| 1. |
- Roselli, Carolina, et al.
(author)
-
Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
-
Journal article (peer-reviewed)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 2. |
- Anderson, Christopher D., et al.
(author)
-
Genetic variants in CETP increase risk of intracerebral hemorrhage
- 2016
-
In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 80:5, s. 730-740
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10(-4) ) with no heterogeneity across studies (I(2) = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10(-6) ).INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.
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| 3. |
- Ben Abdesslem, Fehmi, et al.
(author)
-
Understanding usage and activity in cellular networks by investigating HTTP requests
- 2015. - 11
-
In: 2015 12th Annual IEEE Consumer Communications and Networking Conference (CCNC). - 9781479963904 ; , s. 570-575
-
Conference paper (peer-reviewed)abstract
- The number of mobile devices is estimated to now exceed the world’s population, using more and more cloud services, and hence generating more and more traffic. Smartphones generate 95% of the total global handset traffic, and while approximately half of this traffic is sent to cellular networks, other handsets such as tablets are also using increasingly the cellular networks. This paper provides a closer look at the traffic generated on cellular networks by exploring billions of HTTP requests sent by millions of users to a nation-wide cellular network during 41 days. We confirm that - as in many other contexts - 20% of the users are responsible for more than 80% of the requests and provide a deeper analysis of the cellular network usage. Furthermore, we characterise the activity of users on their mobile device and which cloud services they use. For instance, almost 30% of the users use the cellular network frequently, mainly using search services and social networks, but 20% of their requests are sent to advertisement and tracking systems.
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| 4. |
- Berndt, Sonja I., et al.
(author)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
-
Journal article (peer-reviewed)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 5. |
- Do, Ron, et al.
(author)
-
Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
-
Journal article (peer-reviewed)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 6. |
- Donini, Lorenzo M, et al.
(author)
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A consensus document on definition and diagnostic criteria for orthorexia nervosa
- 2022
-
In: Eating and Weight Disorders. - Milan : Springer. - 1124-4909 .- 1590-1262. ; 27, s. 3695-3711
-
Journal article (peer-reviewed)abstract
- Purpose: Since the term orthorexia nervosa (ON) was coined from the Greek (ὀρθός, right and ὄρεξις, appetite) in 1997 to describe an obsession with “correct” eating, it has been used worldwide without a consistent definition. Although multiple authors have proposed diagnostic criteria, and many theoretical papers have been published, no consensus definition of ON exists, empirical primary evidence is limited, and ON is not a standardized diagnosis. These gaps prevent research to identify risk and protective factors, pathophysiology, functional consequences, and evidence-based therapeutic treatments. The aims of the current study are to categorize the common observations and presentations of ON pathology among experts in the eating disorder field, propose tentative diagnostic criteria, and consider which DSM chapter and category would be most appropriate for ON should it be included.Methods: 47 eating disorder researchers and multidisciplinary treatment specialists from 14 different countries across four continents completed a three-phase modified Delphi process, with 75% agreement determined as the threshold for a statement to be included in the final consensus document. In phase I, participants were asked via online survey to agree or disagree with 67 statements about ON in four categories: A–Definition, Clinical Aspects, Duration; B–Consequences; C–Onset; D–Exclusion Criteria, and comment on their rationale. Responses were used to modify the statements which were then provided to the same participants for phase II, a second round of feedback, again in online survey form. Responses to phase II were used to modify and improve the statements for phase III, in which statements that met the predetermined 75% of agreement threshold were provided for review and commentary by all participants.Results: 27 statements met or exceeded the consensus threshold and were compiled into proposed diagnostic criteria for ON.Conclusions: This is the first time a standardized definition of ON has been developed from a worldwide, multidisciplinary cohort of experts. It represents a summary of observations, clinical expertise, and research findings from a wide base of knowledge. It may be used as a base for diagnosis, treatment protocols, and further research to answer the open questions that remain, particularly the functional consequences of ON and how it might be prevented or identified and intervened upon in its early stages. Although the participants encompass many countries and disciplines, further research will be needed to determine if these diagnostic criteria are applicable to the experience of ON in geographic areas not represented in the current expert panel.Level of evidence: Level V: opinions of expert committees.© 2022, The Author(s).
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| 7. |
- Donini, Lorenzo M., et al.
(author)
-
Correction : A consensus document on definition and diagnostic criteria for orthorexia nervosa
- 2023
-
In: Eating and Weight Disorders. - Milan : Springer. - 1124-4909 .- 1590-1262. ; 28
-
Journal article (other academic/artistic)abstract
- In this article Rebecca C. Reynolds was missing from the author list. The complete correct author group is given below. Lorenzo M. Donini, Juan Ramón Barrada, Friederike Barthels, Thomas M. Dunn, Camille Babeau, Anna Brytek-Matera, Hellas Cena, Silvia Cerolini, Hye-hyun Cho, Maria Coimbra, Massimo Cuzzolaro, Claudia Ferreira, Valeria Galfano, Maria G. Grammatikopoulou, Souheil Hallit, Linn Håman, Phillipa Hay, Masahito Jimbo, Clotilde Lasson, Eva-Carin Lindgren, Renee McGregor, Marianna Minnetti, Edoardo Mocini, Sahar Obeid, Crystal D. Oberle, Maria-Dolores Onieva-Zafra, Marie-Christine Opitz, María-Laura Parra-Fernández, Reinhard Pietrowsky, Natalija Plasonja, Eleonora Poggiogalle, Adrien Rigó, Rachel F. Rodgers, Maria Roncero, Carmina Saldaña, Cristina Segura-Garcia, Jessica Setnick, Ji-Yeon Shin, Grazia Spitoni, Jana Strahler, Nanette Stroebele-Benschop, Patrizia Todisco, Mariacarolina Vacca, Martina Valente, Màrta Varga, Andrea Zagaria, Hana Flynn Zickgraf, Rebecca C. Reynolds & Caterina Lombardo. The original article [1] has been corrected. © 2023, Springer Nature Switzerland AG.
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| 8. |
- ElBeck, Zaher, et al.
(author)
-
Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
- 2024
-
In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15
-
Journal article (peer-reviewed)abstract
- While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. Consequently, conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment.
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| 9. |
-
Electronic Government : 18th IFIP WG 8.5 International Conference, EGOV 2019, San Benedetto Del Tronto, Italy, September 2–4, 2019, Proceedings
- 2019
-
Editorial proceedings (peer-reviewed)abstract
- This book constitutes the proceedings of the 18th IFIP WG 8.5 International Conference on Electronic Government, EGOV 2019, held in San Benedetto del Tronto, Italy, in September 2019, in conjunction with the IFIP WG 8.5 IFIP International Conference on Electronic Participation (ePart 2019) and the International Conference for E-Democracy and Open Government Conference (CeDEM 2019).The 27 revised full papers presented were carefully reviewed and selected from 64 submissions. The papers are clustered under the following topical sections: E-Government Foundations; E-Government Services and Open Government; Open Data: Social and Technical Aspects; AI, Data Analytics and Automated Decision Making; and Smart Cities.
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| 10. |
- Green, Henrik, et al.
(author)
-
Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities
- 2016
-
In: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 22:2, s. 366-373
-
Journal article (peer-reviewed)abstract
- Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy. (C)2015 AACR.
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| 11. |
- Gulyas, Miklos, et al.
(author)
-
COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
-
Journal article (peer-reviewed)abstract
- Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyse COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.Methods: In the multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells.Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95%CI 0.81-1.27 and HR 1.12; 95%CI 0.78-1.61, respectively). Similarly, in patients with high COX-2 expression in tumor cells (n=71) or stromal cells (n=55), survival did not differ significantly between patients who received celecoxib or placebo (HR 1.07; 95%CI 0.74-1.54 and HR 0.80; 95%CI 0.56-1.15). No significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p=0.48 and 0.25, respectively).Conclusion: In this subgroup analysis of patients with advanced NSCLC, we could not detect any significant interaction between COX-2 expression in tumor or stromal cells and outcome of celecoxib treatment in addition to standard chemotherapy.
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| 12. |
- Gulyas, Miklos, et al.
(author)
-
COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
- 2018
-
In: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 244-250
-
Journal article (peer-reviewed)abstract
- Aim: Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.Methods: In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells.Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81–1.27 and HR 1.12; 95% CI 0.78–1.61, respectively). High COX-2 scores in tumor (n = 71) or stromal cells (n = 55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60–1.54; and HR =1.51; 95% CI 0.86–2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p = .48 and .25, respectively).Conclusions: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.
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| 13. |
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| 14. |
- Halwani, Manar, 1981-
(author)
-
Engagement, directed motivational currents, and second language learning : adult immigrant perspectives
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- The dissertation answers calls for the integration of motivation and engagement theory and research among highly educated adult-migrant language learners. Specifically, the purpose of this dissertation is to propose a model to describe the interactions between the motivation construct Directed Motivational Currents (DMCs) and the engagement construct Engagement with Language (EWL). The site of this dissertation is Sweden and hence the language learners of this dissertation were learning Swedish to enter the Swedish employment market. This thesis is a qualitative study with a social-dynamic approach to DMCs and EWL, and second language learning is viewed as a highly interactive process. The dissertation consists of three studies. Each study is based in a different formal language learning setting with the following groups of participants: (1) voluntary migrants with university degrees; (2) voluntary and forced migrant medical doctors, and (3) forced migrant schoolteachers. Semi-structured interviews, observation, and questionnaires were used to collect data to describe DMCs and EWL in concert. The findings of the thesis are that the lenses of DMCs and EWL can be combined to reveal more detail about highly educated adult-migrant language learners learning than earlier models. The findings also suggested ways in which the DMCs and EWL constructs interact, and that these are influenced by learners’ visions of their current and future selves, and by effective profession-oriented language teaching. Based on the analysis of the data from the three studies a novel model, Engagement in Directed Motivational Currents (EDMCs), is posited. This novel model captures the multidirectional interaction between DMCs and EWL, and how DMCs are nurtured by cognitive, affective and social engagement, and EWL is energized by motivational structure and goal, and emotionality. The posited model has relevance for second language pedagogy beyond highly educated migrant adult language learning contexts, and for future research in the area of long-term motivation and EWL in relation to second language learning.
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| 15. |
- Hasmats, Johanna, et al.
(author)
-
Using whole exome sequencing to identify genetic candidates for carboplatin and gemcitabine induced toxicities
-
Journal article (other academic/artistic)abstract
- Chemotherapies are associated with significant inter-individual variability in therapeutic effect and adverse drug reactions. In lung cancer the use of gemcitabine and carboplatin induces grade 3-4 myelosuppression in about ¼ of the patients while an equal fraction of patients are basically unaffected in terms of myelosuppressive side effects. We therefore set out to try to identify genetic markers for gemcitabine / carboplatin induced myelosuppression. We selected 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0-1 after the first chemotherapy cycle) by the chemotherapy out of 243 lung cancer patients treated with gemcitabine / carboplatin. These patients were exome sequenced and their genetic differences compared using six different bioinformatic strategies; whole exome non-synonymous SNV association analysis, deviation from Hardy-Weinberg equilibrium, analysis of genes selected by a priori biological knowledge, analysis of genes selected from gene expression meta-analysis of toxicity data sets, Ingenuity pathway analysis and FunCoup network enrichment analysis. All patients were successfully sequenced and 5000-7000 non-synonymous single nucleotide variants were identified in each patient. PI3 (elastase specific inhibitor in neutrophils) showed the strongest association in the single SNV analysis (nominal p=0.0005). Further, variants within IL37, an inhibitor of the innate immune system, and CSAG1, a tumor antigen, differed among the two patient groups and appeared among the top hits in several of the performed analysis, indicating that the approach identifies genetic variants associated with the immune system and tumor differentiation, which might be important for the sensitivity to chemotherapeutic agents. However, the associations reported here are in a need of replication before clinical interpretations can be made.
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| 16. |
- Jansson, Johan, 1973-, et al.
(author)
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Adoption of alternative fuel vehicles : Influence from neighbors, family and coworkers
- 2017
-
In: Transportation Research Part D. - : Elsevier BV. - 1361-9209 .- 1879-2340. ; 54, s. 61-73
-
Journal article (peer-reviewed)abstract
- During the last years, many governments have set targets for increasing the share of biofuels in the transportation sector. Understanding consumer behavior is essential in designing policies that efficiently increase the uptake of cleaner technologies. In this paper we analyze adopters and non-adopters of alternative fuel vehicles (AFVs). We use diffusion of innovation theory and the established notion that the social system and interpersonal influence play important roles in adoption. Based on a nationwide database of car owners we analyze interpersonal influence on adoption from three social domains: neighbors, family and coworkers. The results point primarily at a neighbor effect in that AFV adoption is more likely if neighbors also have adopted. The results also point at significant effects of interpersonal influence from coworkers and family members but these effects weaken or disappear when income, education level, marriage, age, gender and green party votes are controlled for. The results extend the diffusion of innovation and AFV literature with empirical support for interpersonal influence based on objective data where response bias is not a factor. Implications for further research, environmental and transport policy, and practitioners are discussed.
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| 17. |
- Klevmarken, N. Anders, et al.
(author)
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Simulating the future of the Swedish baby-boom generations
- 2007
-
Reports (other academic/artistic)abstract
- For the purpose of studying the consequences of the ageing of the Swedish population a group of scientists have enlarged the microsimulation model SESIM - originally developed at the Swedish Ministry of Finance - with modules that simulate health status, take up of sickness benefits, retirement, the utilization of health care and social care and the dynamics of the income and wealth distributions. This paper motivates and reviews the structure of these modules with a focus on problems and solutions. It also summarizes the main results of the simulations. A complete description of the models and results are forthcoming in a volume included in the Elsevier series Contributions to Economic Analysis.
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| 18. |
- Knowles, Joshua W., et al.
(author)
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Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene
- 2015
-
In: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:4, s. 1739-1751
-
Journal article (peer-reviewed)abstract
- Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.
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| 19. |
- Lagou, Vasiliki, et al.
(author)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
-
In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
-
Journal article (peer-reviewed)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 20. |
- Lango Allen, Hana, et al.
(author)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
-
Journal article (peer-reviewed)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 21. |
- Lindgren, Anna, et al.
(author)
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Adiponectin receptor 2 deficiency results in reduced atherosclerosis in the brachiocephalic artery in apolipoprotein e deficient mice.
- 2013
-
In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11
-
Journal article (peer-reviewed)abstract
- Adiponectin has been shown to have beneficial cardiovascular effects and to signal through the adiponectin receptors, AdipoR1 and AdipoR2. The original aim of this study was to investigate the effect of combined AdipoR1 and AdipoR2 deficiency (AdipoR1(-/-)AdipoR2(-/-)) on atherosclerosis. However, we made the interesting observation that AdipoR1 (-/-) AdipoR2 (-/-) leads to embryonic lethality demonstrating the critical importance of the adiponectin signalling system during development. We then investigated the effect of AdipoR2-ablation on the progression of atherosclerosis in apolipoprotein E deficient (ApoE (-/-) ) mice. AdipoR2(-/-)ApoE(-/-) mice fed an atherogenic diet had decreased plaque area in the brachiocephalic artery compared with AdipoR2 (+/+) ApoE(-/-) littermate controls as visualized in vivo using an ultrasound biomicroscope and confirmed by histological analyses. The decreased plaque area in the brachiocephalic artery could not be explained by plasma cholesterol levels or inflammatory status. However, accumulation of neutral lipids was decreased in peritoneal macrophages from AdipoR2(-/-)ApoE(-/-) mice after incubation with oxidized LDL. This effect was associated with lower CD36 and higher ABCA1 mRNA levels in peritoneal macrophages from AdipoR2(-/-)ApoE(-/-) mice compared with AdipoR2(+/+)ApoE(-/-) controls after incubation with oxidized LDL. In summary, we show that adiponectin receptors are crucial during embryonic development and that AdipoR2-deficiency slows down the progression of atherosclerosis in the brachiocephalic artery of ApoE-deficient mice.
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| 22. |
- Lindgren, Ola, et al.
(author)
-
Differential Islet and Incretin Hormone Responses in Morning vs. Afternoon after Standardized Meal in Healthy Men.
- 2009
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:8, s. 2887-2892
-
Journal article (peer-reviewed)abstract
- Context: The insulin response to meal ingestion is more rapid in the morning than in the afternoon. Whether this is explained by a corresponding variation in the incretin hormones is not known. Objective: Assess islet and incretin hormones after meal ingestion in the morning versus afternoon. Design, Settings and Participants: Ingestion at 8am and at 5pm of a standardized meal (524 kcal) in healthy lean males (n=12) at a University Clinical Research Unit. Main Outcome Measures: 1)Early (30 min) area under the curve (AUC30) of plasma levels of insulin and intact (i) and total (t) glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) after meal ingestion. 2)Estimation of ss-cell function by model analysis of glucose and C-peptide. Results: Peak glucose was lower in the morning than in the afternoon (6.1+/-0.2 vs. 7.4+/-0.3 mmol/l, P=0.001). AUC30insulin (4.9+/-0.6 vs 2.8+/-0.4 nmol/l*30 min; P=0.012), AUC30tGLP-1 (300+/-40 vs. 160+/-30 pmol/l*30 min, P=0.002), AUC30iGIP (0.7+/-0.1 vs. 0.3+/-0.1 nmol/l* 30 min, P=0.002) and AUC30tGIP (1.1+/-0.1 vs. 0.6+/-0.1nmol/l*min, P=0.007) were all higher in the morning. AUC30iGLP-1 (r=0.68, P=0.021) and AUC39iGIP (r=0.78, P=0.001) both correlated to AUC30insulin. Model analysis of ss-cell function showed a higher first hour potentiation factor in the morning (P=0.009). This correlated negatively with the 60 min glucose level (r=-0.63, P<0.001). Conclusions: The early release of GLP-1 and GIP are more pronounced in the morning than in the afternoon. This may contribute to the more rapid early insulin response, more pronounced potentiation of ss-cell function and lower glucose after the morning meal.
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| 23. |
- Lindgren, Ola, et al.
(author)
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Incretin Effect after Oral Amino Acid Ingestion in Humans.
- 2015
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:3, s. 1172-1176
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Journal article (peer-reviewed)abstract
- Context: The incretin effect is the augmented insulin secretion by oral versus intravenous glucose at matching glucose levels. We previously demonstrated an augmented insulin secretion when fat is given orally rather than intravenously, suggesting an incretin effect also after fat. However, whether there is an incretin effect is also present after amino acid ingestion is not known. Objective: To explore insulin secretion and islet hormones after oral and intravenous amino acid administration at matched total amino acid concentrations in healthy subjects. Design: Amino acid mixture (Vaminolac(R)) was administered orally or intravenously at a rate resulting in matching total amino acid concentrations to twelve male volunteers with age 22.5±1.4 yr and BMI 22.4±1.4 kg/m(2), who had no history of diabetes. Main outcome measures: Area under the 120 min curve (AUC) for insulin, C-peptide, glucagon, intact and total glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and insulin secretory rate and insulin clearance. Results: Insulin, C-peptide and glucagon levels increased after both oral and intravenous administration, but insulin secretion was 25% higher after oral than after intravenous amino acid challenges (P=0.006), whereas there was no significant difference in the glucagon response. Intact and total GIP rose after oral but not after intravenous amino acid administration, whereas intact and total GLP-1 levels did not change significantly in either test. Conclusion: Oral amino acid mixture ingestion elicits a stronger insulin secretory response than intravenous amino acid at matching amino acid levels and that this is associated with increased GIP level, suggesting that an incretin effect exists also after oral amino acids, possibly mediated by GIP.
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| 24. |
- Lindgren, Ola, et al.
(author)
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Incretin Hormone and Insulin Responses to Oral Versus Intravenous Lipid Administration in Humans.
- 2011
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 96, s. 2519-2524
-
Journal article (peer-reviewed)abstract
- Context: The incretin effect is responsible for the higher insulin response to oral glucose than to iv glucose at matching glucose levels. It is not known whether this effect is restricted to glucose only. Objective: The aim of the study was to examine whether insulin and incretin hormone responses are higher after oral vs. iv challenge of a lipid emulsion with matching triglyceride levels in humans. Design, Settings, and Participants: A lipid emulsion (Intralipid) was administered orally (3 ml/kg) or iv (variable infusion rates to match triglyceride levels after oral ingestion) in healthy lean males (n = 12) at a University Clinical Research Unit. Samples were collected during 300 min. Main Outcome Measures: We measured the suprabasal area under the curve for insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and the insulin secretory rate based on C-peptide levels by deconvolution. Results: Triglyceride levels increased similarly after oral and iv lipid; also, glucose and free fatty acid levels were similar in the two tests. Oral lipid elicited a clear insulin and C-peptide response, whereas no insulin or C-peptide responses were observed during iv lipid. Total and intact GIP and GLP-1 levels both increased after oral lipid administration but were not significantly altered after iv lipid. Conclusions: At matching triglyceride levels and with no difference in glucose and free fatty acid levels, oral lipid ingestion but not iv lipid infusion elicits a clear insulin response in association with increased GIP and GLP-1 concentrations. This may suggest that the incretin hormones also contribute to the islet response to noncarbohydrate nutrients.
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| 25. |
- Mahajan, Anubha, et al.
(author)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
-
In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Journal article (peer-reviewed)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 26. |
- Mannberg, Andrea, 1977-, et al.
(author)
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Do tax incentives affect households' adoption of ‘green’ cars? : A panel study of the Stockholm congestion tax
- 2014
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In: Energy Policy. - : Elsevier BV. - 0301-4215 .- 1873-6777. ; 74, s. 286-299
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Journal article (peer-reviewed)abstract
- Policymakers have made several attempts to introduce local and national policies to reduce CO2 emissions and stimulate the consumer adoption of alternative fuel vehicles (ethanol/E85 cars). The purpose of this paper is to analyze how a local policy measure impacts the composition of the car fleet over time. More specifically, we take advantage of the natural experiment setting caused by the introduction of the Stockholm congestion tax (2006) to analyze how the tax affected purchases of ethanol cars that were exempted from the tax. To estimate effects, we employ a Difference-in-differences methodology. By using a comprehensive database of the car fleet and car owners, sociodemographic and geographic factors are analyzed, which is unique in the existing literature. Our results suggest that the congestion tax had a significant impact on ethanol car purchases although the effect fades away over time. Furthermore, there is a positive relationship between the level of education and ethanol car purchases. Previous adoption of an ethanol car is found to be the strongest predictor of ethanol car purchases. Finally, data indicate that Stockholmers substantially increased purchases of ethanol cars half a year before the introduction of the congestion tax, which we refer to as an anticipation effect.
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| 27. |
- Mannberg, Andrea, et al.
(author)
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Påverkar skatteundantag hushållens benägenhet att köpa miljöbilar? En studie av Stockholms trängselskatt
- 2015
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In: Ekonomisk Debatt. - 0345-2646. ; 43:1, s. 32-39
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Journal article (peer-reviewed)abstract
- Sedan januari 2006 är in- och ut-passage genom tullarna i Stockholm belagt med en avgift för bilister. Som ett led i riksdagens mål att helt eliminera utsläppen av växthusgaser 2050 och ha en bilpark oberoende av fossila bränslen 2030 (Regeringens proposition 2008/09:162) undantogs sk miljöbilar från trängselskatten mellan 2006 och 2009. I denna studie har vi undersökt om undantaget av miljöbilar från trängselskatten i Stockholm påverkade sannolikheten att köpa etanolbil (E85). Våra resultat visar att undantaget för etanolbilar i trängselskatten hade en signifikant effekt på etanolbilsförsäljningeni Stockholm.
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| 28. |
- Mark, Davis, et al.
(author)
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A year in the public life of superbugs: News media on antimicrobial resistance and implications for health communications
- 2020
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In: Social Science and Medicine. - : Elsevier BV. - 0277-9536. ; 256
-
Journal article (peer-reviewed)abstract
- News media can be an important source of information about emerging health threats. They are also significant sites for the production of narrative on threats to life that help to condition and reflect the responses of governments and publics. Antimicrobial resistance (AMR) is one such health threat with particular significance because it represents the failure to manage the risks to antibiotics and other antimicrobials, health technologies that have provided the basis for modern medicine. Knowledge of how news media address this situation is an important element for an effective public health response to AMR and helps to extend the social analysis of health and media. Based on an analysis of television, printed and digital news for 2017 in Australia, this paper examines the patterns and meanings of AMR news. It shows that AMR is a fragmented story mainly framed by scientific discovery. These stories reassure audiences that science is seeking out the means of arresting AMR and, therefore, also constructs lay publics as passive witnesses to the AMR story. This pattern of AMR story-telling furthers the social standing of science and scientists, but it also neglects deliberation on collective action, important lacunae in the social response to AMR.
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| 29. |
- Mark, Davis, et al.
(author)
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Understanding media publics and the antimicrobial resistance crisis
- 2018
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In: Global Public Health. - : Informa UK Limited. - 1744-1692 .- 1744-1706. ; 13:9, s. 1158-1168
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Journal article (peer-reviewed)abstract
- Antimicrobial resistance (AMR) imperils health for people across the world. This enormous challenge is being met with the rationalisation of prescription, dispensing and consumption of antimicrobials in clinical settings and in the everyday lives of members of the general population. Individuals need to be reached outside clinical settings to prepare them for the necessary changes to the pharmaceutical management of infections; efforts that depend on media and communications and, therefore, how the AMR message is mediated, received and applied. In 2016, the UK Review on Antimicrobial Resistance called on governments to support intense, worldwide media activity to promote public awareness and to further efforts to rationalise the use of antimicrobial pharmaceuticals. In this article, we consider this communications challenge in light of contemporary currents of thought on media publics, including: the tendency of health communications to cast experts and lay individuals in opposition; the blaming of individuals who appear to ‘resist’ expert advice; the challenges presented by negative stories of AMR and their circulation in public life, and; the problems of public trust tied to the construction and mediation of expert knowledge on the effective management of AMR.
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| 30. |
- Mylrea-Foley, Bronacha, et al.
(author)
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Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise : the TRUFFLE 2 randomised trial protocol
- 2022
-
In: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:4
-
Journal article (peer-reviewed)abstract
- Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years.Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (>= 4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire.Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy.
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| 31. |
- Saini, Nishant, et al.
(author)
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Bandgap engineered Cu 2 ZnGe x Sn 1−x S 4 solar cells using an adhesive TiN back contact layer
- 2021
-
In: Journal of Alloys and Compounds. - : Elsevier BV. - 0925-8388. ; 880
-
Journal article (peer-reviewed)abstract
- Kesterite-based solar cells are mainly restricted by their lower than expected open-circuit voltage (V ) due to non-radiative recombination. Therefore, an approach to reduce bulk and interface recombination through band gap grading to induce a back surface field is attempted. This contribution presents the challenges in the formation of compositional grading of the wide bandgap material Cu ZnGe Sn S (CZGTS) and successful fabrication of solar cells with an additional adhesive TiN interlayer. It is observed that the TiN interlayer improves adhesion between CZGTS and the back contact. The microstructure of the Cu ZnSnS (CZTS) film is significantly affected by the concentration of Ge, and the existence of a Ge concentration gradient is strongly correlated to the formation of smaller Ge-rich and larger Sn-rich grains. The bandgap grading is exploited with a moderate Ge concentration of up to (Ge/(Ge+Sn) = 0.25) in CZTS. As the Ge profile stretched all the way to the front interface, the cliff-like band alignment at the front interface of the absorber could negate the beneficial effect of Ge inclusion in the bulk and back interface of the absorber. Ordering the absorber can introduce an additional downward shift in the valence band. In one of the samples, the increased ordering and high concentration of Ge in CZTS are suggested to enhance the hole barrier at the back interface. It is concluded that the effect of the bandgap grading with Ge can only be realized with optimization of interface band alignment and back contact formation. oc 2 x 1−x 4 2 4
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| 32. |
- Saini, Nishant, et al.
(author)
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Bandgap engineered Cu2ZnGexSn1−xS4 solar cells using an adhesive TiN back contact layer
- 2021
-
In: Journal of Alloys and Compounds. - : Elsevier. - 0925-8388 .- 1873-4669. ; 880
-
Journal article (peer-reviewed)abstract
- Kesterite-based solar cells are mainly restricted by their lower than expected open-circuit voltage (Voc) due to non-radiative recombination. Therefore, an approach to reduce bulk and interface recombination through band gap grading to induce a back surface field is attempted. This contribution presents the challenges in the formation of compositional grading of the wide bandgap material Cu2ZnGexSn1−xS4 (CZGTS) and successful fabrication of solar cells with an additional adhesive TiN interlayer. It is observed that the TiN interlayer improves adhesion between CZGTS and the back contact. The microstructure of the Cu2ZnSnS4 (CZTS) film is significantly affected by the concentration of Ge, and the existence of a Ge concentration gradient is strongly correlated to the formation of smaller Ge-rich and larger Sn-rich grains. The bandgap grading is exploited with a moderate Ge concentration of up to (Ge/(Ge+Sn) = 0.25) in CZTS. As the Ge profile stretched all the way to the front interface, the cliff-like band alignment at the front interface of the absorber could negate the beneficial effect of Ge inclusion in the bulk and back interface of the absorber. Ordering the absorber can introduce an additional downward shift in the valence band. In one of the samples, the increased ordering and high concentration of Ge in CZTS are suggested to enhance the hole barrier at the back interface. It is concluded that the effect of the bandgap grading with Ge can only be realized with optimization of interface band alignment and back contact formation.
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| 33. |
- Sbarra, AN, et al.
(author)
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Mapping routine measles vaccination in low- and middle-income countries
- 2021
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 589:7842, s. 415-
-
Journal article (peer-reviewed)abstract
- The safe, highly effective measles vaccine has been recommended globally since 1974, yet in 2017 there were more than 17 million cases of measles and 83,400 deaths in children under 5 years old, and more than 99% of both occurred in low- and middle-income countries (LMICs)1–4. Globally comparable, annual, local estimates of routine first-dose measles-containing vaccine (MCV1) coverage are critical for understanding geographically precise immunity patterns, progress towards the targets of the Global Vaccine Action Plan (GVAP), and high-risk areas amid disruptions to vaccination programmes caused by coronavirus disease 2019 (COVID-19)5–8. Here we generated annual estimates of routine childhood MCV1 coverage at 5 × 5-km2pixel and second administrative levels from 2000 to 2019 in 101 LMICs, quantified geographical inequality and assessed vaccination status by geographical remoteness. After widespread MCV1 gains from 2000 to 2010, coverage regressed in more than half of the districts between 2010 and 2019, leaving many LMICs far from the GVAP goal of 80% coverage in all districts by 2019. MCV1 coverage was lower in rural than in urban locations, although a larger proportion of unvaccinated children overall lived in urban locations; strategies to provide essential vaccination services should address both geographical contexts. These results provide a tool for decision-makers to strengthen routine MCV1 immunization programmes and provide equitable disease protection for all children.
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| 34. |
- Sörenson, Sverre, et al.
(author)
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Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy
- 2013
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In: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 49:1, s. 115-120
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Journal article (peer-reviewed)abstract
- Aim of the study: The primary purpose of this study is to investigate if pretreatment plasma levels of vascular endothelial growth factor (VEGF) are predictive of the effect of celecoxib on survival in advanced non-small cell lung cancer (NSCLC) treated with palliative chemotherapy. A secondary objective is to describe the course of plasma VEGF levels during and after treatment with cytotoxic chemotherapy combined with celecoxib or placebo. less thanbrgreater than less thanbrgreater thanMethods: In a previously published double-blind multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and World Health Organisation (WHO) performance status 0-2 were randomised to receive celecoxib 400 mg b.i.d. or placebo in combination with two-drug platinum-based chemotherapy. Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Celecoxib was given for a maximum of one year but was stopped earlier in case of disease progression or prohibitive toxicity. In a subset of patients, plasma VEGF levels were examined at onset of treatment and at 6, 12 and 20 weeks. less thanbrgreater than less thanbrgreater thanResults: VEGF levels at start of treatment were obtained in 107 patients at four study sites. The median value was 70 pg/ml. Mean values declined during the first 12 weeks and then increased at 20 weeks. A subpopulation treatment effect pattern plot (STEPP) analysis showed an inverse relationship between initial plasma VEGF and the impact of celecoxib on survival with zero effect at 200 pg/ml. The effect on survival by celecoxib in the whole subset of patients was positive (hazard ratio (HR)=0.64 [confidence interval (CI) 0.43-0.95], p=0.028). less thanbrgreater than less thanbrgreater thanConclusion: Low pretreatment plasma levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.
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| 35. |
- Tuisku, Jouni, et al.
(author)
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Effects of age, BMI and sex on the glial cell marker TSPO : a multicentre [11C]PBR28 HRRT PET study
- 2019
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089. ; 46:11, s. 2329-2338
-
Journal article (peer-reviewed)abstract
- Purpose The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [C-11]PBR28. Methods [C-11]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (V-T) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results There were significant positive correlations between age and V-T in the frontal and temporal cortex. BMI showed a significant negative correlation with V-T in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher V-T. A subgroup analysis revealed a positive correlation between V-T and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.
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| 36. |
- Valerio, Lorenzo, et al.
(author)
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Offloading Cellular Traffic with Opportunistic Networks : A Feasibility Study
- 2015. - 17
-
In: 2015 14th Annual Mediterranean Ad Hoc Networking Workshop (MED-HOC-NET). - 9781467373067
-
Conference paper (peer-reviewed)abstract
- The widespread diffusion of powerful mobile devices with diverse networking and multimedia capabilities, and the associated blossoming of content-centric multimedia services is contributing to the exponential increase of data traffic in cellular networks. Mobile data offloading is a promising technique to cope with these problems, which allows to deliver data originally targeted for cellular networks to complementary networking technologies. Among the various forms of mobile data offloading in this study we focus on offloading through opportunistic networks. Differently from previous studies in this field we evaluate the efficiency of opportunistic offloading schemes by using a real cellular traffic dataset collected in a large metropolitan area over a period of one month. We focus our analysis on video requests for popular video providers, and we evaluate the potential benefits of using an opportunistic data dissemination scheme to request this videos from local users instead of using the cellular network. As a benchmark, we compare the performance of such system with a simple caching mechanism. We show that a simple opportunistic offloading scheme can improve the performance of the caching system even if only 10% of the users participate in the opportunistic dissemination. This means that operators could offload their network efficiently without needing to deploy additional caching infrastructure.
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| 37. |
- Wessel, Jennifer, et al.
(author)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Journal article (peer-reviewed)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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| 38. |
- Willer, Cristen J., et al.
(author)
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Discovery and refinement of loci associated with lipid levels
- 2013
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
-
Journal article (peer-reviewed)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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| 39. |
- Zhou, Wei, et al.
(author)
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Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease
- 2022
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In: Cell Genomics. - : Elsevier. - 2666-979X. ; 2:10
-
Journal article (peer-reviewed)abstract
- Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
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