| 1. |
- Keller, H. U., et al.
(author)
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E-Type Asteroid (2867) Steins as Imaged by OSIRIS on Board Rosetta
- 2010
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 327:5962, s. 190-193
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Journal article (peer-reviewed)abstract
- The European Space Agency's Rosetta mission encountered the main-belt asteroid (2867) Steins while on its way to rendezvous with comet 67P/Churyumov-Gerasimenko. Images taken with the OSIRIS (optical, spectroscopic, and infrared remote imaging system) cameras on board Rosetta show that Steins is an oblate body with an effective spherical diameter of 5.3 kilometers. Its surface does not show color variations. The morphology of Steins is dominated by linear faults and a large 2.1-kilometer-diameter crater near its south pole. Crater counts reveal a distinct lack of small craters. Steins is not solid rock but a rubble pile and has a conical appearance that is probably the result of reshaping due to Yarkovsky-O'Keefe-Radzievskii-Paddack (YORP) spin-up. The OSIRIS images constitute direct evidence for the YORP effect on a main-belt asteroid.
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| 2. |
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| 3. |
- Alvarsson, Jonathan, et al.
(author)
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Benchmarking Study of Parameter Variation When Using Signature Fingerprints Together with Support Vector Machines
- 2014
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In: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 54:11, s. 3211-3217
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Journal article (peer-reviewed)abstract
- QSAR modeling using molecular signatures and support vector machines with a radial basis function is increasingly used for virtual screening in the drug discovery field. This method has three free parameters: C, ?, and signature height. C is a penalty parameter that limits overfitting, ? controls the width of the radial basis function kernel, and the signature height determines how much of the molecule is described by each atom signature. Determination of optimal values for these parameters is time-consuming. Good default values could therefore save considerable computational cost. The goal of this project was to investigate whether such default values could be found by using seven public QSAR data sets spanning a wide range of end points and using both a bit version and a count version of the molecular signatures. On the basis of the experiments performed, we recommend a parameter set of heights 0 to 2 for the count version of the signature fingerprints and heights 0 to 3 for the bit version. These are in combination with a support vector machine using C in the range of 1 to 100 and gamma in the range of 0.001 to 0.1. When data sets are small or longer run times are not a problem, then there is reason to consider the addition of height 3 to the count fingerprint and a wider grid search. However, marked improvements should not be expected.
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| 4. |
- Alvarsson, Jonathan, et al.
(author)
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Large-scale ligand-based predictive modelling using support vector machines
- 2016
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In: Journal of Cheminformatics. - : Springer Science and Business Media LLC. - 1758-2946. ; 8
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Journal article (peer-reviewed)abstract
- The increasing size of datasets in drug discovery makes it challenging to build robust and accurate predictive models within a reasonable amount of time. In order to investigate the effect of dataset sizes on predictive performance and modelling time, ligand-based regression models were trained on open datasets of varying sizes of up to 1.2 million chemical structures. For modelling, two implementations of support vector machines (SVM) were used. Chemical structures were described by the signatures molecular descriptor. Results showed that for the larger datasets, the LIBLINEAR SVM implementation performed on par with the well-established libsvm with a radial basis function kernel, but with dramatically less time for model building even on modest computer resources. Using a non-linear kernel proved to be infeasible for large data sizes, even with substantial computational resources on a computer cluster. To deploy the resulting models, we extended the Bioclipse decision support framework to support models from LIBLINEAR and made our models of logD and solubility available from within Bioclipse.
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| 5. |
- Alvarsson, Jonathan, 1981-
(author)
-
Ligand-based Methods for Data Management and Modelling
- 2015
-
Doctoral thesis (other academic/artistic)abstract
- Drug discovery is a complicated and expensive process in the billion dollar range. One way of making the drug development process more efficient is better information handling, modelling and visualisation. The majority of todays drugs are small molecules, which interact with drug targets to cause an effect. Since the 1980s large amounts of compounds have been systematically tested by robots in so called high-throughput screening. Ligand-based drug discovery is based on modelling drug molecules. In the field known as Quantitative Structure–Activity Relationship (QSAR) molecules are described by molecular descriptors which are used for building mathematical models. Based on these models molecular properties can be predicted and using the molecular descriptors molecules can be compared for, e.g., similarity. Bioclipse is a workbench for the life sciences which provides ligand-based tools through a point and click interface. The aims of this thesis were to research, and develop new or improved ligand-based methods and open source software, and to work towards making these tools available for users through the Bioclipse workbench. To this end, a series of molecular signature studies was done and various Bioclipse plugins were developed.An introduction to the field is provided in the thesis summary which is followed by five research papers. Paper I describes the Bioclipse 2 software and the Bioclipse scripting language. In Paper II the laboratory information system Brunn for supporting work with dose-response studies on microtiter plates is described. In Paper III the creation of a molecular fingerprint based on the molecular signature descriptor is presented and the new fingerprints are evaluated for target prediction and found to perform on par with industrial standard commercial molecular fingerprints. In Paper IV the effect of different parameter choices when using the signature fingerprint together with support vector machines (SVM) using the radial basis function (RBF) kernel is explored and reasonable default values are found. In Paper V the performance of SVM based QSAR using large datasets with the molecular signature descriptor is studied, and a QSAR model based on 1.2 million substances is created and made available from the Bioclipse workbench.
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| 6. |
- Alvarsson, Jonathan, et al.
(author)
-
Ligand-Based Target Prediction with Signature Fingerprints
- 2014
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In: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 54:10, s. 2647-2653
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Journal article (peer-reviewed)abstract
- When evaluating a potential drug candidate it is desirable to predict target interactions in silico prior to synthesis in order to assess, e.g., secondary pharmacology. This can be done by looking at known target binding profiles of similar compounds using chemical similarity searching. The purpose of this study was to construct and evaluate the performance of chemical fingerprints based on the molecular signature descriptor for performing target binding predictions. For the comparison we used the area under the receiver operating characteristics curve (AUC) complemented with net reclassification improvement (NRI). We created two open source signature fingerprints, a bit and a count version, and evaluated their performance compared to a set of established fingerprints with regards to predictions of binding targets using Tanimoto-based similarity searching on publicly available data sets extracted from ChEMBL. The results showed that the count version of the signature fingerprint performed on par with well-established fingerprints such as ECFP. The count version outperformed the bit version slightly; however, the count version is more complex and takes more computing time and memory to run so its usage should probably be evaluated on a case-by-case basis. The NRI based tests complemented the AUC based ones and showed signs of higher power.
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| 7. |
- Eklund, Martin, et al.
(author)
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The C1C2 : a framework for simultaneous model selection and assessment
- 2008
-
In: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 9, s. 360-
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Journal article (peer-reviewed)abstract
- BACKGROUND: There has been recent concern regarding the inability of predictive modeling approaches to generalize to new data. Some of the problems can be attributed to improper methods for model selection and assessment. Here, we have addressed this issue by introducing a novel and general framework, the C1C2, for simultaneous model selection and assessment. The framework relies on a partitioning of the data in order to separate model choice from model assessment in terms of used data. Since the number of conceivable models in general is vast, it was also of interest to investigate the employment of two automatic search methods, a genetic algorithm and a brute-force method, for model choice. As a demonstration, the C1C2 was applied to simulated and real-world datasets. A penalized linear model was assumed to reasonably approximate the true relation between the dependent and independent variables, thus reducing the model choice problem to a matter of variable selection and choice of penalizing parameter. We also studied the impact of assuming prior knowledge about the number of relevant variables on model choice and generalization error estimates. The results obtained with the C1C2 were compared to those obtained by employing repeated K-fold cross-validation for choosing and assessing a model. RESULTS: The C1C2 framework performed well at finding the true model in terms of choosing the correct variable subset and producing reasonable choices for the penalizing parameter, even in situations when the independent variables were highly correlated and when the number of observations was less than the number of variables. The C1C2 framework was also found to give accurate estimates of the generalization error. Prior information about the number of important independent variables improved the variable subset choice but reduced the accuracy of generalization error estimates. Using the genetic algorithm worsened the model choice but not the generalization error estimates, compared to using the brute-force method. The results obtained with repeated K-fold cross-validation were similar to those produced by the C1C2 in terms of model choice, however a lower accuracy of the generalization error estimates was observed. CONCLUSION: The C1C2 framework was demonstrated to work well for finding the true model within a penalized linear model class and accurately assess its generalization error, even for datasets with many highly correlated independent variables, a low observation-to-variable ratio, and model assumption deviations. A complete separation of the model choice and the model assessment in terms of data used for each task improves the estimates of the generalization error.
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| 8. |
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| 9. |
- Lapins, Maris, et al.
(author)
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A Unified Proteochemometric Model for Prediction of Inhibition of Cytochrome P450 Isoforms
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6, s. e66566-
-
Journal article (peer-reviewed)abstract
- A unified proteochemometric (PCM) model for the prediction of the ability of drug-like chemicals to inhibit five major drug metabolizing CYP isoforms (i.e. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was created and made publicly available under the Bioclipse Decision Support open source system at www.cyp450model.org. In regards to the proteochemometric modeling we represented the chemical compounds by molecular signature descriptors and the CYP-isoforms by alignment-independent description of composition and transition of amino acid properties of their protein primary sequences. The entire training dataset contained 63 391 interactions and the best PCM model was obtained using signature descriptors of height 1, 2 and 3 and inducing the model with a support vector machine. The model showed excellent predictive ability with internal AUC = 0.923 and an external AUC = 0.940, as evaluated on a large external dataset. The advantage of PCM models is their extensibility making it possible to extend our model for new CYP isoforms and polymorphic CYP forms. A key benefit of PCM is that all proteins are confined in one single model, which makes it generally more stable and predictive as compared with single target models. The inclusion of the model in Bioclipse Decision Support makes it possible to make virtual instantaneous predictions (∼100 ms per prediction) while interactively drawing or modifying chemical structures in the Bioclipse chemical structure editor.
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| 10. |
- Lapins, Maris, et al.
(author)
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Proteochemometric modeling of HIV protease susceptibility
- 2008
-
In: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 9, s. 181-
-
Journal article (peer-reviewed)abstract
- BACKGROUNDA major obstacle in treatment of HIV is the ability of the virus to mutate rapidly into drug-resistant variants. A method for predicting the susceptibility of mutated HIV strains to antiviral agents would provide substantial clinical benefit as well as facilitate the development of new candidate drugs. Therefore, we used proteochemometrics to model the susceptibility of HIV to protease inhibitors in current use, utilizing descriptions of the physico-chemical properties of mutated HIV proteases and 3D structural property descriptions for the protease inhibitors. The descriptions were correlated to the susceptibility data of 828 unique HIV protease variants for seven protease inhibitors in current use; the data set comprised 4792 protease-inhibitor combinations.RESULTSThe model provided excellent predictability (R2 = 0.92, Q2 = 0.87) and identified general and specific features of drug resistance. The model's predictive ability was verified by external prediction in which the susceptibilities to each one of the seven inhibitors were omitted from the data set, one inhibitor at a time, and the data for the six remaining compounds were used to create new models. This analysis showed that the over all predictive ability for the omitted inhibitors was Q2 inhibitors = 0.72.CONCLUSIONOur results show that a proteochemometric approach can provide generalized susceptibility predictions for new inhibitors. Our proteochemometric model can directly analyze inhibitor-protease interactions and facilitate treatment selection based on viral genotype. The model is available for public use, and is located at HIV Drug Research Centre.
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| 11. |
- Ljungvall, K, et al.
(author)
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Early post-natal exposure to low dose oral di(2ethylhexyl) phthalate affects the peripheral LH-concentration in plasma, but does not affect mating behavior in the post-pubertal boar
- 2006
-
In: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 21:2, s. 160-166
-
Journal article (peer-reviewed)abstract
- In a split-litter design experiment, boars were exposed orally three times weekly to 300 mg/kg of di(2-ethylhexyl) phthalate (DEHP) between 3 and 7 weeks of age. Post-puberty, i.e. at 6 months of age the effects on endocrinology and mating behavior were examined. The response to stimulation with a synthetic GnRH-analogue at 9 months of age resulted initially in lower concentration of LH in the exposed animals, compared to the control animals. We did not find any effects of DEHP on the mating behavior. Also, the effects of DEHP during the treatment period on the plasma concentrations of testosterone, oestradiol and LH were examined. During the exposure period there was a transient decrease in plasma concentrations of LH in the control group, which did not occur in the boars exposed to DEHR The data suggest that DEHP in low repeated oral doses causes lasting effects on the hypothalamus-pituitary-gonadal axis. (c) 2005 Elsevier Inc. All rights reserved.
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| 12. |
- Shoombuatong, Watshara, et al.
(author)
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Towards Predicting the Cytochrome P450 Modulation : From QSAR to proteochemometric modeling.
- 2017
-
In: Current drug metabolism. - : Bentham Science Publishers Ltd.. - 1389-2002 .- 1875-5453. ; 18:6, s. 540-555
-
Journal article (peer-reviewed)abstract
- Drug metabolism determines the fate of a drug when it enters the human body and is a critical factor in defining their absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics. Among the various drug metabolizing enzymes, cytochrome P450s (CYP450) constitute an important protein family that aside from functioning in xenobiotic metabolism is also responsible for a diverse array of other roles encompassing steroid and cholesterol biosynthesis, fatty acid metabolism, calcium homeostasis, neuroendocrine functions and growth regulation. Although CYP450 typically convert xenobiotics into safe metabolites, there are some situations whereby the metabolite is more toxic than its parent molecule. Computational modeling has been instrumental in CYP450 research by rationalizing the nature of the binding event (i.e. inhibit or induce CYP450s) or metabolic stability of query compounds of interest. A plethora of computational approaches encompassing ligand, structure and systems based approaches have been utilized to model CYP450-ligand interactions. This review provides a brief background on the CYP450 family (i.e. its roles, advantages and disadvantages as well as its modulators) and then discusses the various computational approaches that have been used to model CYP450-ligand interaction. Particular focus is given to the use of quantitative structure-activity relationship (QSAR) and more recent proteochemometric modeling studies. Finally, a perspective on the current state of the art and future trends of the field is provided.
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| 13. |
- Simeon, Saw, et al.
(author)
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Origin of aromatase inhibitory activity via proteochemometric modeling
- 2016
-
In: PeerJ. - : PeerJ. - 2167-8359. ; 4
-
Journal article (peer-reviewed)abstract
- Aromatase, the rate-limiting enzyme that catalyzes the conversion of androgen to estrogen, plays an essential role in the development of estrogen-dependent breast cancer. Side effects due to aromatase inhibitors (AIs) necessitate the pursuit of novel inhibitor candidates with high selectivity, lower toxicity and increased potency. Designing a novel therapeutic agent against aromatase could be achieved computationally by means of ligand-based and structure-based methods. For over a decade, we have utilized both approaches to design potential AIs for which quantitative structure-activity relationships and molecular docking were used to explore inhibitory mechanisms of AIs towards aromatase. However, such approaches do not consider the effects that aromatase variants have on different AIs. In this study, proteochemometrics modeling was applied to analyze the interaction space between AIs and aromatase variants as a function of their substructural and amino acid features. Good predictive performance was achieved, as rigorously verified by 10-fold cross-validation, external validation, leave-one-compound-out cross-validation, leave-one-protein-out cross-validation and Y-scrambling tests. The investigations presented herein provide important insights into the mechanisms of aromatase inhibitory activity that could aid in the design of novel potent AIs as breast cancer therapeutic agents.
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| 14. |
- Spjuth, Ola, et al.
(author)
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Bioclipse : an open source workbench for chemo- and bioinformatics
- 2007
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In: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 8, s. 59-
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Journal article (peer-reviewed)abstract
- BACKGROUND: There is a need for software applications that provide users with a complete and extensible toolkit for chemo- and bioinformatics accessible from a single workbench. Commercial packages are expensive and closed source, hence they do not allow end users to modify algorithms and add custom functionality. Existing open source projects are more focused on providing a framework for integrating existing, separately installed bioinformatics packages, rather than providing user-friendly interfaces. No open source chemoinformatics workbench has previously been published, and no successful attempts have been made to integrate chemo- and bioinformatics into a single framework. RESULTS: Bioclipse is an advanced workbench for resources in chemo- and bioinformatics, such as molecules, proteins, sequences, spectra, and scripts. It provides 2D-editing, 3D-visualization, file format conversion, calculation of chemical properties, and much more; all fully integrated into a user-friendly desktop application. Editing supports standard functions such as cut and paste, drag and drop, and undo/redo. Bioclipse is written in Java and based on the Eclipse Rich Client Platform with a state-of-the-art plugin architecture. This gives Bioclipse an advantage over other systems as it can easily be extended with functionality in any desired direction. CONCLUSION: Bioclipse is a powerful workbench for bio- and chemoinformatics as well as an advanced integration platform. The rich functionality, intuitive user interface, and powerful plugin architecture make Bioclipse the most advanced and user-friendly open source workbench for chemo- and bioinformatics. Bioclipse is released under Eclipse Public License (EPL), an open source license which sets no constraints on external plugin licensing; it is totally open for both open source plugins as well as commercial ones. Bioclipse is freely available at http://www.bioclipse.net.
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| 15. |
- Spjuth, Ola, 1977-, et al.
(author)
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Bioclipse-R : Integrating management and visualization of life science data with statistical analysis
- 2013
-
In: Bioinformatics. - : Oxford University Press. - 1367-4803 .- 1367-4811. ; 29:2, s. 286-289
-
Journal article (peer-reviewed)abstract
- Bioclipse, a graphical workbench for the life sciences, provides functionality for managing and visualizing life science data. We introduce Bioclipse-R, which integrates Bioclipse and the statistical programming language R. The synergy between Bioclipse and R is demonstrated by the construction of a decision support system for anticancer drug screening and mutagenicity prediction, which shows how Bioclipse-R can be used to perform complex tasks from within a single software system.
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| 16. |
- Spjuth, Ola, 1977-, et al.
(author)
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Harmonising and linking biomedical and clinical data across disparate data archives to enable integrative cross-biobank research
- 2016
-
In: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 24:4, s. 521-528
-
Journal article (peer-reviewed)abstract
- A wealth of biospecimen samples are stored in modern globally distributed biobanks. Biomedical researchers worldwide need to be able to combine the available resources to improve the power of large-scale studies. A prerequisite for this effort is to be able to search and access phenotypic, clinical and other information about samples that are currently stored at biobanks in an integrated manner. However, privacy issues together with heterogeneous information systems and the lack of agreed-upon vocabularies have made specimen searching across multiple biobanks extremely challenging. We describe three case studies where we have linked samples and sample descriptions in order to facilitate global searching of available samples for research. The use cases include the ENGAGE (European Network for Genetic and Genomic Epidemiology) consortium comprising at least 39 cohorts, the SUMMIT (surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes tools) consortium and a pilot for data integration between a Swedish clinical health registry and a biobank. We used the Sample avAILability (SAIL) method for data linking: first, created harmonised variables and then annotated and made searchable information on the number of specimens available in individual biobanks for various phenotypic categories. By operating on this categorised availability data we sidestep many obstacles related to privacy that arise when handling real values and show that harmonised and annotated records about data availability across disparate biomedical archives provide a key methodological advance in pre-analysis exchange of information between biobanks, that is, during the project planning phase.
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| 17. |
- Woolhead, G., et al.
(author)
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"Tu" or "Vous?". A European qualitative study of dignity and communication with older people in health and social care settings
- 2006
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In: Patient Education and Counseling. - : Elsevier BV. - 0738-3991 .- 1873-5134. ; 61:3, s. 363-371
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Journal article (peer-reviewed)abstract
- Objective: To examine the experiences of communication between older people and health and social care providers in six European countries. Methods: Focus groups were carried out with groups of older people (91 focus groups, 391 participants), and health and social care professionals (85 focus groups, 424 participants), in order to gain insights into concepts of good communications. Data collection and analysis continued concurrently according to the method of constant comparison. Results: Different styles of communication between professionals and older people were found to be capable of enhancing or jeopardising dignity. The use of appropriate forms of address, listening, giving people choice, including them, respecting their need for privacy and politeness, and making them feel valued emerged as significant ways to maintain older peoples' sense of self-worth and dignity. Despite being aware of good communication practices, health and social care professionals often failed to implement them. Lack of time, staff, resource scarcity, regulation and bureaucracy were cited as barriers, as was a lack of awareness and effort. Conclusions and practice implications: The findings have important implications for health and social care professionals when they engage with older people. © 2005 Elsevier Ireland Ltd. All rights reserved.
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