| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Clark, Andrew G., et al.
(författare)
-
Evolution of genes and genomes on the Drosophila phylogeny
- 2007
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
-
Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
|
|
| 6. |
- Adam, A, et al.
(författare)
-
Abstracts from Hydrocephalus 2016.
- 2017
-
Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 14:Suppl 1
-
Tidskriftsartikel (refereegranskat)
|
|
| 7. |
- Weinstein, John N., et al.
(författare)
-
The cancer genome atlas pan-cancer analysis project
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:10, s. 1113-1120
-
Tidskriftsartikel (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Jensen, NK, et al.
(författare)
-
Too sick to work, too healthy to qualify: a cross-country analysis of the effect of changes to disability benefits
- 2019
-
Ingår i: Journal of epidemiology and community health. - : BMJ. - 1470-2738 .- 0143-005X. ; 73:8, s. 717-722
-
Tidskriftsartikel (refereegranskat)abstract
- Denmark and Sweden have implemented reforms that narrowed disability benefit eligibility criteria. Such reforms in combination with increasing work demands create a pincer movement where in particular those with moderate health problems might be unable to comply with work demands, but still not qualify for permanent disability benefits, ending up with temporary means-tested or no benefits. This paper examines whether this actually happened before and after the reforms.MethodsThe Survey of Health, Ageing and Retirement in Europe (SHARE) study waves 1–2 and 4–6 in Denmark and Sweden for the age group 50–59 years (N=5384) was used to analyse changes in employment rates and benefits among people with different levels of health before, during and after disability benefit reforms. Interaction between time and health in relation to employment versus permanent or temporary benefits was used as a criterion for whether our hypotheses was confirmed.ResultsOverall, employment rates have increased in the age group, but only among the healthy. The OR for receiving temporary or no benefits increased from 1.25 (95% CI: 0.81 to 1.90) before to 1.73 (95% CI: 1.14 to 2.61) after policy reforms for the 29% with moderate health problems and from 2.89 (95% CI: 1.66 to 5.03) to 6.71 (95% CI: 3.94 to 11.42) among the 11% with severe health problems. The interaction between time and health was statistically significant (p<0.001).ConclusionPeople with impaired health and workability are forced into a life with temporary means-tested or no benefits when pressed by rising work demands and stricter disability benefit eligibility criteria.
|
|
| 11. |
|
|
| 12. |
- Tabor, J. B., et al.
(författare)
-
Role of biomarkers and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion: a systematic review
- 2023
-
Ingår i: British Journal of Sports Medicine. - 0306-3674. ; 57:12
-
Forskningsöversikt (refereegranskat)abstract
- ObjectiveDetermine the role of fluid-based biomarkers, advanced neuroimaging, genetic testing and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion (SRC). DesignSystematic review. Data sourcesSearches of seven databases from 1 January 2001 through 24 March 2022 using keywords and index terms relevant to concussion, sports and neurobiological recovery. Separate reviews were conducted for studies involving neuroimaging, fluid biomarkers, genetic testing and emerging technologies. A standardised method and data extraction tool was used to document the study design, population, methodology and results. Reviewers also rated the risk of bias and quality of each study. Eligibility criteria for selecting studiesStudies were included if they: (1) were published in English; (2) represented original research; (3) involved human research; (4) pertained only to SRC; (5) included data involving neuroimaging (including electrophysiological testing), fluid biomarkers or genetic testing or other advanced technologies used to assess neurobiological recovery after SRC; (6) had a minimum of one data collection point within 6 months post-SRC; and (7) contained a minimum sample size of 10 participants. ResultsA total of 205 studies met inclusion criteria, including 81 neuroimaging, 50 fluid biomarkers, 5 genetic testing, 73 advanced technologies studies (4 studies overlapped two separate domains). Numerous studies have demonstrated the ability of neuroimaging and fluid-based biomarkers to detect the acute effects of concussion and to track neurobiological recovery after injury. Recent studies have also reported on the diagnostic and prognostic performance of emerging technologies in the assessment of SRC. In sum, the available evidence reinforces the theory that physiological recovery may persist beyond clinical recovery after SRC. The potential role of genetic testing remains unclear based on limited research. ConclusionsAdvanced neuroimaging, fluid-based biomarkers, genetic testing and emerging technologies are valuable research tools for the study of SRC, but there is not sufficient evidence to recommend their use in clinical practice. PROSPERO registration numberCRD42020164558.
|
|
| 13. |
- Yuh, Esther L, et al.
(författare)
-
Pathological computed tomography features associated with adverse outcomes after mild traumatic brain injury : A TRACK-TBI study with external validation in CENTER-TBI.
- 2021
-
Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 78:9, s. 1137-1148
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood.OBJECTIVE: To identify pathological CT features associated with adverse outcomes after mTBI.DESIGN, SETTING, AND PARTICIPANTS: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021.EXPOSURES: Acute nonpenetrating head trauma.MAIN OUTCOMES AND MEASURES: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months.RESULTS: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI .98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study.CONCLUSIONS AND RELEVANCE: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up.
|
|
| 14. |
- Abrahamsson, B., et al.
(författare)
-
Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project
- 2020
-
Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER. - 0939-6411 .- 1873-3441. ; 152, s. 236-247
-
Tidskriftsartikel (refereegranskat)abstract
- OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.
|
|
| 15. |
|
|
| 16. |
- Bergström, Christel A. S., et al.
(författare)
-
Early pharmaceutical profiling to predict oral drug absorption : Current status and unmet needs
- 2014
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57, s. 173-199
-
Tidskriftsartikel (refereegranskat)abstract
- Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silica and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered. (C) 2013 Elsevier B.V. All rights reserved.
|
|
| 17. |
- Borg, E, et al.
(författare)
-
Language development in hearing-impaired children - Establishment of a reference material for a 'Language test for hearing-impaired children', LATHIC
- 2002
-
Ingår i: International Journal of Pediatric Otorhinolaryngology. - 1872-8464. ; 65:1, s. 15-26
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: In Sweden, there has previously been no normalised test material for the evaluation of language development in individual hearing-impaired children, and for the assessment of various methods of auditory habilitation. The purpose of the present study was to compose, apply and evaluate a test for language development in hearing-impaired children, and to establish the first set of reference values related to age, sex, type and degree of hearing impairment. Methods: A test consisting of nine subtests was assembled and developed for, and subsequently applied to, hearing-impaired children in the age range 4-6 years. The inclusion criteria were a pure tone average of 80 dBHL or less and oral language (Swedish) as the first language. Two hundred and eleven hearing-impaired children and 87 normal hearing control children were tested. Results: The results show that: (1) children with hearing impairment-also unilateral-have a delayed language development; (2) the delay is greater in children with larger losses and tends to decrease with increasing age; (3) 6-year-olds with hearing loss greater than 60 dB have not reached the level of the control group; (4) no difference between right- or left sided deafness with respect to language development was observed; (5) a reference material, applicable during clinical assessment, was established for the most common types of hearing impairment. Conclusions: The test designed gave graded measures of important aspects of language development in hearing-impaired children. The results merit further application of the test material. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
- Darwich, Adam S., et al.
(författare)
-
IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3 : Identifying gaps in system parameters by analysing In Silico performance across different compound classes
- 2017
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 626-642
-
Tidskriftsartikel (refereegranskat)abstract
- Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
- Goodwin, G. M., et al.
(författare)
-
Evidence-based guidelines for treating bipolar disorder : Revised third edition recommendations from the British Association for Psychopharmacology
- 2016
-
Ingår i: Journal of Psychopharmacology. - : SAGE PUBLICATIONS LTD. - 0269-8811 .- 1461-7285. ; 30:6, s. 495-553
-
Forskningsöversikt (refereegranskat)abstract
- The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
- Hemingway, H, et al.
(författare)
-
The effectiveness and cost-effectiveness of biomarkers for the prioritisation of patients awaiting coronary revascularisation: a systematic review and decision model.
- 2010
-
Ingår i: Health Technology Assessment. - : National Coordinating Centre for Health Technology Assessment. - 1366-5278 .- 2046-4924. ; 14:9, s. 1-178
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine the effectiveness and cost-effectiveness of a range of strategies based on conventional clinical information and novel circulating biomarkers for prioritising patients with stable angina awaiting coronary artery bypass grafting (CABG).DATA SOURCES: MEDLINE and EMBASE were searched from 1966 until 30 November 2008.REVIEW METHODS: We carried out systematic reviews and meta-analyses of literature-based estimates of the prognostic effects of circulating biomarkers in stable coronary disease. We assessed five routinely measured biomarkers and the eight emerging (i.e. not currently routinely measured) biomarkers recommended by the European Society of Cardiology Angina guidelines. The cost-effectiveness of prioritising patients on the waiting list for CABG using circulating biomarkers was compared against a range of alternative formal approaches to prioritisation as well as no formal prioritisation. A decision-analytic model was developed to synthesise data on a range of effectiveness, resource use and value parameters necessary to determine cost-effectiveness. A total of seven strategies was evaluated in the final model.RESULTS: We included 390 reports of biomarker effects in our review. The quality of individual study reports was variable, with evidence of small study (publication) bias and incomplete adjustment for simple clinical information such as age, sex, smoking, diabetes and obesity. The risk of cardiovascular events while on the waiting list for CABG was 3 per 10,000 patients per day within the first 90 days (184 events in 9935 patients with a mean of 59 days at risk). Risk factors associated with an increased risk, and included in the basic risk equation, were age, diabetes, heart failure, previous myocardial infarction and involvement of the left main coronary artery or three-vessel disease. The optimal strategy in terms of cost-effectiveness considerations was a prioritisation strategy employing biomarker information. Evaluating shorter maximum waiting times did not alter the conclusion that a prioritisation strategy with a risk score using estimated glomerular filtration rate (eGFR) was cost-effective. These results were robust to most alternative scenarios investigating other sources of uncertainty. However, the cost-effectiveness of the strategy using a risk score with both eGFR and C-reactive protein (CRP) was potentially sensitive to the cost of the CRP test itself (assumed to be 6 pounds in the base-case scenario).CONCLUSIONS: Formally employing more information in the prioritisation of patients awaiting CABG appears to be a cost-effective approach and may result in improved health outcomes. The most robust results relate to a strategy employing a risk score using conventional clinical information together with a single biomarker (eGFR). The additional prognostic information conferred by collecting the more costly novel circulating biomarker CRP, singly or in combination with other biomarkers, in terms of waiting list prioritisation is unlikely to be cost-effective.
|
|
| 27. |
|
|
| 28. |
- Lagerberg, Tove B, et al.
(författare)
-
Measuring intelligibility in spontaneous speech using syllables perceived as understood
- 2021
-
Ingår i: Journal of communication disorders. - : Elsevier BV. - 1873-7994 .- 0021-9924. ; 92
-
Tidskriftsartikel (refereegranskat)abstract
- Intelligibility, the ability to convey a message by speech, is one of the most important variables in speech-language pathology. The assessment of intelligibility is a challenge especially when it comes to spontaneous speech. The aim of the study was to investigate validity and reliability of a method for assessment of intelligibility, syllables perceived as understood (SPU); a method that is more time-efficient than previous methods based on transcription, as it does not require a master transcript for reference.A group of 20 adult listeners transcribed stimuli consisting of spontaneous speech from 16 children (14 with speech sound disorder and two with typical speech and language development, age 4:4 to 8:1, M=6:0). Intelligibility was calculated based on these orthographic transcripts, as a) proportion of syllables perceived as understood (SPU) and b) proportion of syllables correctly understood (SCU), with reference to a master transcript. Validity was checked through investigation of the correlation and difference between these two measures. Reliability was analysed with inter-listener reliability by intra-class correlation.The correlation between SPU and SCU (the gold standard intelligibility score) was strong and statistically significant, with SPU being consistently higher than SCU. Inter-listener reliability for single measures of intra-class correlation of the assessment by syllables perceived as understood was moderate to low, whereas the inter-listener reliability for average measures of intra-class correlation was high.The method based on SPU might be used for assessment of intelligibility if the median from several listeners is used or when comparing results from the same listener over time. The SPU method might therefore be a valuable tool in a clinical and research context as a more valid option than rating scales and a more time-efficient method than the gold standard SCU method. However, it should be noted that the reliability of the SPU is not as high as for the SCU.
|
|
| 29. |
- Lennernäs, Hans, et al.
(författare)
-
In Vivo Predictive Dissolution (IPD) and Biopharmaceutical Modeling and Simulation : Future Use of Modern Approaches and Methodologies in a Regulatory Context
- 2017
-
Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:4, s. 1307-1314
-
Tidskriftsartikel (refereegranskat)abstract
- The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational Models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo meeting in 2015 was dedicated: to the presentation of the most recent progress in the development of the regulatory use of PBPK in silk() modeling, in vivo predictive dissolution (IPD) tests, and their application to biowaivers. There are still several areas for improvement of in vitro dissolution testing by means of generating results relevant for the intraluminal conditions in the GI tract. The major opportunity is probably in combining IPD testing and physiologically based in silico models where the in vitro data provide input to the absorption predictions. The OrBiTo project and other current research projects include-definition of test media representative for the more distal parts of the GI tract, models capturing supersaturation and precipitation phenomena, and influence of motility waves on shear and other forces of hydrodynamic origin, addressing the inter individual variability in composition and characteristics of GI fluids, food effects, definition of biorelevant buffer systems, and intestinal water volumes. In conclusion, there is currently a mismatch between the extensive industrial usage of modern in vivo predictive tools and very limited inclusion of such data in regulatory files. However, there is a great interest among all stakeholders to introduce recent progresses in prediction of in vivo GI drug absorption into regulatory context.
|
|
| 30. |
- Lennernäs, Hans, et al.
(författare)
-
Oral biopharmaceutics tools - Time for a new initiative - An introduction to the IMI project OrBiTo
- 2014
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57:SI, s. 292-299
-
Forskningsöversikt (refereegranskat)abstract
- OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silica biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
|
|
| 31. |
- Margolskee, Alison, et al.
(författare)
-
IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1 : Characterisation of the OrBiTo database of compounds
- 2017
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 598-609
-
Tidskriftsartikel (refereegranskat)abstract
- Predicting oral bioavailability (F-oral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9 L/h (interquartile range: 11.6-43.6 L/h; n = 23), volume of distribution was 80.8 L (54.5-239 L; n = 23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n = 22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.
|
|
| 32. |
- Margolskee, Alison, et al.
(författare)
-
IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2 : An introduction to the simulation exercise and overview of results
- 2017
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 610-625
-
Tidskriftsartikel (refereegranskat)abstract
- Orally administered drugs are subject to a number of barriers impacting bioavailability (F-oral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp (R), and GastroPlus (TM)) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, F-oral and relative AUC (F-rel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
- McAllister, Mark, et al.
(författare)
-
Developing Clinically Relevant Dissolution Specifications (CRDSs) for Oral Drug Products: Virtual Webinar Series
- 2022
-
Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:5, s. 1010-1010
-
Tidskriftsartikel (refereegranskat)abstract
- A webinar series that was organised by the Academy of Pharmaceutical Sciences Biopharmaceutics focus group in 2021 focused on the challenges of developing clinically relevant dissolution specifications (CRDSs) for oral drug products. Industrial scientists, together with regulatory and academic scientists, came together through a series of six webinars, to discuss progress in the field, emerging trends, and areas for continued collaboration and harmonisation. Each webinar also hosted a Q&A session where participants could discuss the shared topic and information. Although it was clear from the presentations and Q&A sessions that we continue to make progress in the field of CRDSs and the utility/success of PBBM, there is also a need to continue the momentum and dialogue between the industry and regulators. Five key areas were identified which require further discussion and harmonisation.
|
|
| 37. |
- Mogren, A., et al.
(författare)
-
Children and adolescents with speech sound disorders are more likely to have orofacial dysfunction and malocclusion
- 2022
-
Ingår i: Clinical and Experimental Dental Research. - : Wiley. - 2057-4347. ; 8:5, s. 1130-1141
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Children with speech sound disorders (SSD) form a heterogeneous group that differs in terms of underlying cause and severity of speech difficulties. Orofacial dysfunction and malocclusions have been reported in children with SSD. However, the association is not fully explored. Objectives: Our aims were to describe differences in orofacial function and malocclusion between a group of children and adolescents with compared to without SSD and to explore associations between those parameters among the group with SSD. Methods: A total of 105 participants were included, 61 children with SSD (6.0-16.7 years, mean age 8.5 +/- 2.8, 14 girls and 47 boys) and 44 children with typical speech development (TSD) (6.0-12.2 years, mean age 8.8 +/- 1.6, 19 girls and 25 boys). Assessments of orofacial function included an orofacial screening test and assessment of bite force, jaw stability, chewing efficiency, and intraoral sensory-motor function. Possible malocclusions were also assessed. Result: Children with SSD had both poorer orofacial function and a greater prevalence of malocclusion than children with TSD. Furthermore, children with SSD and poorer orofacial function had a greater risk of malocclusion. Conclusion: Our result suggests that children with SSD are more prone to having poorer orofacial function and malocclusion than children with TSD. This illustrates the importance of assessing coexisting orofacial characteristics in children with SSD, especially since orofacial dysfunction may be linked to an increased risk of malocclusion. This result highlights the need for a multiprofessional approach.
|
|
| 38. |
- Mogren, A., et al.
(författare)
-
Malocclusion in children with speech sound disorders and motor speech involvement: a cross-sectional clinical study in Swedish children
- 2022
-
Ingår i: European Archives of Paediatric Dentistry. - : Springer Science and Business Media LLC. - 1818-6300 .- 1996-9805. ; 23:4, s. 619-628
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives The objectives of this study were to investigate the occurrence, types and severity of malocclusions in children with speech sound disorder (SSD) persisting after 6 years of age, and to compare these findings to a control group of children with typical speech development (TSD). Methods In total, 105 children were included: 61 with SSD and motor speech involvement (mean age 8:5 +/- 2:8 years; range 6:0-16:7 years, 14 girls and 47 boys) and 44 children with TSD (mean age 8:8 +/- 1:6; range 6:0-12:2 years, 19 girls and 25 boys). Extra-oral and intra-oral examinations were performed by an orthodontist. The severity of malocclusion was scored using the IOTN-DHC Index. Results There were differences between the SSD and TSD groups with regard to the prevalence, type, and severity of malocclusions; 61% of the children in the SSD group had a malocclusion, as compared to 29% in the TSD group. In addition, the malocclusions in the SSD group were rated as more severe. Functional posterior crossbite and habitual lateral and/or anterior shift appeared more frequently in the SSD group. Class III malocclusion, anterior open bite and scissors bite were found only in the SSD group. Conclusion Children with SSD and motor speech involvement are more likely to have a higher prevalence of and more severe malocclusions than children with TSD.
|
|
| 39. |
|
|
| 40. |
|
|
| 41. |
|
|
| 42. |
- Strombergsson, S., et al.
(författare)
-
Audience Response System-Based Evaluation of Intelligibility of Children's Connected Speech - Validity, Reliability and Listener Differences
- 2020
-
Ingår i: Journal of Communication Disorders. - : Elsevier BV. - 0021-9924 .- 1873-7994. ; 87
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: We assessed audience response systems (ARS)-based evaluation of intelligibility, with a view to find a valid and reliable intelligibility measure that is accessible to non-trained participants. In addition, we investigated potential listener differences between pediatric speech and language pathologists (SLPs) and untrained adults. Method: Sixteen one-minute samples of connected speech were compiled, collected from 14 children with a speech sound disorder (SSD) and two children with typical speech. 16 SLPs and 13 untrained adults participated in a series of ARS listening sessions, where they were fitted with headphones and hand controls, and instructed to click a button whenever they did not understand the child speaking. Listeners' button clicks were registered and, for each speech sample, totaled into an (un)intelligibility index. The proportion of syllables perceived correctly - based on orthographic listener transcripts - was used as a reference score of intelligibility. Results: The ARS-based intelligibility scores correlated strongly with the intelligibility reference score. Reliability was high across listener groups and weaker for single listeners. No significant difference was found between the evaluations of SLPs and untrained adults. Conclusions: ARS-based evaluation offers a valid and reliable measure of intelligibility of particular value in research as a practical tool for collecting input from listeners without experience or knowledge of SSDs. We stress that the ARS design presupposes a listener panel, and that evaluations obtained from individual listeners are predictably inadequate in terms of reliability.
|
|
| 43. |
- Strombergsson, Sofia, et al.
(författare)
-
Understanding acceptability of disordered speech through Audience Response Systems-based evaluation
- 2021
-
Ingår i: Speech Communication. - : Elsevier BV. - 0167-6393 .- 1872-7182. ; 131, s. 13-22
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: We explore the validity and reliability of an Audience Response Systems (ARS)-based measure of acceptability, applied to speech produced by children with speech sound disorder (SSD). We further explore how the suggested measure relates to an ARS-based measure of intelligibility. Finally, we explore potential differences between speech-language pathologists (SLPs), untrained adults, and children in their assessments. Method: Fifty-three listeners participated in ARS-based assessments of acceptability and intelligibility: 19 SLPs, 18 untrained adults, and 16 children (aged 6-10 years). The listeners assessed speech samples collected from 14 children with SSD and 2 children with typical speech. The validity of the ARS-based acceptability measure was investigated through correlation analyses with reference to rating-based acceptability, as well as to measures of intelligibility and speech proficiency. Results: The ARS-based acceptability measure correlated strongly with all assumed related measures. Listeners reacted more often to affected acceptability than to unintelligibility. Child listeners reacted less frequently to acceptability disruption than the SLPs and untrained adults. Conclusions: ARS-based assessment of acceptability provides a valid and reliable measure of acceptability. The ARS-based methodology captures an anticipated pattern where listeners react more often to disruptions of acceptability than to unintelligibility. Children appear less sensitive to traits signaling SSD than SLPs and other adults are; however, replication is required to establish this for sure.
|
|
