| 1. |
- Zheng, Hou-Feng, et al.
(author)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Journal article (peer-reviewed)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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| 2. |
- Fransson, Göran, 1968-, et al.
(author)
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On the Swedish National Grade School for Digital Technologies in Education – GRADE : Expectations and experiences of doctorial students and supervisors
- 2018
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In: ICERI2018 Proceedings. - Sevilla : IATED. - 9788409059485 ; , s. 769-774
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Conference paper (peer-reviewed)abstract
- The Swedish National Graduate School for Digital Technologies in Education (GRADE) is a cooperative venture between six Swedish universities established during 2018. Within the field of educational sciences and in the area of digital technologies in education, GRADE aims to strengthen the expertise in the area and to increase national and international cooperation in research training activities.Over a number of years, and from multitude of sources (cf. Brown & Davis, 2004; Fisher, Higgins & Loveless, 2006; Kafai & Resnick 1996), research has stressed that increased digitalization in schools leads to a complexity that needs to be taken into account on different levels, from different perspectives and with different designs, methodologies and theoretical perspectives (cf. Olofsson, Lindberg, Fransson & Hauge, 2015; Price, Jewitt & Brown, 2013; Tondeur, Valcke & van Braak, 2008). At a micro-level, the learning situation of students, teachers and school-leaders changes and it becomes important to deepen the knowledge about the impact digital technologies has on the fundamental conditions for teaching and learning of different school subjects (cf. Chun, Kern & Smith 2016; Leung & Baccaglini-Frank, 2017). On a macro-level, conditions for education as such changes and digital technologies becomes an important object of study as agents of change (Wong & Li, 2008). The digitalization of K-12 schools has long been highlighted in policy as a necessity (cf. Kirkman et al, 2002; OECD, 2010). However, research and evaluations (cf. Fransson et al, 2012; OECD, 2015; Wastiau et al, 2013) show that many substantial challenges remain. One of the fundamental pillars of GRADE is the interdisciplinary approach. Several disciplines are present (Applied IT, Curriculum studies, Education, Informatics, Technology and Learning, Educational work, Work-interated Learning) in researching digital technologies in K-12 schools with the ambition to contribute to the continued implementation, integration and use of digital technologies in Swedish K-12 schools that stems from the evidence-based knowledge produced within the activities of GRADE. The research within GRADE will be characterized by close cooperation with stakeholders from school practice, with the aim to contribute to concrete school development. In GRADE, a multi-level approach that involves multiple layers or levels of school activities will be encouraged. When possible, studies will be longitudinal. This will imply studies from an organizational and management perspective, e.g. studies of school leaders and other members of senior management positions responsible for digital technology use and implementation. Also implied are studies of teachers' teaching practices and didactical considerations, as well as studies of the students in classrooms and their learning using digital technologies. This will also imply that several issues with a bearing on the digitalization of education, for example regarding school policy, teaching, learning, assessment and professional development will be researched from different perspectives and with different methodological approaches. In this paper, these points of departure will be explored based on the expectations and experiences of the first twelve admitted doctoral students and their supervisors.
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| 3. |
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| 4. |
- Patterson, Christopher C., et al.
(author)
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Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25year period 1989-2013 : a multicentre prospective registration study
- 2019
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In: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:3, s. 408-417
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6years.Methods: Age/sex-standardised incidence rates for the 0- to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends.Results: Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high-incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0- to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5- to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10- to 14-year-old age group (3.3% and 2.6% per annum, respectively). Significant 4year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012.Conclusions/interpretation: Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4year periodicity, no plausible explanation for this can be given.
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| 5. |
- Patterson, Cc, et al.
(author)
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Seasonal variation in month of diagnosis in children with type 1 diabetes registered in 23 European centers during 1989-2008 : little short-term influence of sunshine hours or average temperature
- 2015
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In: Pediatric Diabetes. - : Wiley-Blackwell. - 1399-543X .- 1399-5448. ; 16:8, s. 573-580
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Journal article (peer-reviewed)abstract
- BACKGROUND: The month of diagnosis in childhood type 1 diabetes shows seasonal variation.OBJECTIVE: We describe the pattern and investigate if year-to-year irregularities are associated with meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population-based European registries during 1989-2008.METHODS: Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends.RESULTS: Significant sinusoidal pattern was evident in all but two small centers with peaks in November to February and relative amplitudes ranging from ±11 to ±38% (median ±17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10-14 yr. There were no differences in seasonal pattern between four 5-yr sub-periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 °C excess) but not with sunshine hours.CONCLUSIONS: Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.
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| 6. |
- Själander, Sara, et al.
(author)
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Assessment of Use vs Discontinuation of Oral Anticoagulation After Pulmonary Vein Isolation in Patients With Atrial Fibrillation
- 2017
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In: JAMA cardiology. - : American Medical Association. - 2380-6583 .- 2380-6591. ; 2:2, s. 146-152
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Journal article (peer-reviewed)abstract
- IMPORTANCE: Pulmonary vein isolation (PVI) is a recommended treatment for patients with atrial fibrillation, but it is unclear whether it results in a lower risk of stroke.OBJECTIVES: To investigate the proportion of patients discontinuing anticoagulation treatment after PVI in association with the CHA(2)DS(2)-VASc (congestive heart failure, hypertension, age >= 75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65-74 years, sex category [female]) score, identify factors predicting stroke after PVI, and explore the risk of cardiovascular events after PVI in patients with and without guideline-recommended anticoagulation treatment.DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort studywas conducted using Swedish national health registries from January 1, 2006, to December 31, 2012, with a mean-follow up of 2.6 years. A total of 1585 patients with atrial fibrillation undergoing PVI from the Swedish Catheter Ablation Register were included, with information about exposure to warfarin in the national quality register Auricula. Data analysis was performed from January 1, 2015, to April 30, 2016.EXPOSURES: Warfarin treatment.MAIN OUTCOMES AND MEASURES: Ischemic stroke, intracranial hemorrhage, and death.RESULTS: In this cohort of 1585 patients, 73.0% were male, the mean (SD) age was 59.0 (9.4) years, and the mean (SD) CHA(2)DS(2)-VASc score was 1.5 (1.4). Of the 1585 patients, 1175 were followed up for more than 1 year after PVI. Of these, 360 (30.6%) discontinued warfarin treatment during the first year. In patients with a CHA(2)DS(2)-VASc score of 2 or more, patients discontinuing warfarin treatment had a higher rate of ischemic stroke (5 events in 312 years at risk [1.6% per year]) compared with those continuing warfarin treatment (4 events in 1192 years at risk [0.3% per year]) (P = .046). Patients with a CHA(2)DS(2)-VASc score of 2 or more or those who had previously experienced an ischemic stroke displayed a higher risk of stroke if warfarin treatment was discontinued (hazard ratio, 4.6; 95% CI, 1.2-17.2; P = .02 and hazard ratio, 13.7; 95% CI, 2.0-91.9; P = .007, respectively).CONCLUSIONS AND RELEVANCE: These findings indicate that discontinuation ofwarfarin treatment after PVI is not safe in high-risk patients, especially those who have previously experienced an ischemic stroke.
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| 7. |
- Sunduru, Naresh, et al.
(author)
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N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors
- 2017
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In: Journal of enzyme inhibition and medicinal chemistry (Print). - : Informa UK Limited. - 1475-6366 .- 1475-6374. ; 32:1, s. 513-521
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Journal article (peer-reviewed)abstract
- Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b] pyri-din-2-yl) phenyl) acetamide, 4g, with an IC50 of 2.6 mu M as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-phenylphenoxy)-N-(3-(oxazolo[4,5-b] pyridin-2-yl)phenyl) acetamide, 4i, with an IC50 of 0.35 mu M.
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| 8. |
- Svensson, MK, et al.
(author)
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The risk for diabetic nephropathy is low in young adults in a 17-year follow-up of the Diabetes Incidence Study in Sweden (DISS) : Higher age and BMI at diabetes onset can be important risk factors
- 2015
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In: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 31:2, s. 138-146
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Journal article (peer-reviewed)abstract
- AIMS: To estimate the occurrence of diabetic nephropathy (DN) in a population-based cohort of patients diagnosed with diabetes as young adults (15-34 years). Methods: All 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) were invited to a follow-up study 15-19 years after diagnosis and 468 (58%) participated. Islet cell antibodies were used to classify type of diabetes.RESULTS: After median 17 years of diabetes 15% of all patients, 14% T1DM and 25% T2DM, were diagnosed with DN. 91% had micro- and 8.6% macroalbuminuria. Older age at diagnosis (HR 1.05; 95% CI 1.01-1.10 per year) was an independent and a higher BMI at diabetes diagnosis (HR 1.04; 95% CI 1.00-1.09 per 1 kg/m(2) ) a near-significant predictor of development of DN. Age at onset of diabetes (p = 0.041), BMI (p = 0.012) and HbA1c (p < 0.001) were significant predictors of developing DN between 9 and 17 years of diabetes. At 17 years of diabetes duration, a high HbA1c level (OR 1.06; 95% CI 1.03-1.08 per 1 mmol/mol increase) and systolic blood pressure (OR 1.08; 95% CI 1.05-1.12 per 1 mmHg increase) were associated with DN.CONCLUSIONS: Patients with T2DM diagnosed as young adults seem to have an increased risk to develop DN compared to those with T1DM. Older age and higher BMI at diagnosis of diabetes were risk markers of development of DN. In addition, poor glycaemic control but not systolic blood pressure at 9 years of follow up were risk markers for later development of DN.
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| 9. |
- Björck, Fredrik, et al.
(author)
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Outcomes in a Warfarin-Treated Population With Atrial Fibrillation
- 2016
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In: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 1:2, s. 172-180
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Journal article (peer-reviewed)abstract
- IMPORTANCE Vitamin K antagonist (eg, warfarin) use is nowadays challenged by the non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). NOAC studies were based on comparisons with warfarin arms with times in therapeutic range (TTRs) of 55.2% to 64.9%, making the results less credible in health care systems with higher TTRs. OBJECTIVES To evaluate the efficacy and safety of well-managed warfarin therapy in patients with nonvalvular AF, the risk of complications, especially intracranial bleeding, in patients with concomitant use of aspirin, and the impact of international normalized ratio (INR) control. DESIGN, SETTING, AND PARTICIPANTS A retrospective, multicenter cohort study based on Swedish registries, especially AuriculA, a quality register for AF and oral anticoagulation, was conducted. The register contains nationwide data, including that from specialized anticoagulation clinics and primary health care centers. A total of 40 449 patients starting warfarin therapy owing to nonvalvular AF during the study period were monitored until treatment cessation, death, or the end of the study. The study was conducted from January 1, 2006, to December 31, 2011, and data were analyzed between February 1 and November 15, 2015. Associating complications with risk factors and individual INR control, we evaluated the efficacy and safety of warfarin treatment in patients with concomitant aspirin therapy and those with no additional antiplatelet medications. EXPOSURES Use of warfarin with and without concomitant therapy with aspirin. MAIN OUTCOMES AND MEASURES Annual incidence of complications in association with individual TTR (iTTR), INR variability, and aspirin use and identification of factors indicating the probability of intracranial bleeding. RESULTS Of the 40 449 patients included in the study, 16 201 (40.0%) were women; mean (SD) age of the cohort was 72.5 (10.1) years, and the mean CHA(2)DS(2)-VASc (cardiac failure or dysfunction, hypertension, age >= 75 years [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65-74 years, and sex category [female]) score was 3.3 at baseline. The annual incidence, reported as percentage (95% CI) of all-cause mortality was 2.19% (2.07-2.31) and, for intracranial bleeding, 0.44%(0.39-0.49). Patients receiving concomitant aspirin had annual rates of any major bleeding of 3.07%(2.70-3.44) and thromboembolism of 4.90% (4.43-5.37), and those with renal failure were at higher risk of intracranial bleeding (hazard ratio, 2.25; 95% CI, 1.32-3.82). Annual rates of any major bleeding and any thromboembolism in iTTR less than 70% were 3.81% (3.51-4.11) and 4.41% (4.09-4.73), respectively, and, in high INR variability, were 3.04%(2.85-3.24) and 3.48% (3.27-3.69), respectively. For patients with iTTR 70% or greater, the level of INR variability did not alter event rates. CONCLUSIONS AND RELEVANCE Well-managed warfarin therapy is associated with a low risk of complications and is still a valid alternative for prophylaxis of AF-associated stroke. Therapy should be closely monitored for patients with renal failure, concomitant aspirin use, and poor INR control.
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| 10. |
- Deplano, Alessandro, et al.
(author)
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Novel propanamides as fatty acid amide hydrolase inhibitors
- 2017
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 136, s. 523-542
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Journal article (peer-reviewed)abstract
- Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroary1)-2-(4(2-(trifluoromethyl)pyridin-4-y0amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or noncompetitive (TPA14) inhibition modes.
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