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31.
Elin M. Svensson Mats O. Karlsson 《Journal of pharmacokinetics and pharmacodynamics》2014,41(2):153-158
The objective of this work was to facilitate the development of nonlinear mixed effects models by establishing a diagnostic method for evaluation of stochastic model components. The random effects investigated were between subject, between occasion and residual variability. The method was based on a first-order conditional estimates linear approximation and evaluated on three real datasets with previously developed population pharmacokinetic models. The results were assessed based on the agreement in difference in objective function value between a basic model and extended models for the standard nonlinear and linearized approach respectively. The linearization was found to accurately identify significant extensions of the model’s stochastic components with notably decreased runtimes as compared to the standard nonlinear analysis. The observed gain in runtimes varied between four to more than 50-fold and the largest gains were seen for models with originally long runtimes. This method may be especially useful as a screening tool to detect correlations between random effects since it substantially quickens the estimation of large variance–covariance blocks. To expedite the application of this diagnostic tool, the linearization procedure has been automated and implemented in the software package PsN. 相似文献
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Sarah Keildson Joao Fadista Claes Ladenvall ?sa K. Hedman Targ Elgzyri Kerrin S. Small Elin Grundberg Alexandra C. Nica Daniel Glass J. Brent Richards Amy Barrett James Nisbet Hou-Feng Zheng Tina R?nn Kristoffer Str?m Karl-Fredrik Eriksson Inga Prokopenko MAGIC Consortium DIAGRAM Consortium MuTHER Consortium Timothy D. Spector Emmanouil T. Dermitzakis Panos Deloukas Mark I. McCarthy Johan Rung Leif Groop Paul W. Franks Cecilia M. Lindgren Ola Hansson 《Diabetes》2014,63(3):1154-1165
Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10−5) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10−4). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10−6) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r2 = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10−3). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity. 相似文献
35.
Longitudinal Association Between Physical Activity and Frailty Among Community-Dwelling Older Adults
Xuxi Zhang MPH Siok Swan Tan PhD Carmen Betsy Franse PhD Lovorka Bilajac PhD Tamara Alhambra-Borrás PhD Jorge Garcés-Ferrer PhD Arpana Verma MD PhD Greg Williams MSc Gary Clough PGCert Elin Koppelaar PhD Tasos Rentoumis MSc Rob van Staveren MSc Antonius J. J. Voorham PhD Francesco Mattace-Raso MD PhD Amy van Grieken PhD Hein Raat MD PhD 《Journal of the American Geriatrics Society》2020,68(7):1484-1493
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Amy Lane Elizabeth Green Elin Schold Davis Beth Rolland Janet T. Stohler 《Occupational Therapy in Health Care》2014,28(2):177-187
This paper highlights the critical need for a diverse span of services targeted at older drivers that is clear and understandable to health care professionals, service providers, and consumers. The paper describes how a panel of expert driver rehabilitation specialists and researchers on older drivers affirmed consensus statements addressing the need for clarification of terms and services. It also presents a new document that describes a spectrum of driver services from education to specific driver rehabilitation services. The document will provide consumers, referral sources, payers, and stakeholders invested in older drivers’ services, with the information to refer the right people to the right service at the right time. 相似文献
38.
Eric Morin Cecilia Lindskog Martin Johansson Lars Egevad Per Sandström Ulrika Harmenberg Lena Claesson-Welsh Elin Sjöberg 《The Journal of pathology》2020,250(4):387-396
Renal cell carcinoma (RCC) treatment has improved in the last decade with the introduction of drugs targeting tumor angiogenesis. However, the 5-year survival of metastatic disease is still only 10–15%. Here, we explored the prognostic significance of compartment-specific expression of Neuropilin 1 (NRP1), a co-receptor for vascular endothelial growth factor (VEGF). NRP1 expression was analyzed in RCC tumor vessels, in perivascular tumor cells, and generally in the tumor cell compartment. Moreover, complex formation between NRP1 and the main VEGF receptor, VEGFR2, was determined. Two RCC tissue microarrays were used; a discovery cohort consisting of 64 patients and a validation cohort of 314 patients. VEGFR2/NRP1 complex formation in cis (on the same cell) and trans (between cells) configurations was determined by in situ proximity ligation assay (PLA), and NRP1 protein expression in three compartments (endothelial cells, perivascular tumor cells, and general tumor cell expression) was determined by immunofluorescent staining. Expression of NRP1 in perivascular tumor cells was explored as a marker for RCC survival in the two RCC cohorts. Results were further validated using a publicly available gene expression dataset of clear cell RCC (ccRCC). We found that VEGFR2/NRP1 trans complexes were detected in 75% of the patient samples. The presence of trans VEGFR2/NRP1 complexes or perivascular NRP1 expression was associated with a reduced tumor vessel density and size. When exploring NRP1 as a biomarker for RCC prognosis, perivascular NRP1 and general tumor cell NRP1 protein expression correlated with improved survival in the two independent cohorts, and significant results were obtained also at the mRNA level using the publicly available ccRCC gene expression dataset. Only perivascular NRP1 expression remained significant in multivariable analysis. Our work shows that perivascular NRP1 expression is an independent marker of improved survival in RCC patients, and reduces tumor vascularization by forming complexes in trans with VEGFR2 in the tumor endothelium. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. 相似文献
39.
Anna?M?Wirsing Oddveig?G?Rikardsen Sonja?E?Steigen Lars?Uhlin-Hansen Elin?Hadler-OlsenEmail author 《BMC clinical pathology》2014,14(1):38
Background
Oral squamous cell carcinomas are often heavily infiltrated by immune cells. The organization of B-cells, follicular dendritic cells, T-cells and high-endothelial venules into structures termed tertiary lymphoid structures have been detected in various types of cancer, where their presence is found to predict favourable outcome. The purpose of the present study was to evaluate the incidence of tertiary lymphoid structures in oral squamous cell carcinomas, and if present, analyse whether they were associated with clinical outcome.Methods
Tumour samples from 80 patients with oral squamous cell carcinoma were immunohistochemically stained for B-cells, follicular dendritic cells, T-cells, germinal centre B-cells and high-endothelial venules. Some samples were sectioned at multiple levels to assess whether the presence of tertiary lymphoid structures varied within the tumour.Results
Tumour-associated tertiary lymphoid structures were detected in 21 % of the tumours and were associated with lower disease-specific death. The presence of tertiary lymphoid structures varied within different levels of a tissue block.Conclusions
Tertiary lymphoid structure formation was found to be a positive prognostic factor for patients with oral squamous cell carcinoma. Increased knowledge about tertiary lymphoid structure formation in oral squamous cell carcinoma might help to develop and guide immune-modulatory cancer treatments.40.
Margaret Sällberg Chen Elin Strömberg Gerald Lee Vogel 《Acta odontologica Scandinavica》2014,72(7):557-560
Background. Previous studies have shown that a calcium (Ca) pre-rinse given before a 228 ppm fluoride (F) rinse greatly increased salivary fluoride. Objectives. The aim of this randomized controlled trial is to examine if Ca pre-rinse could increase the fluoride concentration in the overnight unstimulated saliva after a 905 ppm F-rinse. Materials and methods. Pre-rinses containing 150 mM, 75 mM or 0 mM Ca-lactate prepared by a validated pharmaceutical cGPM procedure were tested by nine subjects in a randomized order immediately followed by a 905 ppm F-rinse. The fluoride concentration was measured in unstimulated saliva collected 10 h later. Results and conclusions. The Ca pre-treatment significantly increased F level in overnight saliva following the 905 ppm fluoride rinse by 1.7× relative to the 905 ppm F-rinse alone; however, a significant effect was only observed with the highest (150 mM) Ca concentration as pre-rinse. Clinical relevance. High concentration F rinses (905 ppm) are commonly recommended for patients at high-risk of caries. A pre-treatment with high levels of Ca may further improve the cariostatic effect of this ion. 相似文献