al.
(författare)
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Economic Evaluation of Management of Dementia Patients - A Systematic Literature Review
- 2018
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: The objective is to systematically review the literature on economic evaluations of the interventions for the management of dementia and Alzheimer patients in home, hospital or institutional care. Methods: A systematic search of published economic evaluation studies in English was conducted using specified key words in relevant databased and websites. Data extracted included methods and empirical evidence (costs, effects, incremental cost-effectiveness ratio) and we assessed if the conclusions made in terms of cost-effectiveness were supported by the reported evidence. The included studies were also assessed for reporting quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results: Twelve studies were identified and there was a considerable heterogeneity in methodological approaches, target populations, study time frames, and perspectives as well as types of interventions. Interventions for the management of dementia patients are in general, not cost-effective. Interventions at the community and home setting for managing both the dementia patients and caregivers on a large scale may have the potential to save societal resources. Conclusion: More effectiveness studies as well as good quality economic evaluations are required before implementation decisions on management strategies can be made based on cost-effectiveness.
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| 5. |
- Saha, Sanjib, et al.
(författare)
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Economic Evaluation of Nonpharmacological Interventions for Dementia Patients and their Caregivers - A Systematic Literature Review
- 2018
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The rising prevalence of dementia represents an important public health issue. There is currently no available cure for dementia disorders, only symptom-relieving therapies which can be either pharmacological or non-pharmacological. The number of non-pharmacological interventions for patients with dementia disorders and their caregivers have been increasing in recent years without much knowledge on their cost-effectiveness. The objective is to review the existing evidence on cost-effectiveness of non-pharmacological interventions targeting patients with dementia disorders, their caregivers, and the patient-caregiver dyad. Method: A systematic search of published economic evaluation studies in English was conducted using specified key words in relevant databased and websites. Data extracted included methods and empirical evidence (costs, effects, ICER) and we assessed if the conclusions made in terms of cost-effectiveness were supported by the reported evidence. The included studies were also assessed for reporting quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results: We included seventeen studies in this review categorised into three groups: physical exercise, occupational therapy, and psychological/psychosocial treatment. In almost all the studies (except one), economic evaluation was performed for a randomised controlled trial alongside the non-pharmacological intervention or retrospectively. There was a considerable heterogeneity in methodological approaches, target populations, study time frames, and perspectives as well as types of intervention. This prevents an informative comparison between most of the studies. However, we found that physical exercise was the most-effective non-pharmacological interventions for patients with dementia. For occupational therapy and psychological/psychosocial interventions we found mixed results although the majority was not cost-effective. Conclusion: More economic evaluations studies are required in non-pharmacological interventions. However, the interventions need to have a strong study design with the intention to perform economic evaluation in parallel.
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| 6. |
- Saha, Sanjib, et al.
(författare)
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Economic Evaluation of Pharmacological Treatments in Dementia Disorders - A Systematic Literature Review
- 2018
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The objective is to systematically review the literature on economic evaluations of pharmacological treatments of dementia disorders. A systematic search of published economic evaluation studies in English was conducted using specified key words in relevant databased and websites. Data extracted included methods and empirical evidence (costs, effects, incremental cost-effectiveness ratio) and we assessed if the conclusions made in terms of cost-effectiveness were supported by the reported evidence. The included studies were also assessed for reporting quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Fourteen studies were included in this review. There was a considerable heterogeneity in methodological approaches, use of simulation models, target populations, study time frames, and perspectives as well as comparators used. Keeping these issues in mind, we find that Cholinesterase Inhibitors (ChEIs), and especially donepezil, are dominating no treatment (i.e. less costly and more effective) for mild to moderate AD patients. For moderate to severe AD patients memantine is cost-effective compared to memantine or ChEIs alone. However, the effect of these drugs on survival is yet not established, which could have a major impact on the cost-effectiveness of these drugs. Conclusion: Pharmaceutical treatments are cost-effective comparing to no treatment for dementia patients. However, more research is required on the long-term effectiveness of these drugs, especially on the effects of drugs on survival.
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