| 1. |
- Aad, G, et al.
(författare)
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- 2015
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swepub:Mat__t
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| 13. |
- Reiling, E., et al.
(författare)
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Genetic association analysis of LARS2 with type 2 diabetes
- 2010
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:1, s. 103-110
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Tidskriftsartikel (refereegranskat)abstract
- LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk. We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent. No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95-1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90-1.08], p = 0.78, n = 35,715 respectively). In this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.
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| 14. |
- Terhal, Paulien A., et al.
(författare)
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A Study of the Clinical and Radiological Features in a Cohort of 93 Patients with a COL2A1 Mutation Causing Spondyloepiphyseal Dysplasia Congenita or a Related Phenotype
- 2015
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Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 167A:3, s. 461-475
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n=64), others having SEMD (n=5), Kniest dysplasia (n=7), spondyloperipheral dysplasia (n=2), or Torrance-like dysplasia (n=2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.
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| 15. |
- Litjens, Carlijn H. C., et al.
(författare)
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Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis
- 2023
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Ingår i: Antibiotics. - : MDPI. - 2079-6382. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainment of pharmacodynamic (PD) thresholds (AUC:MIC of >119) in plasma and cranial CSF of adults and children with tuberculous meningitis. A physiologically based pharmacokinetic (PBPK) model was developed to predict linezolid cranial CSF profiles based on reported plasma concentrations. Simulated steady-state PK curves in plasma and cranial CSF after linezolid doses of 300 mg BID, 600 mg BID, and 1200 mg QD in adults resulted in geometric mean AUC:MIC ratios in plasma of 118, 281, and 262 and mean cranial CSF AUC:MIC ratios of 74, 181, and 166, respectively. In children using similar to 10 mg/kg BID linezolid, AUC:MIC values at steady-state in plasma and cranial CSF were 202 and 135, respectively. Our model predicts that 1200 mg per day in adults, either 600 mg BID or 1200 mg QD, results in reasonable (87%) target attainment in cranial CSF. Target attainment in our simulated paediatric population was moderate (56% in cranial CSF). Our PBPK model can support linezolid dose optimization efforts by simulating target attainment close to the site of TBM disease.
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| 16. |
- Bukkems, V. E., et al.
(författare)
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Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments
- 2022
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Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 61:8, s. 1129-1141
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objective Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling.Methods Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (C-trough) values were compared with the target (0.23 mg/L) derived from in vivo exposure-response analysis.Results A decrease of 55% in maternal doravirine area under the plasma concentration-time curve (AUC)(0-24h) was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM C-trough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure.Conclusion Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data.
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- Hoste, E, et al.
(författare)
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OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 5913-
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Tidskriftsartikel (refereegranskat)abstract
- OTULIN is a deubiquitinase that specifically cleaves linear ubiquitin chains. Here we demonstrate that the ablation ofOtulinselectively in keratinocytes causes inflammatory skin lesions that develop into verrucous carcinomas. Genetic deletion ofTnfr1, knockin expression of kinase-inactiveRipk1or keratinocyte-specific deletion ofFaddandMlklcompletely rescues mice with OTULIN deficiency from dermatitis and tumorigenesis, thereby identifying keratinocyte cell death as the driving force for inflammation. Single-cell RNA-sequencing comparing non-lesional and lesional skin reveals changes in epidermal stem cell identity in OTULIN-deficient keratinocytes prior to substantial immune cell infiltration. Keratinocytes lacking OTULIN display a type-1 interferon and IL-1β response signature, and genetic or pharmacologic inhibition of these cytokines partially inhibits skin inflammation. Finally, expression of a hypomorphic mutantOtulinallele, previously shown to cause OTULIN-related autoinflammatory syndrome in humans, induces a similar inflammatory phenotype, thus supporting the importance of OTULIN for restraining skin inflammation and maintaining immune homeostasis.
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| 20. |
- Koetsier, Jarno, et al.
(författare)
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Blood-based multivariate methylation risk score for cognitive impairment and dementia
- 2024
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Ingår i: ALZHEIMERS & DEMENTIA. - : John Wiley & Sons. - 1552-5260 .- 1552-5279.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection. METHODS: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts. RESULTS: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 x 10(-3)). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia = 2.59). DISCUSSION: Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk.
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| 21. |
- Reiling, Erwin, et al.
(författare)
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The Association of Mitochondrial Content with Prevalent and Incident Type 2 Diabetes.
- 2010
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 95, s. 1909-1915
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Tidskriftsartikel (refereegranskat)abstract
- Context: It has been shown that mitochondrial DNA (mtDNA) content is associated with type 2 diabetes (T2D) and related traits. However, empirical data, often based on small samples, did not confirm this observation in all studies. Therefore, the role of mtDNA content in T2D remains elusive. Objective: In this study, we assessed the heritability of mtDNA content in buccal cells and analyzed the association of mtDNA content in blood with prevalent and incident T2D. Design and Setting: mtDNA content from cells from buccal and blood samples was assessed using a real-time PCR-based assay. Heritability of mtDNA content was estimated in 391 twins from the Netherlands Twin Register. The association with prevalent T2D was tested in a case control study from The Netherlands (n = 329). Incident T2D was analyzed using prospective samples from Finland (n = 444) and The Netherlands (n = 238). Main Outcome Measures: We measured the heritability of mtDNA content and the association of mtDNA content in blood with prevalent and incident T2D. Results: A heritability of mtDNA content of 35% (19-48%) was estimated in the twin families. We did not observe evidence of an association between mtDNA content and prevalent or incident T2D and related traits. Furthermore, we observed a decline in mtDNA content with increasing age that was male specific (P = 0.001). Conclusion: In this study, we show that mtDNA content has a heritability of 35% in Dutch twins. There is no association between mtDNA content in blood and prevalent or incident T2D and related traits in our study samples.
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| 24. |
- Fennell, P., et al.
(författare)
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Challenges and Lessons Learned in Applying Sensitivity Analysis to Building Stock Energy Models
- 2022
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Ingår i: Building Simulation Conference Proceedings. - : KU Leuven. - 2522-2708. ; , s. 2203-2210
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Konferensbidrag (refereegranskat)abstract
- Uncertainty Analysis (UA) and Sensitivity Analysis (SA) offer essential tools to determine the limits of inference of a model and explore the factors which have the most effect on the model outputs. However, despite a well-established body of work applying UA and SA to models of individual buildings, a review of the literature relating to energy models for larger groups of buildings undertaken by Fennell et al. (2019) highlighted very limited application at larger scales. This contribution describes the efforts undertaken by a group of research teams in the context of IEA-EBC Annex 70 working with a diverse set of Building Stock Models (BSMs) to apply global sensitivity analysis methods and compare their results. Since BSMs are a class of model defined by their output and coverage rather than their structure and inputs, they represent a diverse set of modelling approaches. Key challenges for the application of SA are identified and explored, including the influence of model form, input data types and model outputs. This study combines results from 7 different modelling teams, each using different models across a range of urban areas to explore these challenges and begin the process of developing standardised workflows for SA of BSMs.
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| 25. |
- Gümüş, H. G., et al.
(författare)
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Behavioral testing and litter effects in the rabbit
- 2018
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 353, s. 236-241
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Tidskriftsartikel (refereegranskat)abstract
- Background: Behavioral testing provides an essential approach in further developing our understanding of brain structure and function. The aim of our study was to outline a more expanded approach to cognition- and anxiety-related behavior in the rabbit. Methods: Twenty-one 70-day old rabbits (13 female, 8 male) were exposed to open field test, dark-light box test and object recognition testing with variations in inter-trial-interval, olfactory recognition and object location testing. Independent T-tests were used to compare data by individual baseline characteristics, i.e. birth weight, weight at testing, sex, litter #, litter size. Results: In the open field test, median time spent in the center was 3.64 s (0.84-41.36) for the 9 rabbits who entered the center; median distance moved in the arena was 874.42 cm (54.20-3444.83). In the dark light box test, 12 rabbits entered the light compartment. In the object recognition task, rabbits spent significantly less time exploring the familiar object compared to the novel (0.40 s [0-2.8] vs. 3.17 s [1.30-32.69]; P = 0.003) when using a 30-min inter-trial interval, as well with a 90-min inter-trial interval: 0.87 s [0-7.8] vs. 7.65 s [0-37.6] (P = 0.008). However, recognition was lost when using a 24-h inter-trial interval (time spent exploring the familiar object: 3.33 [0-10.90]; novel object:3.87 [1.15-48.53]; n.s). In the object location task and in olfactory object recognition task, median discrimination indexes were 0.69 (-1 to 1) and 0.37 (-0.38 to 0.78) respectively, higher than level expected by chance (P < 0.001). Litter size >3 during the neonatal period was associated with increased explorative behavior in the dark light box test (P = 0.046) and in the visual object recognition task (P = 0.005), whereas body weight and sex were not. Conclusions: Settings and outcome measures for multiple behavioral tests, providing reference values and considerations for future developmental studies are reported. Discrimination and memory in the rabbit appear to relate to litter characteristics, although a larger sample size is needed to confirm our findings.
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| 26. |
- Hulme, Mike, et al.
(författare)
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Letter: Science-Policy Interface: Beyond Assessments
- 2011
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 333:6043, s. 697-698
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 27. |
- Langevin, Jared, et al.
(författare)
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Developing a common approach for classifying building stock energy models
- 2020
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Ingår i: Renewable and Sustainable Energy Reviews. - : Elsevier BV. - 1879-0690 .- 1364-0321. ; 133
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Tidskriftsartikel (refereegranskat)abstract
- Buildings contribute 40% of global greenhouse gas emissions; therefore, strategies that can substantially reduce emissions from the building stock are key components of broader efforts to mitigate climate change and achieve sustainable development goals. Models that represent the energy use of the building stock at scale under various scenarios of technology deployment have become essential tools for the development and assessment of such strategies. Within the past decade, the capabilities of building stock energy models have improved considerably, while model transferability and sharing has increased. Given these advancements, a new scheme for classifying building stock energy models is needed to facilitate communication of modeling approaches and the handling of important model dimensions. In this article, we present a new building stock energy model classification framework that leverages international modeling expertise from the participants of the International Energy Agency's Annex 70 on Building Energy Epidemiology. Drawing from existing classification studies, we propose a multi-layer quadrant scheme that classifies modeling techniques by their design (top-down or bottom-up) and degree of transparency (black-box or white-box); hybrid techniques are also addressed. The quadrant scheme is unique from previous classification approaches in its non-hierarchical organization, coverage of and ability to incorporate emerging modeling techniques, and treatment of additional modeling dimensions. The new classification framework will be complemented by a reporting protocol and online registry of existing models as part of ongoing work in Annex 70 to increase the interpretability and utility of building stock energy models for energy policy making.
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| 29. |
- Chen, W., et al.
(författare)
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Structure determination of Pt3Ti(111) by automated tensor LEED
- 1993
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Ingår i: Journal of Physics. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 5, s. 4585-4594
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Tidskriftsartikel (refereegranskat)abstract
- An analysis of low-energy electron diffraction (LEED) I-V spectra from the clean Pt3Ti(111) surface was performed by comparing measured intensities with data calculated using an automated tensor LEED program, which employs a directed search optimization procedure. It was found that the topmost layer is pure Pt and that the other layers have the bulk composition. The first and second interlayer spacings are 2.23+or-0.03 AA and 2.21+or-0.03 AA respectively, corresponding to a contraction of 0.9% and 1.8% of the bulk value. The perpendicular buckling is 0.04 AA +or-0.05 AA in the top layer and 0.15 AA +or-0.04 AA in the second layer. The results are in full accordance with previous investigations of the physical and chemical properties of this surface.
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| 31. |
- Luck, Gary W., et al.
(författare)
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Quantifying the Contribution of Organisms to the Provision of Ecosystem Services
- 2009
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Ingår i: BioScience. - : Oxford University Press (OUP). - 0006-3568 .- 1525-3244. ; 59:3, s. 223-235
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Tidskriftsartikel (refereegranskat)abstract
- Research on ecosystem services has grown rapidly over the last decade. Two conceptual frameworks have been published to guide ecological assessments of organisms that deliver services-the concepts of service-providing units (SPUs) and ecosystem service providers (ESPs). Here, we unite these frameworks and present an SPU-ESP continuum that offers a coherent conceptual approach for synthesizing the latest developments in ecosystem service research, and can direct future studies at all levels of organization. In particular, we show how the service-provider concept call be applied tit the population, functional group, and community levels, We strongly emphasize the need to identify and quantify the organisms and their characteristics (e.g., functional traits) that provide services, and to assess service provision relative to the demands of human beneficiaries. We use key examples from the literature to illustrate the new approach and to highlight gaps in knowledge, particularly in relation to the impact of species interactions and ecosystem dynamics on service provision.
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| 32. |
- van der Merwe, Maria, et al.
(författare)
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Collective reflections on the first cycle of a collaborative learning platform to strengthen rural primary healthcare in Mpumalanga, South Africa
- 2021
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Ingår i: Health Research Policy and Systems. - : BioMed Central. - 1478-4505. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Frontline managers and health service providers are constrained in many contexts from responding to community priorities due to organizational cultures focused on centrally defined outputs and targets. This paper presents an evaluation of the Verbal Autopsy with Participatory Action Research (VAPAR) programme—a collaborative learning platform embedded in the local health system in Mpumalanga, South Africa—for strengthening of rural primary healthcare (PHC) systems. The programme aims to address exclusion from access to health services by generating and acting on research evidence of practical, local relevance. Methods: Drawing on existing links in the provincial and national health systems and applying rapid, participatory evaluation techniques, we evaluated the first action-learning cycle of the VAPAR programme (2017–19). We collected data in three phases: (1) 10 individual interviews with programme stakeholders, including from government departments and parastatals, nongovernmental organizations and local communities; (2) an evaluative/exploratory workshop with provincial and district Department of Health managers; and (3) feedback and discussion of findings during an interactive workshop with national child health experts. Results: Individual programme stakeholders described early outcomes relating to effective research and stakeholder engagement, and organization and delivery of services, with potential further contributions to the establishment of an evidence base for local policy and planning, and improved health outcomes. These outcomes were verified with provincial managers. Provincial and national stakeholders identified the potential for VAPAR to support engagement between communities and health authorities for collective planning and implementation of services. Provincial stakeholders proposed that this could be achieved through a two-way integration, with VAPAR stakeholders participating in routine health planning and review activities and frontline health officials being involved in the VAPAR process. Findings were collated into a revised theory of change. Conclusions: The VAPAR learning platform was regarded as a feasible, acceptable and relevant approach to facilitate cooperative learning and community participation in health systems. The evaluation provides support for a collaborative learning platform within routine health system processes and contributes to the limited evaluative evidence base on embedded health systems research.
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