| 1. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Forouzanfar, Mohammad H, et al.
(författare)
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Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013.
- 2015
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 386:10010, s. 2287-2323
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.FUNDING: Bill & Melinda Gates Foundation.
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| 4. |
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| 5. |
- Stanton, Biba R, et al.
(författare)
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Diffusion tensor imaging in sporadic and familial (D90A SOD1) forms of amyotrophic lateral sclerosis
- 2009
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Ingår i: Archives of Neurology. - : American Medical Association. - 0003-9942 .- 1538-3687. ; 66:1, s. 109-115
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The basis of heterogeneity in the clinical presentation and rate of progression of amyotrophic lateral sclerosis (ALS) is poorly understood. OBJECTIVES: To use diffusion tensor imaging as a measure of axonal pathologic features in vivo in ALS and to compare a homogeneous form of familial ALS (homozygous D90A SOD1 [superoxide dismutase 1]) with sporadic ALS. DESIGN: Cross-sectional diffusion tensor imaging study. SETTING: Tertiary referral neurology clinic. PATIENTS: Twenty patients with sporadic ALS, 6 patients with homozygous D90A SOD1 ALS, and 21 healthy control subjects. MAIN OUTCOME MEASURE: Fractional anisotropy in cerebral white matter. RESULTS: Patients with homozygous D90A SOD1 ALS showed less extensive pathologic white matter in motor and extramotor pathways compared with patients with sporadic ALS, despite similar disease severity assessed clinically using a standard functional rating scale. Fractional anisotropy correlated with clinical measures of severity and upper motor neuron involvement. CONCLUSION: In vivo diffusion tensor imaging measures demonstrate differences in white matter degeneration between sporadic ALS and a unique familial form of the disease, indicating that genotype influences the distribution of cerebral pathologic features in ALS.
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| 6. |
- Alexander, Stephen P. H., et al.
(författare)
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The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
- 2023
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Ingår i: BRITISH JOURNAL OF PHARMACOLOGY. - : British pharmacological society. - 0007-1188 .- 1476-5381. ; 180
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Tidskriftsartikel (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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| 7. |
- Christopoulos, Arthur, et al.
(författare)
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THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.
- 2021
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Ingår i: British journal of pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 178 Suppl 1
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Forskningsöversikt (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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| 8. |
- Evangelou, Evangelos, et al.
(författare)
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A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
- 2014
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 73:12, s. 2130-2136
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
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| 9. |
- Falster, Daniel, et al.
(författare)
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AusTraits, a curated plant trait database for the Australian flora
- 2021
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Ingår i: Scientific Data. - : Nature Portfolio. - 2052-4463. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- We introduce the AusTraits database - a compilation of values of plant traits for taxa in the Australian flora (hereafter AusTraits). AusTraits synthesises data on 448 traits across 28,640 taxa from field campaigns, published literature, taxonomic monographs, and individual taxon descriptions. Traits vary in scope from physiological measures of performance (e.g. photosynthetic gas exchange, water-use efficiency) to morphological attributes (e.g. leaf area, seed mass, plant height) which link to aspects of ecological variation. AusTraits contains curated and harmonised individual- and species-level measurements coupled to, where available, contextual information on site properties and experimental conditions. This article provides information on version 3.0.2 of AusTraits which contains data for 997,808 trait-by-taxon combinations. We envision AusTraits as an ongoing collaborative initiative for easily archiving and sharing trait data, which also provides a template for other national or regional initiatives globally to fill persistent gaps in trait knowledge.
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| 10. |
- Fogh, Isabella, et al.
(författare)
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A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis
- 2014
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Ingår i: Human Molecular Genetics. - Oxford : Oxford University Press. - 0964-6906 .- 1460-2083. ; 23:8, s. 2220-2231
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Tidskriftsartikel (refereegranskat)abstract
- Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (90) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P 1.11 10(8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P 8.62 10(9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P 7.69 10(9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as 12 using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
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| 11. |
- Gandaglia, Giorgio, et al.
(författare)
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Clinical Characterization of Patients Diagnosed with Prostate Cancer and Undergoing Conservative Management : A PIONEER Analysis Based on Big Data
- 2024
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Ingår i: European Urology. - 0302-2838. ; 85:5, s. 457-465
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Tidskriftsartikel (refereegranskat)abstract
- Background: Conservative management is an option for prostate cancer (PCa) patients either with the objective of delaying or even avoiding curative therapy, or to wait until palliative treatment is needed. PIONEER, funded by the European Commission Innovative Medicines Initiative, aims at improving PCa care across Europe through the application of big data analytics. Objective: To describe the clinical characteristics and long-term outcomes of PCa patients on conservative management by using an international large network of real-world data. Design, setting, and participants: From an initial cohort of >100 000 000 adult individuals included in eight databases evaluated during a virtual study-a-thon hosted by PIONEER, we identified newly diagnosed PCa cases (n = 527 311). Among those, we selected patients who did not receive curative or palliative treatment within 6 mo from diagnosis (n = 123 146). Outcome measurements and statistical analysis: Patient and disease characteristics were reported. The number of patients who experienced the main study outcomes was quantified for each stratum and the overall cohort. Kaplan-Meier analyses were used to estimate the distribution of time to event data. Results and limitations: The most common comorbidities were hypertension (35–73%), obesity (9.2–54%), and type 2 diabetes (11–28%). The rate of PCa-related symptomatic progression ranged between 2.6% and 6.2%. Hospitalization (12–25%) and emergency department visits (10–14%) were common events during the 1st year of follow-up. The probability of being free from both palliative and curative treatments decreased during follow-up. Limitations include a lack of information on patients and disease characteristics and on treatment intent. Conclusions: Our results allow us to better understand the current landscape of patients with PCa managed with conservative treatment. PIONEER offers a unique opportunity to characterize the baseline features and outcomes of PCa patients managed conservatively using real-world data. Patient summary: Up to 25% of men with prostate cancer (PCa) managed conservatively experienced hospitalization and emergency department visits within the 1st year after diagnosis; 6% experienced PCa-related symptoms. The probability of receiving therapies for PCa decreased according to time elapsed after the diagnosis.
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| 12. |
- Grossmann, Igor, et al.
(författare)
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Insights into the accuracy of social scientists' forecasts of societal change
- 2023
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Ingår i: Nature Human Behaviour. - : Springer Nature. - 2397-3374. ; 7, s. 484-501
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Tidskriftsartikel (refereegranskat)abstract
- How well can social scientists predict societal change, and what processes underlie their predictions? To answer these questions, we ran two forecasting tournaments testing the accuracy of predictions of societal change in domains commonly studied in the social sciences: ideological preferences, political polarization, life satisfaction, sentiment on social media, and gender-career and racial bias. After we provided them with historical trend data on the relevant domain, social scientists submitted pre-registered monthly forecasts for a year (Tournament 1; N = 86 teams and 359 forecasts), with an opportunity to update forecasts on the basis of new data six months later (Tournament 2; N = 120 teams and 546 forecasts). Benchmarking forecasting accuracy revealed that social scientists' forecasts were on average no more accurate than those of simple statistical models (historical means, random walks or linear regressions) or the aggregate forecasts of a sample from the general public (N = 802). However, scientists were more accurate if they had scientific expertise in a prediction domain, were interdisciplinary, used simpler models and based predictions on prior data. How accurate are social scientists in predicting societal change, and what processes underlie their predictions? Grossmann et al. report the findings of two forecasting tournaments. Social scientists' forecasts were on average no more accurate than those of simple statistical models.
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| 13. |
- Hanna, Stephanie J., et al.
(författare)
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Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans
- 2023
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans.
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| 14. |
- Heil, Katharina F., 1987-
(författare)
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A Systems Biological Approach to Parkinson's Disease
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s Disease (PD) is the second most common neurodegenerative disease in the Western world. Itshows a high degree of genetic and phenotypic complexity with many implicated factors, various diseasemanifestations but few clear causal links. Ongoing research has identified a growing number of molecularalterations linked to the disease.Dopaminergic neurons in the substantia nigra, specifically their synapses, are the key-affected region in PD.Therefore, this work focuses on understanding the disease effects on the synapse, aiming to identify potentialgenetic triggers and synaptic PD associated mechanisms. Currently, one of the main challenges in this area isdata quality and accessibility.In order to study PD, publicly available data were systematically retrieved and analysed. 418 PD associatedgenes could be identified, based on mutations and curated annotations. I curated an up-to-date and completesynaptic proteome map containing a total of 6,706 proteins. Region specific datasets describing thepresynapse, postsynapse and synaptosome were also delimited. These datasets were analysed, investigatingsimilarities and differences, including reproducibility and functional interpretations.The use of Protein-Protein-Interaction Network (PPIN) analysis was chosen to gain deeper knowledgeregarding specific effects of PD on the synapse. Thus I generated a customised, filtered, human specificProtein-Protein Interaction (PPI) dataset, containing 211,824 direct interactions, from four public databases.Proteomics data and PPI information allowed the construction of PPINs. These were analysed and a set oflow level statistics, including modularity, clustering coefficient and node degree, explaining the network’stopology from a mathematical point of view were obtained.Apart from low-level network statistics, high-level topology of the PPINs was studied. To identify functionalnetwork subgroups, different clustering algorithms were investigated. In the context of biological networks, theunderlying hypothesis is that proteins in a structural community are more likely to share common functions.Therefore I attempted to identify PD enriched communities of synaptic proteins. Once identified, they werecompared amongst each other. Three community clusters could be identified as containing largely overlappinggene sets. These contain 24 PD associated genes. Apart from the known disease associated genes in thesecommunities, a total of 322 genes was identified. Each of the three clusters is specifically enriched for specificbiological processes and cellular components, which include neurotransmitter secretion, positive regulation ofsynapse assembly, pre- and post-synaptic membrane, scaffolding proteins, neuromuscular junctiondevelopment and complement activation (classical pathway) amongst others.The presented approach combined a curated set of PD associated genes, filtered PPI information andsynaptic proteomes. Various small- and large-scale analytical approaches, including PPIN topology analysis,clustering algorithms and enrichment studies identified highly PD affected synaptic proteins and subregions.Specific disease associated functions confirmed known research insights and allowed me to propose a newlist of so far unknown potential disease associated genes. Due to the open design, this approach can be usedto answer similar research questions regarding other complex diseases amongst others.
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| 15. |
- Kenna, Kevin P., et al.
(författare)
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NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1037-1042
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
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| 16. |
- Lewis, Cathryn M, et al.
(författare)
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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II : Schizophrenia
- 2003
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 73:1, s. 34-48
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
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| 17. |
- Lockett, Nigel, et al.
(författare)
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‘Lost in Space’: The Role of Social Networking in University-based Entrepreneurial Learning
- 2017
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Ingår i: Industry & higher education. - : SAGE Publications. - 0950-4222 .- 2043-6858. ; 31:2, s. 67-80
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Tidskriftsartikel (refereegranskat)abstract
- While entrepreneurship education increasingly uses various means to connect students to the ‘real world’, the impact of social networking on learning remains under-explored. This qualitative study of student entrepreneurs in UK and Sweden shows that their entrepreneurial journey becomes increasingly complex, requiring skills and knowledge not solely developed through formal or non-formal learning. Social networks, and associated informal learning, are shown to be critical in developing social capital important to the students’ entrepreneurial journey. This study exposes a key value of social networking and encourages educators to embed activities that facilitate students’ informal learning within the curriculum.
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| 18. |
- Lockett, Nigel, et al.
(författare)
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The Bermuda Triangle in Entrepreneurship Education: The Role of Social Capital in Entrepreneurial Learning
- 2015
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Ingår i: Institute for Small Business and Entrepreneurship; November 11-12, Glasgow, Scotland.
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Konferensbidrag (refereegranskat)abstract
- Objectives. We aim to explore the relationship between the role of social capital and entrepreneurial learning by investigating the entrepreneurial journey of student and graduate entrepreneurs.Prior Work. It is widely acknowledged that the most powerful resource of an entrepreneur is their network: individuals, groups or organisations that support, advice and even finance an entrepreneur’s growth. Because of this, entrepreneurship education programmes have been using entrepreneurs to connect students to the ‘real world’, providing them an initial network of entrepreneurs and the skills to develop their own network. Nonetheless, the real impact of networking on students learning has not yet been fully explored.Approach. This qualitative study uses unstructured interviews with three student and graduate entrepreneurs at both the University of Leeds and Chalmers University of Technology. Interviews focused on understanding the six entrepreneurs’ journey through entrepreneurial activities (critical incidents) and how social networks influenced these activities; interviewees were asked to reflect on their entrepreneurial journey, covering secondary school, university, post-university and expectations for the immediate future.Results. Main findings evidenced that the UK three entrepreneurs started to show some kind of entrepreneurial behaviour during secondary school education. All respondents though increased their network awareness through their entrepreneurial journey: from “don’t know” to “know” to “need”. Moreover, at the beginning the network was mostly informal (family and friends), becoming more formal according to the increased complexity of the entrepreneurial activity. During their entrepreneurial journey, interviewees agreed that at the beginning nobody taught them how to be entrepreneur or even the skills they needed to carry on the entrepreneurial activity. But once their journey became more complex and serious, they needed skills and knowledge that they were not able to develop by their own; in that moment entrepreneurs realised that their network could provide them with people from who learn new capabilities, using informal learning processes to close the gap between their scarcities and needs.Implications. The study exposes that networks facilitate entrepreneurial learning through informal learning processes which need to be translated into entrepreneurship education in a higher education context. One way is to legitimise social networking activities within the university environment, while another is embedding social networking into formal and non-formal entrepreneurship education.Value. Social networking is not simply building a contact list; it is part of the social capital needed to help the entrepreneurial journey. This study exposes the previously missing value of social networking and encourages educators to embed activities within the curriculum that facilitate students’ informal learning.
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| 19. |
- Lockett, Nigel, et al.
(författare)
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The contribution of universities to student and graduate entrepreneurs' social capital: a current fairytale?
- 2016
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Ingår i: Engage HEI Conference, University of Central Lancashire, UK, May 19-20.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- This paper explores how universities contribute to the acquisition of social capital of their student and graduate entrepreneurs. The objective is to identify under what circumstances universities facilitate this in the context of entrepreneurial learning. The study builds on collaboration between three European universities: Chalmers University of Technology, Universidad de Malaga and University of Leeds.Entrepreneurial learning and education literature underpin this study. Stemming from this, the theoretical framework is complemented by research about the impact of social capital on entrepreneurs’ development, and its relevance to the concept of the entrepreneurial university.A qualitative methodological approach involving critical incident technique is used to map student and graduate entrepreneurs’ entrepreneurial journey based on a timeline, specifying stakeholders associated with critical events (entrepreneurial activities of any kind). A visual aid technique was used throughout the interview to assist interviewees in recalling their verbal history. 24 individuals fulfilling criteria: (1) university final year students or first year after graduation; (2) have or were engaged in some entrepreneurial activity; (3) 50% completed some formal entrepreneurship education were interviewed. Nvivo was used to analyse the data through narrative analysis of the social informal learning; i.e. how interviewees learned from others what they needed to learn in order to carry out their entrepreneurial activities. Preliminary analyses of the data identified that entrepreneurship education programmes in these universities engage experienced entrepreneurs to connect students to the ‘real world’, providing them an initial network of role models, as well as skills to develop their own network. It seems that respondents’ entrepreneurial learning follows a pattern. Early stages of the entrepreneurial journey relied on informal learning. As respondents’ entrepreneurial activities expand to include a more complex structure and wider network of stakeholders, they became aware of their need of a more formal learning. To satisfy this need, respondents engaged in non-formal education programmes and, when necessary, they enrolled in formal education programmes. Nevertheless, respondents also used other informal learning sources to cover their self-perceived knowledge gaps. Consequently, this illustrates how interdisciplinarity and entrepreneurship reaches beyond business school learning.Results also suggest that the intertwining of social capital and learning in entrepreneurship occurs before university, from the very first moment that respondents engage in some type of entrepreneurial activity. However, the university is vital in facilitating integrated understanding and developed maturity to manage the complexity of formal, non-formal and informal learning. This comprehensive understanding becomes an essential part of the respondents’ entrepreneurial social capital.This paper contributes by exposing the previously missing value of social networking in entrepreneurship education at universities. At an institutional-level, it legitimises university inclusion of social networking activities into formal and non-formal entrepreneurship education, and encouragement of informal entrepreneurship learning. Moreover, at an individual-level, it motivates educators to embed these activities within the curriculum in order to facilitate entrepreneurial learning. Considering that social networking goes beyond simply building a contact list and that it is part of the social capital necessary for the entrepreneurial journey, this study exposes the previously missing value of social networking in entrepreneurial education programmes. It encourages educators to embed social networking activities into the curriculum to facilitate entrepreneurial learning. The study highlights the importance of social capital acquired at university, as part of student/graduate entrepreneurial journeys. This revitalises the role of the university as a key enabler of economic, social and cultural impact through student/graduate entrepreneurs. Thus, the fairy tale question is answered: universities contribution to student and graduate entrepreneurs’ social capital is no longer a fantasy.Future research needs to be focus on understanding the student/graduate entrepreneurial journey, considering not only entrepreneurial activities as critical incidents, but also other interactions in the entrepreneur’s life. Moreover, the inclusion of other countries and universities to identify a clearer pattern of how universities contribute to acquisition of social capital of their student and graduate entrepreneurs.
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| 20. |
- Lockett, Nigel, et al.
(författare)
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The university is dead; long live the university: Are universities the principle source of social capital for student and graduate entrepreneurs?
- 2016
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Ingår i: ECSB Entrepreneurship Education (3E) Conference, May 11-13, Leeds UK. ; , s. 1-15
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Konferensbidrag (refereegranskat)abstract
- This paper explores the role of social capital acquired by students during student and graduate entrepreneurial journeys at university. The objective is to understand how universities can facilitate social capital acquisition in the context of entrepreneurial learning. The study builds on a collaboration between three European universities: Chalmers University of Technology (Sweden), University of Leeds (United Kingdom), and Universidad de Malaga (Spain).We ask:1.What is the relationship between social capital and entrepreneurial learning? What is the added value as perceived by student and graduate entrepreneurs?2.How can educators use the development of social capital to enhance entrepreneurial learning, particularly across formal, non-formal and informal entrepreneurial learning activities?3.What are implications for the future of universities as centres of knowledge, creativity and learning?The study is underpinned by relevant literature regarding entrepreneurial learning and education. It also addresses the impact of social capital on the development of entrepreneurs, and the research regarding the entrepreneurial university.The study utilises a qualitative methodological approach, drawing on what is termed the critical incident technique. To start, student/graduate entrepreneurs were asked to map their entrepreneurial journey based on a timeline, specifying stakeholders whom they associated to critical events. This visual aid was then used throughout the interview, in which respondents provided a verbal history about their timeline and the critical relationships which had influenced their own entrepreneurial behaviour.We selected 24 respondents based on three criteria: (1) they had to be a university final year student or in their first year of graduation (both undergraduate and postgraduate students from various subjects were selected); (2) they had to have been engaged in some entrepreneurial activity; (3) the sample was split 50:50 between individuals having completed some formal entrepreneurship education (credit-bearing courses) and individuals without any formal entrepreneurship education. Gender and country variables were also considered. Data was analysed using narrative analysis of the individual learning, and social network analysis of the socialised learning (to address network and social capital developments). Building on social learning theory, socialised learning is understood to include observation and emulation of role models -role-sets- as part of an individual’s identity and legitimacy development.Preliminary analyses of the data inform us that mentors known in informal and non-formal education events and incubators are the main source to ask for help when respondents feel they need to. Maybe because the interview is retroactive, respondents were aware of this need before it was too late; in fact, respondents were the ones who deliberately contact these people to ask them for help in their various entrepreneurial activities. This paper contributes to knowledge and understanding by exposing a previously understudied value of social networking in entrepreneurship education at universities. At an institutional-level, it legitimizes university inclusion of social networking activities into formal and non-formal entrepreneurship education, and the encouragement of informal entrepreneurial learning. Moreover, at an individual-level, it motivates educators to embed these activities within the curriculum in order to facilitate entrepreneurial learning. Nonetheless, to more fully understand the student/graduate entrepreneurial journey, more research is needed. Future work should not only consider entrepreneurial activities as critical incidents, but also the relevance of other interactions in the entrepreneur’s life, leading to a greater understanding of their economic, social and cultural impact.Social networking goes beyond simply building a contact list; it is part of the social capital necessary for the entrepreneurial journey. This study exposes a previously missing value of social networking in entrepreneurial education programmes. It encourages educators to embed social networking activities into the curriculum to facilitate entrepreneurial learning. The study highlights the importance of social capital acquired at university, as part of the student/graduate entrepreneurial journeys. This revitalises the role of the university as a key enabler of economic, social and cultural impact through student/graduate entrepreneurs. Thus, the university is dead (as was traditionally understood); long live the (entrepreneurial) university.
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| 21. |
- Majounie, Elisa, et al.
(författare)
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Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
- 2012
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Ingår i: Lancet Neurology. - 1474-4465. ; 11:4, s. 323-330
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Tidskriftsartikel (refereegranskat)abstract
- Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7.0%) of 3377 white individuals from the USA, Europe, and Australia, two (4.1%) of 49 black individuals from the USA, and six (8.3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39.3%) of 552 white individuals with familial MS from Europe and the USA. 59 (6.0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24.8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic MS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. Interpretation A common Mendelian genetic lesion in C9472 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
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| 22. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 23. |
- Quesada Pallares, Carla, et al.
(författare)
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The role of social informal learning in the student/graduate entrepreneurs’ entrepreneurial process
- 2017
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Ingår i: European Association for Research on Learning and Instruction (EARLI) conference, Aug 29-Sept 2, Tamppare Finland.
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Konferensbidrag (refereegranskat)abstract
- This paper aims to analyse the role of social informal learning of student/graduate entrepreneurs during their engagement in entrepreneurial processes while attending university. A qualitative methodological approach involving critical incident technique is used to map the entrepreneurial journeys of 18 students/graduates from Spain, Sweden and the United Kingdom. NVivo v10 software was used to conduct narrative analysis on collected data, focusing only on those entrepreneurial activities that occurred during university. Main findings suggest that student/graduate entrepreneurs tend to rely on mentors met in informal educational contexts in order to develop their entrepreneurial process; this person is contacted by the student/graduate entrepreneur itself with the idea of seeking their help. At an institutional-level, the study legitimises university inclusion of social networking activities into formal and non-formal entrepreneurship education, and encouragement of informal entrepreneurial learning. Moreover, the findings encourage educators to embed social networking activities within the curriculum in order to facilitate entrepreneurial learning.
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| 24. |
- Sou, Tomás, et al.
(författare)
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Model-Based Drug Development in Pulmonary Delivery : Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection
- 2019
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 108:1, s. 630-640
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Tidskriftsartikel (refereegranskat)abstract
- Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.
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| 25. |
- Soukarieh, Fadi, et al.
(författare)
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Design and Evaluation of New Quinazolin-4(3H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa
- 2021
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Ingår i: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 7:9, s. 2666-2685
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Tidskriftsartikel (refereegranskat)abstract
- P. aeruginosa (PA) continues to pose a threat to global public health due to its high levels of antimicrobial resistance (AMR). The ongoing AMR crisis has led to an alarming shortage of effective treatments for resistant microbes, and hence there is a pressing demand for the development of novel antimicrobial interventions. The potential use of antivirulence therapeutics to tackle bacterial infections has attracted considerable attention over the past decades as they hamper the pathogenicity of target microbes with reduced selective pressure, minimizing the emergence of resistance. One such approach is to interfere with the PA pqs quorum sensing system which upon the interaction of PqsR, a Lys-R type transcriptional regulator, with its cognate signal molecules 4-hydroxy-2-heptylquinoline (HHQ) and 2-heptyl-3-hydroxy-4-quinolone (PQS), governs multiple virulence traits and host-microbe interactions. In this study, we report the hit identification and optimization of PqsR antagonists using virtual screening coupled with whole cell assay validation. The optimized hit compound 61 ((R)-2-(4-(3-(6-chloro-4-oxoquinazolin-3(4H)-yl)-2-hydroxypropoxy)phenyl)acetonitrile) was found to inhibit the expression of the PA P-pqsA promoter controlled by PqsR with an IC50 of 1 mu M. Using isothermal titration calorimetry, a K-d of 10 nM for the P-qsR ligand binding domain (PqsR(LBD)) was determined for 61. Furthermore, the crystal structure of 61 with PqsR(LBD) was attained with a resolution of 2.65 angstrom. Compound 61 significantly reduced levels of pyocyanin, PQS, and HHQ in PAO1-L, PA14 lab strains and PAK6085 clinical isolate. Furthermore, this compound potentiated the effect of ciprofloxacin in early stages of biofilm treatment and in Galleria mellonella infected with PA. Altogether, this data shows 61 as a potent PqsR inhibitor with potential for hit to lead optimization toward the identification of a PA QS inhibitor which can be advanced into preclinical development.
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