| 1. |
- Bache, Iben, et al.
(författare)
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An excess of chromosome 1 breakpoints in male infertility.
- 2004
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 12:12, s. 993-1000
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Tidskriftsartikel (refereegranskat)abstract
- In a search for potential infertility loci, which might be revealed by clustering of chromosomal breakpoints, we compiled 464 infertile males with a balanced rearrangement from Mendelian Cytogenetics Network database (MCNdb) and compared their karyotypes with those of a Danish nation-wide cohort. We excluded Robertsonian translocations, rearrangements involving sex chromosomes and common variants. We identified 10 autosomal bands, five of which were on chromosome 1, with a large excess of breakpoints in the infertility group. Some of these could potentially harbour a male-specific infertility locus. However, a general excess of breakpoints almost everywhere on chromosome 1 was observed among the infertile males: 26.5 versus 14.5% in the cohort. This excess was observed both for translocation and inversion carriers, especially pericentric inversions, both for published and unpublished cases, and was significantly associated with azoospermia. The largest number of breakpoints was reported in 1q21; FISH mapping of four of these breakpoints revealed that they did not involve the same region at the molecular level. We suggest that chromosome 1 harbours a critical domain whose integrity is essential for male fertility.
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| 2. |
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| 3. |
- Jerkeman, Mats, et al.
(författare)
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Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON) : a multicentre, open-label, single-arm, phase 2 trial
- 2018
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Ingår i: Tha Lancet Haematology. - : ELSEVIER SCI LTD. - 2352-3026. ; 5:3, s. E109-E116
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Tidskriftsartikel (refereegranskat)abstract
- Background Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone. Methods In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0-3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m(2)) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1-21. The primary endpoint was overall response assessed in the intention-totreat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials. gov, number NCT02460276. Findings Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17.8 months (IQR 14.7-20.9), 38 (76%, 95% CI 63-86) patients had an overall response, including 28 (56%, 42-69) patients who had a complete response and ten (20%, 11-33) who had a partial response. The most common grade 3-4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke. Interpretation Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial.
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| 4. |
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| 5. |
- Eskelund, Christian Winther, et al.
(författare)
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Clonal hematopoiesis evolves from pretreatment clones and stabilizes after end of chemotherapy in patients with MCL
- 2020
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 135:22, s. 2000-2004
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Eskelund et al examined clonal hematopoiesis (CH) in a cohort of patients with mantle cell lymphoma (MCL) treated with first-line chemotherapy and autologous stem cell transplantation. In young, good-risk MCL patients, CH after first-line therapy arises almost entirely from preexisting clones, stabilizes after a period of expansion posttransplantation, and does not negatively impact survival.
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| 6. |
- Eskelund, Christian Winther, et al.
(författare)
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Detailed Long-Term Follow-Up of Patients Who Relapsed After the Nordic Mantle Cell Lymphoma Trials : MCL2 and MCL3
- 2021
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Ingår i: HemaSphere. - : Wolters Kluwer. - 2572-9241. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is an incurable disease with a highly variable clinical course. The prognosis after relapse is generally poor, and no standard of care exists. We investigated the postrelapse outcomes of 149 patients who were initially treated in the Nordic Lymphoma Group trials, MCL2 or MCL3, both representing intensive cytarabine-containing frontline regimens including autologous stem cell transplant. Patients with progression of disease before 24 months (POD24, n = 51, 34%) displayed a median overall survival of 6.6 months compared with 46 months for patients with later POD (n = 98, 66%; P < 0.001). MCL international prognostic index, cell proliferation marker, blastoid morphology, and TP53 mutations showed independent prognostic value irrespective of POD24, and in a combined, exploratory risk score, patients with 0, 1, 2-3, or 4-5 high-risk markers, respectively, displayed a 5-year overall survival of 62%, 39%, 31%, and 0%. By a comparison of median progression-free survival of the different salvage therapies in the relapse setting, bendamustine-rituximab was superior to all other combination chemotherapy regimens; however, it was also associated with longer responses to last line of therapy. Collectively, we confirm the prognostic impact of POD24 and highlight the relevance of other biomarkers, and we emphasize the importance of novel therapies for patients with high-risk features at first POD.
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| 7. |
- Freiburghaus, Catja, et al.
(författare)
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Bortezomib prevents cytarabine resistance in MCL, which is characterized by down-regulation of dCK and up-regulation of SPIB resulting in high NF-κB activity
- 2018
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The addition of high-dose cytarabine to the treatment of mantle cell lymphoma (MCL) has significantly prolonged survival of patients, but relapses are common and are normally associated with increased resistance. To elucidate the mechanisms responsible for cytarabine resistance, and to create a tool for drug discovery investigations, we established a unique and molecularly reproducible cytarabine resistant model from the Z138 MCL cell line.METHODS: Effects of different substances on cytarabine-sensitive and resistant cells were evaluated by assessment of cell proliferation using [methyl-14C]-thymidine incorporation and molecular changes were investigated by protein and gene expression analyses.RESULTS: Gene expression profiling revealed that major transcriptional changes occur during the initial phase of adaptation to cellular growth in cytarabine containing media, and only few key genes, including SPIB, are deregulated upon the later development of resistance. Resistance was shown to be mediated by down-regulation of the deoxycytidine kinase (dCK) protein, responsible for activation of nucleoside analogue prodrugs. This key event, emphasized by cross-resistance to other nucleoside analogues, did not only effect resistance but also levels of SPIB and NF-κB, as assessed through forced overexpression in resistant cells. Thus, for the first time we show that regulation of drug resistance through prevention of conversion of pro-drug into active drug are closely linked to increased proliferation and resistance to apoptosis in MCL. Using drug libraries, we identify several substances with growth reducing effect on cytarabine resistant cells. We further hypothesized that co-treatment with bortezomib could prevent resistance development. This was confirmed and show that the dCK levels are retained upon co-treatment, indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance. The possibility to predict cytarabine resistance in diagnostic samples was assessed, but analysis show that a majority of patients have moderate to high expression of dCK at diagnosis, corresponding well to the initial clinical response to cytarabine treatment.CONCLUSION: We show that cytarabine resistance potentially can be avoided or at least delayed through co-treatment with bortezomib, and that down-regulation of dCK and up-regulation of SPIB and NF-κB are the main molecular events driving cytarabine resistance development.
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| 8. |
- Lindberg, Åsa, et al.
(författare)
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Pre-treatment health-related quality of life parameters have prognostic impact in patients >65 years with newly diagnosed mantle cell lymphoma : The Nordic Lymphoma Group MCL4 (LENA-BERIT) experience
- 2022
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Ingår i: Hematological Oncology. - : Wiley. - 0278-0232 .- 1099-1069. ; 40:1, s. 23-31
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is a rare, often aggressive type of B-cell lymphoma with poor survival and no cure. Cancer and cancer treatment has a negative impact on health-related quality of life (HRQOL) both during active disease and in the long term, and improvement of HRQOL is a crucial objective of cancer therapy in older patients and no curative intent. Baseline HRQOL has in other lymphoma populations been shown to be predictive of outcome. Here, we explored HRQOL, and its association with survival, by the EORTC QLQ-C30 questionnaire, before, during and after chemotherapy in a patient cohort with MCL, treated within the NLG-MCL4 trial, designed to evaluate the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment. Fifty-one patients were enrolled, median age was 71 years (range 62–84), 37 were men (73%). Pre-treatment HRQOL was similar to scores from the reference population with healthy individuals. During treatment, HRQOL deteriorated, but reverted to the same level as the reference population after treatment. There was a correlation between physical function (p = 0.001) and role function (p = 0.006) at baseline and WHO performance status, but not with other clinical or genetic prognostic factors. None of the baseline factors were predictive for treatment related to HRQOL in this cohort. Pre-treatment physical (p = 0.011) and role function (p = 0.032) were independent factors associated with overall survival, and physical function (p = 0.002) was also associated with progression free survival. These findings may possibly be used to design support during treatment and improve rehabilitation. Further investigations are needed for assessment of long-term HRQOL.
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| 9. |
- Lokhande, Lavanya, et al.
(författare)
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Serum proteome modulations upon treatment provides biological insight on response to treatment in relapsed mantle cell lymphoma
- 2022
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Ingår i: Cancer Reports. - : Wiley. - 2573-8348. ; 5:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: The possibility to monitor patient's serum proteome during treatment can provide deepened understanding of the biology associated with response to specific drugs. Non-invasive serum sampling provides an opportunity for sustainable repetitive sampling of patients, which allows for more frequent evaluation of the biological response and enhanced flexibility in treatment selection in contrast to tissue biopsies. Aim: To pin-point biologically relevant changes in pre- and on-treatment serum proteome samples in relapsed mantle cell lymphoma (MCL) patients, leading to insight into mechanisms behind response to treatment in sub-groups of patients. Methods: Pre- and on-treatment serum samples from relapsed MCL patients treated with a triple combination therapy of rituximab, ibrutinib and lenalidomide were available for the study, together with detailed clinicopathological information. A microarray technology targeting 158 serum proteins using 371 antibody-fragments was used to compare the serum proteome at the two time-points. Results: Proteins modulated by the treatment were shown to be associated to a MCL sub-group with ATM/TP53 alterations, which emphasizes the importance of treatment stratification. Absolute values of serum protein levels in on-treatment samples were highly variable and showed no correlation to outcome. To circumvent the challenge of variability in absolute serum protein levels, the velocity of change of individual serum proteins was used to identify proteins associated with clinical response. Increased values of TGF-β1, CD40 and complement component 4 comparing pre- and on-treatment samples were associated with remaining minimal residual disease (MRD) and increased BTK was associated with short progression-free survival (PFS). Conclusion: We show that the genetic sub-type of MCL affects the biological response to treatment in serum and that the change in defined serum proteins reveals the biology associated with clinical response.
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| 10. |
- Mortensen, Jens Jorgen, et al.
(författare)
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GPAW: An open Python package for electronic structure calculations
- 2024
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Ingår i: Journal of Chemical Physics. - 1089-7690 .- 0021-9606. ; 160:9
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Tidskriftsartikel (refereegranskat)abstract
- We review the GPAW open-source Python package for electronic structure calculations. GPAW is based on the projector-augmented wave method and can solve the self-consistent density functional theory (DFT) equations using three different wave-function representations, namely real-space grids, plane waves, and numerical atomic orbitals. The three representations are complementary and mutually independent and can be connected by transformations via the real-space grid. This multi-basis feature renders GPAW highly versatile and unique among similar codes. By virtue of its modular structure, the GPAW code constitutes an ideal platform for the implementation of new features and methodologies. Moreover, it is well integrated with the Atomic Simulation Environment (ASE), providing a flexible and dynamic user interface. In addition to ground-state DFT calculations, GPAW supports many-body GW band structures, optical excitations from the Bethe-Salpeter Equation, variational calculations of excited states in molecules and solids via direct optimization, and real-time propagation of the Kohn-Sham equations within time-dependent DFT. A range of more advanced methods to describe magnetic excitations and non-collinear magnetism in solids are also now available. In addition, GPAW can calculate non-linear optical tensors of solids, charged crystal point defects, and much more. Recently, support for graphics processing unit (GPU) acceleration has been achieved with minor modifications to the GPAW code thanks to the CuPy library. We end the review with an outlook, describing some future plans for GPAW.
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| 11. |
- Precht, Helle, et al.
(författare)
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Can scatter correction software replace a grid in DR pelvic examinations?
- 2019
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Ingår i: Radiation Protection Dosimetry. - : Oxford University Press (OUP). - 1742-3406 .- 0144-8420. ; 187:1, s. 8-16
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Tidskriftsartikel (refereegranskat)abstract
- The purpose was to examine if scatter correction software could replace a grid while maintaining image quality and reducing radiation dose for pelvic DR examinations. Grid images was produced with 70 kV and 16mAs. Anthropomorphic- and Contrast Detail RADiography (CDRAD) non-grid images were produced with 60 kV, 80 kV and 90 kV combined with five different mAs and scatter correction software. The anthropomorphic images were analyzed by absolute Visual Grading Analysis (VGA). The CDRAD images were analyzed using the CDRAD analysis software. The results showed a total of 54.6% non-grid images were evaluated as unsuitable for diagnostic use by the VGA. The CDRAD grid images showed that the IQF_inv values were significantly different (p = 0.0001) when compared to every group of non-grid images. Hereby, the conclusion stated that the scatter correction software did not compensate for the loss in image quality due to scattered radiation at the exposure levels included in a pelvic examination.
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| 12. |
- Salim, Ruth, et al.
(författare)
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Exploring new prognostic biomarkers in Mantle Cell Lymphoma : a comparison of the circSCORE and the MCL35 score
- 2023
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Ingår i: Leukemia and Lymphoma. - 1042-8194. ; 64:8, s. 1414-1423
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is a biologically and clinically heterogeneous disease, emphasizing the need for prognostic biomarkers. In this study we aimed at comparing the prognostic value of two RNA-based risk scores, circSCORE and MCL35, in 149 patients from the MCL2 (ISRCTN87866680) and MCL3 (NCT00514475) patient cohorts. Both risk scores provided significant stratification of high versus low risk for progression free survival (PFS) and overall survival (OS). The circSCORE retained significant prognostic value in adjusted multivariable Cox regressions for PFS, but not for OS. Furthermore, circSCORE added significant prognostic value to MIPI in the pooled cohort (MCL2 and MCL3) for PFS and OS, and for PFS in MCL3 alone, outperforming Ki67 and MCL35. We suggest a new, combined MIPI-circSCORE with improved prognostic value, and with potential for future clinical implementation, if validated in a larger, independent cohort.
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| 13. |
- Sandström Gerdtsson, Anna, et al.
(författare)
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Overexpression of the key metabolic protein CPT1A defines mantle cell lymphoma patients with poor response to standard high dose chemotherapy independent of MIPI and complement established high-risk factors
- 2023
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 108:4, s. 1092-1104
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Tidskriftsartikel (refereegranskat)abstract
- The variable outcome to standard immunochemotherapy for mantle cell lymphoma (MCL) patients is a clinical challenge. Established risk factors, including high MCL international prognostic index (MIPI), high proliferation (Ki-67), non-classic (blastoid/pleomorphic) morphology, and mutated TP53, only partly identify patients in need of alternative treatment. Deepened understanding of biological factors that influence time to progression and relapse would allow for an improved stratification, and identification of novel targets for high-risk patients. We performed gene expression analyses to identify pathways and genes associated with outcome in a cohort of homogeneously treated patients. In addition to deregulated proliferation, we show that thermogenesis, fatty acid degradation and oxidative phosphorylation are altered in patients with poor survival, and that high expression of carnitine palmitoyltransferase 1A (CPT1A), an enzyme involved in fatty acid degradation, can specifically identify high-risk patients independent of the established high-risk factors. We suggest that complementary investigations of metabolism may increase the accuracy of patient stratification and that immunohistochemistry-based assessment of CPT1A can contribute to defining high-risk MCL.
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| 14. |
- Ulsrud, Kirsten, et al.
(författare)
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Pathways to electricity for all : What makes village-scale solar power successful?
- 2018
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Ingår i: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 44, s. 32-40
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Tidskriftsartikel (refereegranskat)abstract
- This article presents new empirical research on what it takes to provide enduring access to affordable, reliable and useful electricity services for all. We analyze and synthesize the long-term experiences with three different systems for village-scale solar power supply in India, Senegal and Kenya. Since this scale of electricity provision forms part of village infrastructure, it requires particular types of knowledge, policies and support mechanisms. This research therefore investigates how village-scale solar systems can be designed, implemented, sustained and replicated in ways that make them accessible and useful for the community members. Drawing on a socio-technical and practice-oriented approach, we show that the electricity system’s degree of adaptedness to its social context affects many important qualities of the system such as the relevance of the available electricity services for the people, the system’soperational and economic sustainability and the potential for replication. Achieving such adaptation notably requires a flexible approach on the part of implementers, funders and local actors before, during and after implementation. We also show the need for institutionalization of decentralized electricity provision, discuss the current ambiguities in policies, regulations and funding mechanisms for village-scale solar power, and provide recommendations to policy makers and donors.
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| 15. |
- Ulsrud, Kirsten, et al.
(författare)
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The Solar Transitions research on solar mini-grids in India : Learning from local cases of innovative socio-technical systems
- 2011
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Ingår i: Energy for Sustainable Development. - : Elsevier. - 0973-0826 .- 2352-4669. ; 15:3, s. 293-303
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Tidskriftsartikel (refereegranskat)abstract
- The article presents new empirical material from a case study on longstanding, pioneering efforts on implementation and use of solar mini-grid systems in the Sunderban Islands in India. These local, socio-technical experiments have been investigated by a trans-disciplinary team of researchers and practitioners in order to gain a deep understanding of the diversity of social and technical factors influencing the ways in which the systems work at different levels. This socio-technical research highlights the dynamics between technology and society and how they are mutually influencing and shaping each other. These dynamics create gradual changes in the socio-technical system of technical devises, people, practices, knowledge and other elements, requiring adjustments also by the implementing actors. A range of technical and non-technical factors at various levels are found to be relevant for the implementation, operation, sustenance and further development of the solar power supply systems. The research points to important factors that should be taken into account and considered when planning similar activities. In addition to the analysis of the research findings, the article includes a brief review of literature on the implementation and use of solar photovoltaic technology in developing countries, with an emphasis on solar mini-grid systems.
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| 16. |
- Ulsrud, Kirsten, et al.
(författare)
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Village-level solar power in Africa : Accelerating access to electricity services through a socio-technical design in Kenya
- 2015
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Ingår i: Energy Research & Social Sciences. - : Elsevier. - 2214-6296. ; 5, s. 34-44
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Tidskriftsartikel (refereegranskat)abstract
- Village-level solar power supply represents a promising potential for access to electricity services. Increased knowledge is needed for the development of solutions that work for the users and are viable in the long run. This article analyzes a solar power model developed and tested through action research in collaboration between a community in Kenya and a team of social scientists and technical experts. The analysis includes the reasons for its socio-technical design, and the actual functioning of the model. The research shows that an energy center model can cover basic electricity needs in areas with dispersed settlement patterns, where mini-grid based systems as well as conventional grid extension meet significant challenges. Such areas are representative for large geographical areas in Africa. We show that portable lanterns and low prices may enhance access to suitable services. Committed follow-up of the local actors, and a flexible socio-technical design – allowing for improvements after implementation – contribute to economic sustainability and smooth functioning. Close attention to the socio-cultural context and the challenges of users, operators and managers is required. Our research draws on theories of socio-technical change and users’ innovation, and presents a five-step analytical framework for analysis of village-level power provision.
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