| 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. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 3. |
- Fusai, Giuseppe Kito, et al.
(författare)
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Pancreatic surgery outcomes: multicentre prospective snapshot study in 67 countries
- 2023
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Ingår i: British Journal of Surgery. - : OXFORD UNIV PRESS. - 0007-1323 .- 1365-2168.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pancreatic surgery remains associated with high morbidity rates. Although postoperative mortality appears to have improved with specialization, the outcomes reported in the literature reflect the activity of highly specialized centres. The aim of this study was to evaluate the outcomes following pancreatic surgery worldwide. Methods: This was an international, prospective, multicentre, cross-sectional snapshot study of consecutive patients undergoing pancreatic operations worldwide in a 3-month interval in 2021. The primary outcome was postoperative mortality within 90 days of surgery. Multivariable logistic regression was used to explore relationships with Human Development Index (HDI) and other parameters. Results: A total of 4223 patients from 67 countries were analysed. A complication of any severity was detected in 68.7 percent of patients (2901 of 4223). Major complication rates (Clavien-Dindo grade at least IIIa) were 24, 18, and 27 percent, and mortality rates were 10, 5, and 5 per cent in low-to-middle-, high-, and very high-HDI countries respectively. The 90-day postoperative mortality rate was 5.4 per cent (229 of 4223) overall, but was significantly higher in the low-to-middle-HDI group (adjusted OR 2.88, 95 per cent c.i. 1.80 to 4.48). The overall failure-to-rescue rate was 21 percent; however, it was 41 per cent in low-to-middle-compared with 19 per cent in very high-HDI countries. Conclusion: Excess mortality in low-to-middle-HDI countries could be attributable to failure to rescue of patients from severe complications. The authors call for a collaborative response from international and regional associations of pancreatic surgeons to address management related to death from postoperative complications to tackle the global disparities in the outcomes of pancreatic surgery (NCT04652271; ISRCTN95140761).
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| 4. |
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| 5. |
- Aghanoori, Mohamad-Reza, et al.
(författare)
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CEBP beta regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth
- 2022
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Nature. - 1420-682X .- 1420-9071. ; 79:4
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBP beta, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBP beta overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBP beta can be a promising therapeutic approach.
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| 6. |
- Birney, Ewan, et al.
(författare)
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Prepublication data sharing
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 461:7261, s. 168-170
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Tidskriftsartikel (refereegranskat)abstract
- Rapid release of prepublication data has served the field of genomics well. Attendees at a workshop in Toronto recommend extending the practice to other biological data sets.
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| 7. |
- D'Souza, Nigel, et al.
(författare)
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Definition of the Rectum An International, Expert-based Delphi Consensus
- 2019
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Ingår i: Annals of Surgery. - : LIPPINCOTT WILLIAMS & WILKINS. - 0003-4932 .- 1528-1140. ; 270:6, s. 955-959
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Tidskriftsartikel (refereegranskat)abstract
- Background: The wide global variation in the definition of the rectum has led to significant inconsistencies in trial recruitment, clinical management, and outcomes. Surgical technique and use of preoperative treatment for a cancer of the rectum and sigmoid colon are radically different and dependent on the local definitions employed by the clinical team. A consensus definition of the rectum is needed to standardise treatment. Methods: The consensus was conducted using the Delphi technique with multidisciplinary colorectal experts from October, 2017 to April, 2018. Results: Eleven different definitions for the rectum were used by participants in the consensus. Magnetic resonance imaging (MRI) was the most frequent modality used to define the rectum (67%), and the preferred modality for 72% of participants. The most agreed consensus landmark (56%) was "the sigmoid take-off,'' an anatomic, image-based definition of the junction of the mesorectum and mesocolon. In the second round, 81% of participants agreed that the sigmoid take-off as seen on computed tomography or MRI achieved consensus, and that it could be implemented in their institution. Also, 87% were satisfied with the sigmoid take-off as the consensus landmark. Conclusion: An international consensus definition for the rectumis the point of the sigmoid take-off as visualized on imaging. The sigmoid take-off can be identified as the mesocolon elongates as the ventral and horizontal course of the sigmoid on axial and sagittal views respectively on cross-sectional imaging. Routine application of this landmark during multidisciplinary team discussion for all patients will enable greater consistency in tumour localisation.
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| 8. |
- 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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| 9. |
- Fogh, Isabella, et al.
(författare)
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Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis
- 2016
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 73:7, s. 812-820
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. OBJECTIVE To identify gene variants influencing survival in ALS. DESIGN, SETTING, AND PARTICIPANTS This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. MAIN OUTCOMES AND MEASURES Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed bymeta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. RESULTS Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 x 10(-9)) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 x 10(-8)). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 x 10(-9)), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 x 10(-8)), corresponding to a 4-month reduction in survival compared with TT carriers. CONCLUSIONS AND RELEVANCE This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.
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| 10. |
- 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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| 11. |
- Geerts, Jaason M., et al.
(författare)
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Guidance for Health Care Leaders During the Recovery Stage of the COVID-19 Pandemic A Consensus Statement
- 2021
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Ingår i: JAMA Network Open. - : American Medical Association. - 2574-3805. ; 4:7
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The COVID-19 pandemic is the greatest global test of health leadership of our generation. There is an urgent need to provide guidance for leaders at all levels during the unprecedented preresolution recovery stage.OBJECTIVE: To create an evidence- and expertise-informed framework of leadership imperatives to serve as a resource to guide health and public health leaders during the postemergency stage of the pandemic.EVIDENCE REVIEW: A literature search in PubMed, MEDLINE, and Embase revealed 10 910 articles published between 2000 and 2021 that included the terms leadership and variations of emergency, crisis, disaster, pandemic, COVID-19, or public health. Using the Standards for Quality Improvement Reporting Excellence reporting guideline for consensus statement development, this assessment adopted a 6-round modified Delphi approach involving 32 expert coauthors from 17 countries who participated in creating and validating a framework outlining essential leadership imperatives.FINDINGS: The 10 imperatives in the framework are; (1) acknowledge staff and celebrate successes; (2) provide support for staff well-being; (3) develop a clear understanding of the current local and global context, along with informed projections; (4) prepare for future emergencies (personnel, resources, protocols, contingency plans, coalitions, and training); (5) reassess priorities explicitly and regularly and provide purpose, meaning, and direction; (6) maximize team, organizational, and system performance and discuss enhancements; (7) manage the backlog of paused services and consider improvements while avoiding burnout and moral distress; (8) sustain learning, innovations, and collaborations, and imagine future possibilities; (9) provide regular communication and engender trust; and (10) in consultation with public health and fellow leaders, provide safety information and recommendations to government, other organizations, staff, and the community to improve equitable and integrated care and emergency preparedness systemwide.CONCLUSIONS AND RELEVANCE: Leaders who most effectively implement these imperatives are ideally positioned to address urgent needs and inequalities in health systems and to cocreate with their organizations a future that best serves stakeholders and communities.
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| 12. |
- Granjard, Alexandre, et al.
(författare)
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Personality Among Swedish Long-Term Unemployed
- 2020
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Ingår i: 32nd Association for Psychological Science Annual Convention. Chicago, Illinois, USA..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- As expected, compared to the normal population, the unemployed population scored one standard deviation higher in Harm Avoidance and lower in Self-directedness. Additionally, the analyses of personality profiles showed that 84.70% were high in Harm Avoidance, 65.30% low in Self-directedness, 38.30% low in Cooperativeness, and 49.50% low in Self- transcendence.
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| 13. |
- Granjard, Alexandre, et al.
(författare)
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Resilience Profiles Among Swedish Long-Term Unemployed
- 2020
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Ingår i: 32nd Association for Psychological Science Annual Convention. Chicago, Illinois, USA.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- A Resilient profile is low in Harm Avoidance (i.e., relaxed, confident, and optimistic) and high in Persistence (i.e., industrious, perseverant, and hard-working) and Self-Directedness (i.e., responsible, reliable, self-acceptant, goal- oriented, and resourceful). We found that, compared to the general population, only 1% of Swedish long-term unemployed had a resilient profile.
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| 14. |
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| 15. |
- Hosseinzadeh, Griffin, et al.
(författare)
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Photometric Classification of 2315 Pan-STARRS1 Supernovae with Superphot
- 2020
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 905:2
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Tidskriftsartikel (refereegranskat)abstract
- The classification of supernovae (SNe) and its impact on our understanding of explosion physics and progenitors have traditionally been based on the presence or absence of certain spectral features. However, current and upcoming wide-field time-domain surveys have increased the transient discovery rate far beyond our capacity to obtain even a single spectrum of each new event. We must therefore rely heavily on photometric classification-connecting SN light curves back to their spectroscopically defined classes. Here, we present Superphot, an open-source Python implementation of the machine-learning classification algorithm of Villar et al., and apply it to 2315 previously unclassified transients from the Pan-STARRS1 Medium Deep Survey for which we obtained spectroscopic host-galaxy redshifts. Our classifier achieves an overall accuracy of 82%, with completenesses and purities of >80% for the best classes (SNe Ia and superluminous SNe). For the worst performing SN class (SNe Ibc), the completeness and purity fall to 37% and 21%, respectively. Our classifier provides 1257 newly classified SNe Ia, 521 SNe II, 298 SNe Ibc, 181 SNe IIn, and 58 SLSNe. These are among the largest uniformly observed samples of SNe available in the literature and will enable a wide range of statistical studies of each class.
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| 16. |
- Jones, Hannah E., et al.
(författare)
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The differential response of human dendritic cells to live and killed Neisseria meningitidis
- 2007
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Ingår i: Cellular Microbiology. - : Hindawi Limited. - 1462-5814. ; 9:12, s. 2856-2869
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Tidskriftsartikel (refereegranskat)abstract
- There is currently no effective vaccine for Neisseria meningitidis (Nm) serogroup B. Generation of optimal immune responses to meningococci could be achieved by targeting meningococcal antigens to human dendritic cells (DCs). Recent studies have shown that diverse DC responses and subsequent generation of protective immunity can be observed if the microbes are viable or killed. This is important because the host is likely to be exposed to both live and killed bacteria during natural infection. There are currently few data on comparative DC responses to live and killed meningococci. We show here that exposure of human DC to live meningococci does not result in a typical maturation response, as determined by the failure to upregulate CD40, CD86, HLA-DR and HLA-Class I. Despite this, live meningococci were potent inducers of IL-12 and IL-10, although the ratios of these cytokines differed from those to killed organisms. Our data also suggest that enhanced phagocytosis of killed organisms compared with live may be responsible for the differential cytokine responses, involving an autocrine IL-10-dependent mechanism. The consequences of these findings upon the effectiveness of antigen presentation and T-cell responses are currently under investigation.
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| 17. |
- 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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| 18. |
- Lindström, Therese, 1976-
(författare)
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The history of the concept of grammaticalisation
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present thesis discusses the history and meaning of the term and concept called grammaticalisation. Linguists usually ascribe the coinage of the term grammaticalisation to Antoine Meillet (1866-1936), who allegedly played a vital role in the history of grammaticalisation. It is also widely acknowledged that grammaticalisation was in some way 'revived' during the 1970s, and that Talmy Givón had an important role in this, as demonstrated by the popularity of the saying 'Today’s morphology is yesterday’s syntax' (taken from one of his articles). I show that Meillet wrote little about grammaticalisation and that he hardly ever used this word, and possibly did not mean for it to be viewed as a term / label. Moreover, the paper in question (Meillet, 1912) is basically a general introduction to a concept which he sees as a continuation of a notion with a long history. In addition, I prove that there are no clear links between Meillet and Givón’s work in the early 1970s. Despite the general acceptance that Meillet coined grammaticalisation, my thesis proves that it could have been coined more than once, and that it does not always mean the same thing to all users. I show that sometimes the term is accompanied by examples which others have used to illustrate lexicalisation, a term which some employ for a process that is seen as the opposite of grammaticalisation. I therefore advocate careful use of our definitions of terminology and concepts, and insist that we should define our notions, instead of letting examples do the work of illustration and definition. Finally, I question whether it is true that grammaticalisation is unidirectional. I research the history of the view that grammaticalisation is a unidirectional process. Grammatical relations can be expressed by different means – e.g. word order, content words becoming grammatical markers, or parts of words being given a function. I believe all these should be compared, in order to improve our knowledge of how languages change and why. I claim that they all represent sub-processes of a superordinate category which I have labelled supergrammaticalisation.
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| 19. |
- Moody, Sandra A., et al.
(författare)
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The direct effects of UV-B radiation on Betula pubescens litter decomposing at four European field sites
- 2001
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Ingår i: Plant Ecology. - 1573-5052. ; 154:1-2, s. 27-36
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Tidskriftsartikel (refereegranskat)abstract
- A co-ordinated series of field experiments were conducted to consider the effects of elevated UV-B radiation applied directly to decomposing plant litter. Betula pubescens was decomposed under ambient and elevated UV-B (simulating a 15% ozone depletion) using outdoor irradiation facilities at Adventdalen, Norway (78° N), Abisko, Sweden (68° N), Amsterdam, The Netherlands (52° N,) and Patras, Greece (38° N). There was no significant effect of treatment on mass loss for samples collected after 2, 12 and 14 months decomposition at Amsterdam, or after 4 months decomposition at Adventdalen. Significant reductions in the mass loss of litter decomposing under elevated UV-B compared to ambient were found at the other 2 sites. The only effect of treatment on litter chemistry during decomposition was a significant reduction in the N concentration of material at Abisko and a significant increase in C:N at Patras for litter decomposing under elevated UV-B. Significant differences were found in the structure of the fungal community decomposing litter in Sweden, the only site to be tested. These data, and the few published studies of the response of decomposition to UV-B incident on litter suggest that, in the ecosystems and climates that have been studied, such direct effects are typically confined to the initial stages of decomposition, and are rather small in magnitude.
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| 20. |
- Murdoch, David R, et al.
(författare)
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Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.
- 2009
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Ingår i: Archives of internal medicine. - : American Medical Association (AMA). - 1538-3679 .- 0003-9926. ; 169:5, s. 463-73
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We sought to provide a contemporary picture of the presentation, etiology, and outcome of infective endocarditis (IE) in a large patient cohort from multiple locations worldwide. METHODS: Prospective cohort study of 2781 adults with definite IE who were admitted to 58 hospitals in 25 countries from June 1, 2000, through September 1, 2005. RESULTS: The median age of the cohort was 57.9 (interquartile range, 43.2-71.8) years, and 72.1% had native valve IE. Most patients (77.0%) presented early in the disease (<30 days) with few of the classic clinical hallmarks of IE. Recent health care exposure was found in one-quarter of patients. Staphylococcus aureus was the most common pathogen (31.2%). The mitral (41.1%) and aortic (37.6%) valves were infected most commonly. The following complications were common: stroke (16.9%), embolization other than stroke (22.6%), heart failure (32.3%), and intracardiac abscess (14.4%). Surgical therapy was common (48.2%), and in-hospital mortality remained high (17.7%). Prosthetic valve involvement (odds ratio, 1.47; 95% confidence interval, 1.13-1.90), increasing age (1.30; 1.17-1.46 per 10-year interval), pulmonary edema (1.79; 1.39-2.30), S aureus infection (1.54; 1.14-2.08), coagulase-negative staphylococcal infection (1.50; 1.07-2.10), mitral valve vegetation (1.34; 1.06-1.68), and paravalvular complications (2.25; 1.64-3.09) were associated with an increased risk of in-hospital death, whereas viridans streptococcal infection (0.52; 0.33-0.81) and surgery (0.61; 0.44-0.83) were associated with a decreased risk. CONCLUSIONS: In the early 21st century, IE is more often an acute disease, characterized by a high rate of S aureus infection. Mortality remains relatively high.
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| 21. |
- van Rheenen, Wouter, et al.
(författare)
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Genome-wide association analyses identify new risk variants and the genetic architecture of 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. 1043-1048
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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| 22. |
- Villar, V. Ashley, et al.
(författare)
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SuperRAENN : A Semisupervised Supernova Photometric Classification Pipeline Trained on Pan-STARRS1 Medium-Deep Survey Supernovae
- 2020
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 905:2
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Tidskriftsartikel (refereegranskat)abstract
- Automated classification of supernovae (SNe) based on optical photometric light-curve information is essential in the upcoming era of wide-field time domain surveys, such as the Legacy Survey of Space and Time (LSST) conducted by the Rubin Observatory. Photometric classification can enable real-time identification of interesting events for extended multiwavelength follow-up, as well as archival population studies. Here we present the complete sample of 5243 SN-like light curves (in g(P1)r(P1)i(P1)z(P1)) from the Pan-STARRS1 Medium-Deep Survey (PS1-MDS). The PS1-MDS is similar to the planned LSST Wide-Fast-Deep survey in terms of cadence, filters, and depth, making this a useful training set for the community. Using this data set, we train a novel semisupervised machine learning algorithm to photometrically classify 2315 new SN-like light curves with host galaxy spectroscopic redshifts. Our algorithm consists of an RF supervised classification step and a novel unsupervised step in which we introduce a recurrent autoencoder neural network (RAENN). Our final pipeline, dubbed SuperRAENN, has an accuracy of 87% across five SN classes (Type Ia, Ibc, II, IIn, SLSN-I) and macro-averaged purity and completeness of 66% and 69%, respectively. We find the highest accuracy rates for SNe Ia and SLSNe and the lowest for SNe Ibc. Our complete spectroscopically and photometrically classified samples break down into 62.0% Type Ia (1839 objects), 19.8% Type II (553 objects), 4.8% Type IIn (136 objects), 11.7% Type Ibc (291 objects), and 1.6% Type I SLSNe (54 objects).
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