| 1. |
- Pinese, Mark, et al.
(författare)
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The Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing. Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.
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| 2. |
- Sodergren, Erica, et al.
(författare)
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The genome of the sea urchin Strongylocentrotus purpuratus.
- 2006
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 314:5801, s. 941-52
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Tidskriftsartikel (refereegranskat)abstract
- We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.
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| 3. |
- Ashton, Susan, et al.
(författare)
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Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:325
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Tidskriftsartikel (refereegranskat)abstract
- Efforts to apply nanotechnology in cancer have focused almost exclusively on the delivery of cytotoxic drugs to improve therapeutic index. There has been little consideration of molecularly targeted agents, in particular kinase inhibitors, which can also present considerable therapeutic index limitations. We describe the development of Accurin polymeric nanoparticles that encapsulate the clinical candidate AZD2811, an Aurora B kinase inhibitor, using an ion pairing approach. Accurins increase biodistribution to tumor sites and provide extended release of encapsulated drug payloads. AZD2811 nanoparticles containing pharmaceutically acceptable organic acids as ion pairing agents displayed continuous drug release for more than 1 week in vitro and a corresponding extended pharmacodynamic reduction of tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration. A specific AZD2811 nanoparticle formulation profile showed accumulation and retention in tumors with minimal impact on bone marrow pathology, and resulted in lower toxicity and increased efficacy in multiple tumor models at half the dose intensity of AZD1152, a water-soluble prodrug of AZD2811. These studies demonstrate that AZD2811 can be formulated in nanoparticles using ion pairing agents to give improved efficacy and tolerability in preclinical models with less frequent dosing. Accurins specifically, and nanotechnology in general, can increase the therapeutic index of molecularly targeted agents, including kinase inhibitors targeting cell cycle and oncogenic signal transduction pathways, which have to date proved toxic in humans.
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| 4. |
- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 5. |
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| 6. |
- Modabbernia, Amirhossein, et al.
(författare)
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Quality of life in Iranian patients with bipolar disorder : a psychometric study of the Persian Brief Quality of Life in Bipolar Disorder (QoL.BD)
- 2016
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Ingår i: Quality of Life Research. - : Springer Science and Business Media LLC. - 0962-9343 .- 1573-2649. ; 25:7, s. 1835-1844
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Tidskriftsartikel (refereegranskat)abstract
- PurposeTo assess the reliability, validity, and factor structure of the Persian Brief Quality of Life in Bipolar Disorder (QoL.BD) in Iranian patients with bipolar disorder (BD).MethodsAfter translation and cross-cultural adaptation of the Brief QoL.BD, we administered the questionnaire to 184 patients diagnosed with BD. To determine factor structure, we performed both exploratory and confirmatory factor analyses. To investigate the reliability, we assessed internal consistency, reproducibility and agreement. Construct validity was assessed by calculating correlations between the Brief QoL.BD and the Short Form-36 (SF-36), Positive And Negative Affect Schedule (PANAS), Hamilton Depression Rating Scale, Young Mania Rating Scale (YMRS) and Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). We also investigated gender differences in interpretations of QoL.BD items.ResultsThe results obtained from reliability analysis confirmed internal consistency (Cronbach’s alpha was 0.87 and 0.89 for two assessments) and reproducibility and agreement (the intraclass correlation coefficient ranged between 0.74 and 0.94). Validity analyses showed that the items loaded on a single-factor structure. The inter-item correlations varied from 0.31 to 0.68. Significantly lower scores on the Brief QoL.BD were observed in people diagnosed with BD I compared to BD II. Significant correlations were observed between the Brief QoL.BD and SF-36 summary measures, HAMD, YMRS, Q-LES-Q-SF and PANAS subscales. Items in the Brief QoL.BD were interpreted similarly by men and women.ConclusionsThe Brief Persian QoL.BD is a psychometrically sound measure with acceptable validity and reliability and provides a rapid assessment tool for measuring QoL in patients with BD.
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| 7. |
- Murray, Conor, et al.
(författare)
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International consensus statement on the design, delivery and evaluation of sport-based interventions aimed at promoting social, psychological and physical well-being in prison
- 2024
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To develop an international consensus statement to advise on designing, delivering and evaluating sport-based interventions (SBIs) aimed at promoting social, psychological and physical well-being in prison.Design: Modified Delphi using two rounds of survey questionnaires and two consensus workshops.Participants: A multidisciplinary panel of more than 40 experts from 15 international jurisdictions was formed, including representation from the following groups and stakeholders: professionals working in the justice system; officials from sport federations and organisations; academics with research experience of prisons, secure forensic mental health settings and SBIs; and policy-makers in criminal justice and sport.Results: A core research team and advisory board developed the initial rationale, statement and survey. This survey produced qualitative data which was analysed thematically. The findings were presented at an in-person workshop. Panellists discussed the findings, and, using a modified nominal group technique, reached a consensus on objectives to be included in a revised statement. The core research team and advisory board revised the statement and recirculated it with a second survey. Findings from the second survey were discussed at a second, virtual, workshop. The core research team and advisory board further revised the consensus statement and recirculated it asking panellists for further comments. This iterative process resulted in seven final statement items; all participants have confirmed that they agreed with the content, objectives and recommendations of the final statement.Conclusions: The statement can be used to assist those that design, deliver and evaluate SBIs by providing guidance on: (1) minimum levels of competence for those designing and delivering SBIs; (2) the design and delivery of inclusive programmes prioritising disadvantaged groups; and (3) evaluation measures which are carefully calibrated both to capture proposed programme outcomes and to advance an understanding of the systems, processes and experiences of sport engagement in prison.
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| 8. |
- Murray, Greg, et al.
(författare)
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Relief of Chronic or Resistant Depression (Re-ChORD): A pragmatic, randomized, open-treatment trial of an integrative program intervention for chronic depression
- 2010
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Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 123:1-3, s. 243-248
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chronic depression is a particularly disabling mood disorder and treatment outcomes are poor with either psychotherapy or pharmacotherapy alone. There is growing evidence that an integrative treatment approach may be optimal. A novel multi-modal, multi-disciplinary treatment program, Re-ChORD, was developed at the University of British Columbia and evaluated in this pilot study. Methods: Re-ChORD consisted of guidelines-based medication management, and group-based interpersonal psychotherapy and occupational therapy. A randomized, parallel-groups, open-treatment trial was conducted comparing Re-ChORD to treatment as usual (TAU). Inclusion criteria were current depression (17-item Ham-D >= 15) and a diagnosis of a chronic depressive disorder. The primary outcome variable was clinical remission (17-item Ham-D <= 7) at 4 month assessment. Results: A total of 64 patients were randomised to Re-ChORD (N = 34) and TAU (N = 30). Under both intention to treat (ITT) and completer analyses, the remission rate was significantly higher in the Re-ChORD than TAU groups. Treatment effect size for remission was of medium magnitude (22.2% and 29.6% over TAU under ITT and completer analyses). Limitations: We did not collect sufficient follow-up data to investigate maintenance of gains. Re-ChORD shares elements with other combined treatments, and the present positive findings cannot be interpreted as being specific to the Re-ChORD program. Conclusions: Consistent with growing evidence that integrative treatments are necessary for chronic depressive disorders. Re-ChORD was demonstrated in this pilot study to produce significantly greater rates of remission than treatment as usual. A larger-scale trial is warranted. (C) 2009 Elsevier By. All rights reserved.
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