| 1. |
- Franceschini, N., et al.
(author)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
-
Journal article (peer-reviewed)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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| 2. |
- Andreoni, I., et al.
(author)
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Follow Up of GW170817 and Its Electromagnetic Counterpart by Australian-Led Observing Programmes
- 2017
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In: Publications Astronomical Society of Australia. - : Cambridge University Press (CUP). - 1323-3580 .- 1448-6083. ; 34
-
Research review (peer-reviewed)abstract
- The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (similar to 2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.
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| 3. |
- Hudson, Lawrence N, et al.
(author)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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In: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
-
Journal article (peer-reviewed)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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| 4. |
- Jones, Gregory T., et al.
(author)
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Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci
- 2017
-
In: Circulation Research. - 0009-7330 .- 1524-4571. ; 120:2, s. 341-
-
Journal article (peer-reviewed)abstract
- Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
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| 5. |
- Franceschini, N, et al.
(author)
-
GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 5141-
-
Journal article (peer-reviewed)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
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| 6. |
- Webb, Thomas R., et al.
(author)
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Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
- 2017
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 69:7, s. 823-836
-
Journal article (peer-reviewed)abstract
- BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits.CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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| 7. |
- Broderick, J. W., et al.
(author)
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LOFAR 144-MHz follow-up observations of GW170817
- 2020
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In: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 494:4, s. 5110-5117
-
Journal article (peer-reviewed)abstract
- We present low-radio-frequency follow-up observations of AT 2017gfo, the electromagnetic counterpart of GW170817, which was the first binary neutron star merger to be detected by Advanced LIGO-Virgo. These data, with a central frequency of 144 MHz, were obtained with LOFAR, the Low-Frequency Array. The maximum elevation of the target is just 13 degrees.7 when observed with LOFAR, making our observations particularly challenging to calibrate and significantly limiting the achievable sensitivity. On time-scales of 130-138 and 371-374 d after the merger event, we obtain 3s upper limits for the afterglow component of 6.6 and 19.5mJy beam(-1), respectively. Using our best upper limit and previously published, contemporaneous higher frequency radio data, we place a limit on any potential steepening of the radio spectrum between 610 and 144 MHz: the two-point spectral index alpha(610)(144) greater than or similar to -2.5. We also show that LOFAR can detect the afterglows of future binary neutron star merger events occurring at more favourable elevations.
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| 8. |
- Gaupp-Berghausen, M, et al.
(author)
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Evaluation of different recruitment methods: Longitudinal, web-based, pan-european physical activity through sustainable transport approaches (PASTA) project
- 2019
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In: Journal of Medical Internet Research. - : JMIR Publications Inc.. - 1438-8871. ; 21:5, s. e11492-
-
Journal article (peer-reviewed)abstract
- Background: Sufficient sample size and minimal sample bias are core requirements for empirical data analyses. Combining opportunistic recruitment with a Web-based survey and data-collection platform yields new benefits over traditional recruitment approaches. Objective: This paper aims to report the success of different recruitment methods and obtain data on participants' characteristics, participation behavior, recruitment rates, and representativeness of the sample. Methods: A longitudinal, Web-based survey was implemented as part of the European PASTA (Physical Activity through Sustainable Transport Approaches) project, between November 2014 and December 2016. During this period, participants were recruited from 7 European cities on a rolling basis. A standardized guide on recruitment strategy was developed for all cities, to reach a sufficient number of adult participants. To make use of the strengths and minimize weakness, a combination of different opportunistic recruitment methods was applied. In addition, the random sampling approach was applied in the city of Örebro. To reduce the attrition rate and improve real-time monitoring, the Web-based platform featured a participant's and a researchers' user interface and dashboard. Results: Overall, 10,691 participants were recruited; most people found out about the survey through their workplace or employer (2300/10691, 21.51%), outreach promotion (2219/10691, 20.76%), and social media (1859/10691, 17.39%). The average number of questionnaires filled in per participant varied significantly between the cities (P<.001), with the highest number in Zurich (11.0, SE 0.33) and the lowest in Örebro (4.8, SE 0.17). Collaboration with local organizations, the use of Facebook and mailing lists, and direct street recruitment were the most effective approaches in reaching a high share of participants.
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| 9. |
- Shimwell, T. W., et al.
(author)
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The LOFAR Two-metre Sky Survey: V. Second data release
- 2022
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 659
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Journal article (peer-reviewed)abstract
- In this data release from the ongoing LOw-Frequency ARray (LOFAR) Two-metre Sky Survey we present 120a 168 MHz images covering 27% of the northern sky. Our coverage is split into two regions centred at approximately 12h45m +44 30a and 1h00m +28 00a and spanning 4178 and 1457 square degrees respectively. The images were derived from 3451 h (7.6 PB) of LOFAR High Band Antenna data which were corrected for the direction-independent instrumental properties as well as direction-dependent ionospheric distortions during extensive, but fully automated, data processing. A catalogue of 4 396 228 radio sources is derived from our total intensity (Stokes I) maps, where the majority of these have never been detected at radio wavelengths before. At 6a resolution, our full bandwidth Stokes I continuum maps with a central frequency of 144 MHz have: a median rms sensitivity of 83 μJy beama 1; a flux density scale accuracy of approximately 10%; an astrometric accuracy of 0.2a; and we estimate the point-source completeness to be 90% at a peak brightness of 0.8 mJy beama 1. By creating three 16 MHz bandwidth images across the band we are able to measure the in-band spectral index of many sources, albeit with an error on the derived spectral index of > a ±a 0.2 which is a consequence of our flux-density scale accuracy and small fractional bandwidth. Our circular polarisation (Stokes V) 20a resolution 120a168 MHz continuum images have a median rms sensitivity of 95 μJy beama 1, and we estimate a Stokes I to Stokes V leakage of 0.056%. Our linear polarisation (Stokes Q and Stokes U) image cubes consist of 480a A a 97.6 kHz wide planes and have a median rms sensitivity per plane of 10.8 mJy beama 1 at 4a and 2.2 mJy beama 1 at 20a; we estimate the Stokes I to Stokes Q/U leakage to be approximately 0.2%. Here we characterise and publicly release our Stokes I, Q, U and V images in addition to the calibrated uv-data to facilitate the thorough scientific exploitation of this unique dataset.
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| 10. |
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| 11. |
- Askling, J., et al.
(author)
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How comparable are rates of malignancies in patients with rheumatoid arthritis across the world? A comparison of cancer rates, and means to optimise their comparability, in five RA registries
- 2016
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 75:10, s. 1789-1796
-
Journal article (peer-reviewed)abstract
- Background The overall incidence of cancer in patients with rheumatoid arthritis (RA) is modestly elevated. The extent to which cancer rates in RA vary across clinical cohorts and patient subsets, as defined by disease activity or treatment is less known but critical for understanding the safety of existing and new antirheumatic therapies. We investigated comparability of, and means to harmonise, malignancy rates in five RA registries from four continents. Methods Participating RA registries were Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (several countries) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data, and sensitivity analyses of sub-cohorts defined by disease activity, treatment change, prior comorbidities and restricted by calendar time or follow-up, respectively. Malignancy rates with 95% CIs were estimated, and standardised for age and sex, based on the distributions from a typical RA clinical trial programme population (fostamatinib). Results There was a high consistency in rates for overall malignancy excluding non-melanoma skin cancer (NMSC), for malignant lymphomas, but not for all skin cancers, across registries, in particular following age/sex standardisation. Standardised rates of overall malignancy excluding NMSC varied from 0.56 to 0.87 per 100 person-years. Within each registry, rates were generally consistent across sensitivity analyses, which differed little from the main analysis. Conclusion In real-world RA populations, rates of both overall malignancy and of lymphomas are consistent.
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| 12. |
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| 13. |
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| 14. |
- Halvarsson, A, et al.
(author)
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Long-term effects of new progressive group balance training for elderly people with increased risk of falling - a randomized controlled trial
- 2013
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In: Clinical rehabilitation. - : SAGE Publications. - 1477-0873 .- 0269-2155. ; 27:5, s. 450-458
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Journal article (peer-reviewed)abstract
- To evaluate the long-term effects of a progressive and specific balance group-based program in healthy elderly individuals with increased risk of falling. Design: Follow-up of a randomized controlled trial at nine and 15 months on a population that has previously been described at three months. Setting: The study was conducted in Stockholm, Sweden. Subjects: 59 community-dwelling elderly (age 67–93 years), recruited by advertisement, were randomly allocated to training or to serve as controls. Intervention: Group balance training three times per week during 12 weeks with a 15 month follow-up time. Main measures: Participants were assessed at baseline, three, nine, and 15 months thereafter for gait function (preferred and fast walking), rapid step execution (single and dual task), fear of falling, and likelihood of depression. Results: Fast gait speed ( p = 0.004), dual task step execution ( p = 0.006) and fear of falling ( p = 0.001) were still improved in the training group at nine months follow-up. Only self-perceived fear of falling remained significantly improved ( p = 0.012) at 15 months follow-up. Although fast gait speed had decreased to baseline level in the training group (1.49 m/s) it remained significantly higher than in the control group (1.37 m/s) at the end of the study, a difference between the groups that was not seen at baseline. Conclusion: This training program provided important positive short and long-term benefits to gait, balance function, and fear of falling.
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| 15. |
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| 16. |
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| 17. |
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| 18. |
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| 19. |
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| 20. |
- Michaud, K., et al.
(author)
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Can rheumatoid arthritis (RA) registries provide contextual safety data for modern RA clinical trials? The case for mortality and cardiovascular disease
- 2016
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 75:10, s. 1797-1805
-
Journal article (peer-reviewed)abstract
- Background We implemented a novel method for providing contextual adverse event rates for a randomised controlled trial (RCT) programme through coordinated analyses of five RA registries, focusing here on cardiovascular disease (CVD) and mortality. Methods Each participating registry (Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (East Europe, Latin America, India) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan)) defined a main cohort from January 2000 onwards. To address comparability and potential bias, we harmonised event definitions and defined several subcohorts for sensitivity analyses based on disease activity, treatment, calendar time, duration of follow-up and RCT exclusions. Rates were standardised for age, sex and, in one sensitivity analysis, also HAQ. Results The combined registry cohorts included 57251 patients with RA (234089 person-years)24.5% men, mean (SD) baseline age 58.2 (13.8) and RA duration 8.2 (11.7) years. Standardised registry mortality rates (per 100 person-years) varied from 0.42 (CORRONA) to 0.80 (NOAR), with 0.60 for RCT patients. Myocardial infarction and major adverse cardiovascular events (MACE) rates ranged from 0.09 and 0.31 (IORRA) to 0.39 and 0.77 (SRR), with RCT rates intermediate (0.18 and 0.42), respectively. Additional subcohort analyses showed small and mostly consistent changes across registries, retaining reasonable consistency in rates across the Western registries. Additional standardisation for HAQ returned higher mortality and MACE registry rates. Conclusions This coordinated approach to contextualising RA RCT safety data demonstrated reasonable differences and consistency in rates for mortality and CVD across registries, and comparable RCT rates, and may serve as a model method to supplement clinical trial analyses for drug development programmes.
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| 21. |
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| 22. |
- Yamanaka, H., et al.
(author)
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Infection rates in patients from five rheumatoid arthritis (RA) registries: Contextualising an RA clinical trial programme
- 2017
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In: RMD Open. - : BMJ. - 2056-5933. ; 3:2
-
Journal article (peer-reviewed)abstract
- Objective Patients with rheumatoid arthritis (RA) have an increased risk of serious infections. Comparing infection rates across RA populations is complicated by differences in background infection risk, population composition and study methodology. We measured infection rates from five RA registries globally, with the aim to contextualise infection rates from an RA clinical trials population. Methods We used data from Consortium of Rheumatology Research of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (Sweden), Norfolk Arthritis Register (UK), CORRONA International (multiple countries) and Institute of Rheumatology Rheumatoid Arthritis (Japan) and an RA clinical trial programme (fostamatinib). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data. Infection definitions were harmonised across registries. Sensitivity analyses to address potential confounding explored subcohorts defined by disease activity, treatment change and/or prior comorbidities and restriction by calendar time or follow-up. Rates of infections were estimated and standardised to the trial population for age/sex and, in one sensitivity analysis also, for Health Assessment Questionnaire (HAQ) score. Results Overall, age/sex-standardised rates of hospitalised infection were quite consistent across registries (range 1.14-1.62 per 100 patient-years). Higher and more consistent rates across registries and with the trial programme overall were seen when adding standardisation for HAQ score (registry range 1.86-2.18, trials rate 2.92) or restricting to a treatment initiation subcohort followed for 18 months (registry range 0.99-2.84, trials rate 2.74). Conclusion This prospective, coordinated analysis of RA registries provided incidence rate estimates for infection events to contextualise infection rates from an RA clinical trial programme and demonstrated relative comparability of hospitalised infection rates across registries. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved.
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| 23. |
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| 24. |
- Albrecht, F., et al.
(author)
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Unraveling Parkinson's disease heterogeneity using subtypes based on multimodal data
- 2022
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In: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020 .- 1873-5126. ; 102, s. 19-29
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Journal article (peer-reviewed)abstract
- Background: Parkinson's disease (PD) is a clinically and neuroanatomically heterogeneous neurodegenerative disease characterized by different subtypes. To this date, no studies have used multimodal data that combines clinical, motor, cognitive and neuroimaging assessments to identify these subtypes, which may provide complementary, clinically relevant information. To address this limitation, we subtyped participants with mild-moderate PD based on a rich, multimodal dataset of clinical, cognitive, motor, and neuroimaging variables. Methods: Cross-sectional data from 95 PD participants from our randomized EXPANd (EXercise in PArkinson's disease and Neuroplasticity) controlled trial were included. Participants were subtyped using clinical, motor, and cognitive assessments as well as structural and resting-state MRI data. Subtyping was done by random forest clustering. We extracted information about the subtypes by inspecting their neuroimaging profiles and descriptive statistics. Results: Our multimodal subtyping analysis yielded three PD subtypes: a motor-cognitive subtype characterized by widespread alterations in brain structure and function as well as impairment in motor and cognitive abilities; a cognitive dominant subtype mainly impaired in cognitive function that showed frontoparietal structural and functional changes; and a motor dominant subtype impaired in motor variables without any brain alterations. Motor variables were most important for the subtyping, followed by gray matter volume in the right medial postcentral gyrus. Conclusions: Three distinct PD subtypes were identified in our multimodal dataset. The most important features to subtype PD participants were motor variables in addition to structural MRI in the sensorimotor region. These findings have the potential to improve our understanding of PD heterogeneity, which in turn can lead to personalized interventions and rehabilitation.
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| 25. |
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| 26. |
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| 27. |
- Aurelius, E, et al.
(author)
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Long-term valacyclovir suppressive treatment after herpes simplex virus type 2 meningitis: a double-blind, randomized controlled trial.
- 2012
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In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 54:9, s. 1304-13
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Journal article (peer-reviewed)abstract
- Herpes simplex virus type 2 (HSV-2) is a common cause of acute and recurrent aseptic meningitis. Our aim was to determine the impact of antiviral suppression on recurrence of meningitis and to delineate the full spectrum of neurological complications.One hundred and one patients with acute primary or recurrent HSV-2 meningitis were assigned to placebo (n = 51) or 0.5 g of valacyclovir twice daily (n = 50) for 1 year after initial treatment with 1 g of valacyclovir 3 times daily for 1 week in a prospective, placebo-controlled, multicenter trial. The primary outcome was time until recurrence of meningitis. The patients were followed up for 2 years.The first year, no significant difference was found between the valacyclovir and placebo groups. The second year, without study drugs, the risk of recurrence of verified and probable HSV-2 meningitis was significantly higher among patients exposed to valacyclovir (hazard ratio, 3.29 [95% confidence interval, 10.06-10.21]). One-third of the patients experienced 1-4 meningitis episodes during the study period. A considerable morbidity rate, comprising symptoms from the central, peripheral, and autonomous nervous system, was found in both groups.Suppressive treatment with 0.5 g of valacyclovir twice daily was not shown to prohibit recurrent meningitis and cannot be recommended for this purpose after HSV meningitis in general. Protection against mucocutaneous lesions was observed, but the dosage was probably inappropriate for the prevention of HSV activation in the central nervous system. The higher frequency of meningitis, after cessation of active drug, could be interpreted as a rebound phenomenon.
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| 28. |
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| 29. |
- Cole, S. G., et al.
(author)
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Arctic games : An analytical framework for identifying options for sustainable natural resource governance
- 2016
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In: The Polar Journal. - : Taylor and Francis Ltd.. - 2154-896X .- 2154-8978. ; 6:1
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Journal article (peer-reviewed)abstract
- Changes in the Arctic are fuelled by a variety of drivers, including global warming, economic growth, improved access to natural resources, technological advances and globalisation processes. Further, the region is characterised by a diverse set of international agreements, national legislations and common pool resources. This presents challenges for actors to suggest, evaluate and agree on sustainable development alternatives. We propose an analytical framework to better understand (1) the types of trade-offs associated with Arctic futures and (2) actors’ incentives for strategic behaviour. In the framework, game theory illuminates incentives and strategies among actors, cost-benefit analysis and economic valuation of ecosystem services help identify socially desirable outcomes and institutional analysis provides insight on how governance structures can support or interfere with policy intervention. We apply the proposed framework by analysing possible oil development futures for Lofoten in Northern Norway. For example, institutional analysis and estimates of costs and benefits of reducing oil spill risk and their distribution among actors are used for discussing incentive structures, including the use of side payments as a mechanism to mitigate conflicting interests.
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| 30. |
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| 31. |
- De Gasperin, F., et al.
(author)
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Cassiopeia A, Cygnus A, Taurus A, and Virgo A at ultra-low radio frequencies
- 2020
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 635
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Journal article (peer-reviewed)abstract
- The four persistent radio sources in the northern sky with the highest flux density at metre wavelengths are Cassiopeia A, Cygnus A, Taurus A, and Virgo A; collectively they are called the A-team. Their flux densities at ultra-low frequencies (< 100 MHz) can reach several thousands of janskys, and they often contaminate observations of the low-frequency sky by interfering with image processing. Furthermore, these sources are foreground objects for all-sky observations hampering the study of faint signals, such as the cosmological 21 cm line from the epoch of reionisation. Aims. We aim to produce robust models for the surface brightness emission as a function of frequency for the A-team sources at ultra-low frequencies. These models are needed for the calibration and imaging of wide-area surveys of the sky with low-frequency interferometers. This requires obtaining images at an angular resolution better than 15″ with a high dynamic range and good image fidelity. Methods. We observed the A-team with the Low Frequency Array (LOFAR) at frequencies between 30 MHz and 77 MHz using the Low Band Antenna system. We reduced the datasets and obtained an image for each A-team source. Results. The paper presents the best models to date for the sources Cassiopeia A, Cygnus A, Taurus A, and Virgo A between 30 MHz and 77 MHz. We were able to obtain the aimed resolution and dynamic range in all cases. Owing to its compactness and complexity, observations with the long baselines of the International LOFAR Telescope will be required to improve the source model for Cygnus A further.
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| 32. |
- De Palma, Adriana, et al.
(author)
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Predicting bee community responses to land-use changes : effects of geographic and taxonomic biases
- 2016
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 6, s. 1-14
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Journal article (peer-reviewed)abstract
- Land-use change and intensification threaten bee populations worldwide, imperilling pollination services. Global models are needed to better characterise, project, and mitigate bees' responses to these human impacts. The available data are, however, geographically and taxonomically unrepresentative; most data are from North America and Western Europe, overrepresenting bumblebees and raising concerns that model results may not be generalizable to other regions and taxa. To assess whether the geographic and taxonomic biases of data could undermine effectiveness of models for conservation policy, we have collated from the published literature a global dataset of bee diversity at sites facing land-use change and intensification, and assess whether bee responses to these pressures vary across 11 regions (Western, Northern, Eastern and Southern Europe; North, Central and South America; Australia and New Zealand; South East Asia; Middle and Southern Africa) and between bumblebees and other bees. Our analyses highlight strong regionally-based responses of total abundance, species richness and Simpson's diversity to land use, caused by variation in the sensitivity of species and potentially in the nature of threats. These results suggest that global extrapolation of models based on geographically and taxonomically restricted data may underestimate the true uncertainty, increasing the risk of ecological surprises.
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| 33. |
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| 34. |
- Franzen-Rohl, E., et al.
(author)
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Herpes simplex virus specific T cell response in a cohort with primary genital infection correlates inversely with frequency of subsequent recurrences
- 2017
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In: Sexually Transmitted Infections. - : BMJ. - 1368-4973 .- 1472-3263. ; 93:3
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Journal article (peer-reviewed)abstract
- Objectives During the last decades, a changing epidemiological pattern of genital herpes simplex virus (HSV) infection has emerged. Primary infection is now caused as often by HSV-1 as by HSV-2. Once established, HSV can be reactivated leading to recurrent mucocutaneous lesions as well as meningitis. Why some otherwise immune-competent individuals experience severe and frequent recurrences is not known, and the immunological mechanism underlying recurrent symptomatic HSV infection is not fully understood. In this study, we investigate and characterise the immune response of patients with first episode of HSV genital infection and its relation to the frequency of symptomatic recurrences. Methods In this cohort study, clinical and immunological data were collected from 29 patients who were followed 1 year after presenting with a first episode of genital or meningeal HSV infection. They were classified by PCR and serology as those with primary HSV-1, primary HSV-2 and non-primary HSV-2 infection. Results HSV-specific interleukin(Il)-4 and II-10 responses at first visit were higher in primary infected HSV-2 infected patients experiencing lower numbers of recurrences during subsequent year. Conclusions The median number of recurrences following primary HSV-2 genital infection may partly be predicted by the strength of an early HSV-specific IL-4 and IL-10 response.
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- Glicksberg, Benjamin S., et al.
(author)
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Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
- 2019
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In: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12
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Journal article (peer-reviewed)abstract
- BackgroundGenetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.ResultsWe identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.ConclusionIn sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
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- Lange, S, et al.
(author)
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The kinase domain of titin controls muscle gene expression and protein turnover
- 2005
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In: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 308:5728, s. 1599-1603
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Journal article (peer-reviewed)abstract
- The giant sarcomeric protein titin contains a protein kinase domain (TK) ideally positioned to sense mechanical load. We identified a signaling complex where TK interacts with the zinc-finger protein nbr1 through a mechanically inducible conformation. Nbr1 targets the ubiquitin-associated p62/SQSTM1 to sarcomeres, and p62 in turn interacts with MuRF2, a muscle-specific RING-B-box E3 ligase and ligand of the transactivation domain of the serum response transcription factor (SRF). Nuclear translocation of MuRF2 was induced by mechanical inactivity and caused reduction of nuclear SRF and repression of transcription. A human mutation in the titin protein kinase domain causes hereditary muscle disease by disrupting this pathway.
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- Nyberg, Fredrik, 1961, et al.
(author)
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Using epidemiological registry data to provide background rates as context for adverse events in a rheumatoid arthritis drug development program: a coordinated approach
- 2015
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In: Pharmacoepidemiology and Drug Safety. - : Wiley. - 1053-8569 .- 1099-1557. ; 24:11, s. 1121-1132
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Journal article (peer-reviewed)abstract
- Purpose Observational studies can provide context for adverse events observed in clinical trials, especially for infrequent events or long-term risks. We developed methods to improve safety contextualization for a rheumatoid arthritis drug development program through coordinated analyses of multiple registries. Methods We identified and characterized differences and similarities across five registries (Swedish Rheumatology Quality of Care Register, Consortium of Rheumatology Researchers of North America [CORRONA], Norfolk Arthritis Register, Institute of Rheumatology Rheumatoid Arthritis, and the new CORRONA International), harmonized outcome definitions, and investigated whether restricted subcohorts improved comparability with trial populations. To address confounding, we identified risk predictors for outcomes of interest (mortality, cardiovascular disease, infection, and malignancy). We used patient-level analyses at each registry and central analysis of standardized group-level data. Results Despite data differences, the coordinated approach enabled consistent variable definitions for key baseline characteristics and outcomes. Selection of restricted subcohorts (e.g., using active joint count criteria) improved baseline comparability with trial patients for some rheumatoid arthritis disease activity measures, but less for other characteristics (e.g., age and comorbidity); however, such selection decreased sample size considerably. For most outcomes, age was the most important risk predictor, emphasizing the importance of age/sex standardization to address confounding. The prospective approach enabled use of recent relevant data; the distributed analysis safeguarded confidentiality of registry data. Conclusions Compared with reliance on published data alone, a forward-looking coordinated approach across multiple observational data sources can improve comparability and consistency and better support sensitivity analyses and data interpretation, in contextualizing safety data from clinical trials. This approach may have utility to support safety assessments across diverse diseases and drug development programs and satisfy future regulatory requirements. Copyright (C) 2015 John Wiley & Sons, Ltd.
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- Rennie, L., et al.
(author)
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Highly challenging balance and gait training for individuals with Parkinson's disease improves pace, rhythm and variability domains of gait - A secondary analysis from a randomized controlled trial
- 2021
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In: Clinical Rehabilitation. - : SAGE Publications. - 0269-2155 .- 1477-0873. ; 35:2, s. 200-212
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Journal article (peer-reviewed)abstract
- Objective: Evaluate immediate and long-term effects of highly challenging balance and gait training on pace-, rhythm-, variability-, asymmetry-, and postural control domains of gait for individuals with Parkinson's disease (PD). Design: Randomized controlled trial - a secondary analysis. Setting: University hospital setting. Participants: One-hundred older adults with mild to moderate PD (Hoehn & Yahr 2 and 3). Intervention: Training group (n = 51): 10 weeks (3 times/week) of intensive balance and gait training, incorporating dual tasks. Control group (n = 49): care as usual. Main outcome measures: Spatiotemporal gait variables collected during normal and fast walking on a pressure-sensitive mat. A linear mixed model was used to evaluate training effects post intervention and at the 6 and 12 month follow-up. Results: Immediate training effects in the pace domain of gait were increased step velocity (normal speed: 8.2 cm/s,P = 0.04; fast: 10.8 cm/s,P < 0.01), increased step length (normal speed: 3 cm,P = 0.05; fast: 2.3 cm,P = 0.05) and reduced swing time variability (fast speed: -2.5 ms,P = 0.02). In the rhythm domain reduced step time (fast speed: -19.3 ms,P = 0.02), stance time (normal: -24.3 ms,P = 0.01; fast: -29.6 ms,P = 0.02) and swing time (fast speed: -8.7 ms,P = 0.04) was seen. Relative to the variability domain, the training decreased step time variability (fast: -2.8 ms,P = 0.02) and stance time variability (fast: -3.9 ms,P = 0.02). No training effects were retained at 6 months. Conclusions: Highly challenging balance and gait training improved pace, rhythm and variability aspects of PD gait in the short-term, but effects are not retained long-term.
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- Wadensten, T., et al.
(author)
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A Smartphone app For Self-Management of Urgency and Mixed Urinary Incontinence : a Randomized Controlled Trial
- 2019
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In: Neurourology and Urodynamics. - : John Wiley & Sons. - 0733-2467 .- 1520-6777. ; 38, s. S361-S363
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Journal article (other academic/artistic)abstract
- Hypothesis / aims of study: Urgency (UUI) and mixed (MUI) urinary incontinence are common clinical problems. They account for almost half of all cases of urinary incontinence (UI) in women [1], and have a potentially large impact on quality of life. Nonetheless, many women are reluctant to seek treatment, sometimes due to UI being a stigmatized condition. The recommended first-line treatment for UUI and MUI is pelvic floor muscle training (PFMT) and lifestyle advice [2], with bladder training as a valuable complement to the treatment. Previous studies have shown that a smartphone app was an effective form of self-management for women with stress urinary incontinence (SUI), both in terms of treatment efficacy [3] and cost-effectiveness. On-going studies show promising results of the app once it was made freely available for download, and a further study of the user experience of the app found that the app provided an appreciated and satisfactory experience. In this study, we aimed to evaluate whether a new smartphone app for the self-management of UUI and MUI in women was effective, in comparison to app-based information only. Study design, materials and methods: Between April 2017 and March 2018, women were consecutively recruited to this randomized controlled trial (RCT) via a screening questionnaire on the homepage of the research project. The trial has been Clinical Trials registered. The inclusion criteria were as follows: woman (gender self-stated and sex assigned at birth), ≥18 years, UUI or MUI with ≥2 leakages/week and ≥12 months of symptom duration. Pregnant women or women who used another PFMT app or anti-muscarinic drugs were not eligible to participate in the study. In order to identify and redirect cases that were better suited to receive usual care, an algorithm was developed by a team of professionals with both clinical and scientific experience from fields such as urogynecology, general practice, urology and incontinence care. The algorithm included questions on the person’s history of cancer in the pelvic region, diabetes, and neurological symptoms and diseases, as well as questions on certain alarm symptoms (e.g. painful urges, dysuria, haematuria, metrorrhagia, recurring urinary tract infections, bladder-emptying difficulties and pyelonephritis). The presence of any alarm symptom led to the respondent being classified as not eligible for the study and instead recommended to contact their usual medical care provider. Women who passed the screening questionnaire and submitted an email address received information about the study, and were asked to fill in an Informed Consent form, a two-day bladder diary and a baseline questionnaire which included the International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form (ICIQ-UI SF), which provides a validated UI symptom score (range 0 - 21 points) with questions on frequency, amount and overall impact. Respondents were then contacted by telephone for an interview during which the symptom-based diagnosis of UUI or MUI was determined, and questions about alarm symptoms and UI symptoms were asked to ensure that the respondent was truly eligible for the study. Throughout the study, there was no face-to-face contact between the research group and the participants, only communication by email and telephone. The participants were randomized 1:1 to the two groups using sealed opaque envelopes prepared by an independent administrator who generated the randomization plan via the online randomization tool at http://www.randomization.com. Women randomized to the intervention group received access to the Treatment App, a smartphone app built on four themes: PFMT; bladder training; psychological education; and lifestyle information (Figure 1). The PFMT and bladder training parts of the app included 11-step and 7-step training programmes, respectively, in addition to information on pelvic floor anatomy and bladder physiology. The psychological education contained information on psychological topics related to UI, and three optional exercises. The Treatment App also offered an option to set three different times for reminder notifications, as well as an automated feedback function. In addition, the app included individual advice based on information from questionnaires and the bladder diary. The advice was generated via a pre-designed template and offered guidance to the most relevant parts of the app for each user. The control group received access to the Information App, a very limited version of the app, containing only brief information on the different topics and no training programmes or other features. Three months after randomization, the participants were asked to fill in a follow-up questionnaire and another bladder diary. In this abstract we present the results of the analysis of the primary outcome measure, the ICIQ-UI SF, measured at baseline and follow-up. Analyses of secondary outcomes, including incontinence episode frequency, are currently on-going and will be presented at a later date. Sample size calculation: Based on the findings of previous studies, improvements in the ICIQ-UI SF of 2.5 points in the Treatment App group and 0.9 points in the Information App group were assumed. To detect this difference with 80% power, 2-side test and a significance of 0.05, a sample size of 49 women was needed in each group. To allow for a dropout rate of 20%, each group needed to include 60 participants, and we therefore aimed to recruit 120 women in total. Statistical analysis: We performed Intention to Treat analysis by using a linear mixed model to estimate the difference between the groups in the ICIQ-UI SF at follow-up. A paired t-test was used for within-groups comparisons of the mean ICIQ-UI SF scores at baseline and follow-up. Results: 123 women were randomized to receive the Treatment App (n=60) or the Information App (n=63). The groups did not differ significantly in baseline measures (e.g. age, BMI, education level) nor in the mean ICIQ-UI SF scores. The mean age was 58.30 (SD 9.55) years and the mean BMI was 26.17 (SD 4.47) kg/m². The symptom-based diagnosis of MUI was more common (n=88) than that of UUI (n=35), and this distribution was equal across the two groups. The majority of women had moderate (n=73), severe (n=43) or very severe (n=4) incontinence, based on the ICIQ-UI SF scores. Two women, both in the Treatment App group, were lost to follow-up. Participants in both groups improved with regard to the mean ICIQ-UI SF score at follow-up (Treatment App group -4.67 (-5.65 to -3.69, 95% CI, p <0.001) and Information App group -1.64 (-2.31 to -0.96, 95% CI, p <0.001)). The improvement was significantly larger in the Treatment App group (p = 0.001) (Figure 2). Interpretation of results: Self-management of UUI or MUI using a mobile app led to highly significant improvements in incontinence symptoms with a significant difference compared to a control group. Thus the findings in this study show that the use of an app that includes treatment with PFMT, bladder training, psychological education and lifestyle advice was effective for women with UUI or MUI. Concluding message: Previous studies have shown that a smartphone app is an effective, easily accessible and appreciated first-line treatment option for women with SUI. The findings in the current study indicate that, provided that certain alarm symptoms or risk factors are not present, a smartphone app may be a useful addition to first-line treatment options for women with UUI or MUI who are interested in eHealth self-management.
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