| 1. |
- Franceschini, N., et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Follow Up of GW170817 and Its Electromagnetic Counterpart by Australian-Led Observing Programmes
- 2017
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Ingår i: Publications Astronomical Society of Australia. - : Cambridge University Press (CUP). - 1323-3580 .- 1448-6083. ; 34
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Forskningsöversikt (refereegranskat)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.
(författare)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci
- 2017
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Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 120:2, s. 341-
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Tidskriftsartikel (refereegranskat)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. |
- Lempiainen, H, et al.
(författare)
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Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 3434-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks (“modules”). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene–protein interactions directly affected by genetic variance in CAD risk loci.
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| 6. |
- Miller, CL, et al.
(författare)
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Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 12092-
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Tidskriftsartikel (refereegranskat)abstract
- Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified >150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.
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| 7. |
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| 8. |
- Askling, J., et al.
(författare)
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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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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 75:10, s. 1789-1796
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Tidskriftsartikel (refereegranskat)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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| 9. |
- Franceschini, N, et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 5141-
-
Tidskriftsartikel (refereegranskat)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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| 10. |
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| 11. |
- Gaupp-Berghausen, M, et al.
(författare)
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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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Ingår i: Journal of Medical Internet Research. - : JMIR Publications Inc.. - 1438-8871. ; 21:5, s. e11492-
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Tidskriftsartikel (refereegranskat)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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| 12. |
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| 13. |
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| 14. |
- Michaud, K., et al.
(författare)
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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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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 75:10, s. 1797-1805
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Tidskriftsartikel (refereegranskat)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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| 15. |
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Verstappen, S. M. M., et al.
(författare)
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Methodological Challenges When Comparing Demographic and Clinical Characteristics of International Observational Registries
- 2015
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Ingår i: Arthritis Care & Research. - : Wiley. - 2151-464X .- 2151-4658. ; 67:12, s. 1637-1645
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Comparisons of data from different registries can be helpful in understanding variations in many aspects of rheumatoid arthritis (RA). The study aim was to assess and improve the comparability of demographic, clinical, and comorbidity data from 5 international RA registries. Methods. Using predefined definitions, 2 subsets of patients (main cohort and subcohort) from 5 international observational registries (Consortium of Rheumatology Researchers of North America Registry [CORRONA], the Swedish Rheumatology Quality of Care Register [SRR], the Norfolk Arthritis Register [NOAR], the Institute of Rheumatology Rheumatoid Arthritis cohort [IORRA], and CORRONA International) were evaluated and compared. Patients ages >18 years with RA, and present in or recruited to the registry from January 1, 2000, were included in the main cohort. Patients from the main cohort with positive rheumatoid factor and/or erosive RA who had received >= 1 synthetic disease-modifying antirheumatic drug (DMARD), and switched to or added another DMARD, were included in the subcohort at time of treatment switch. Results. Age and sex distributions were fairly similar across the registries. The percentage of patients with a high Disease Activity Score in 28 joints score varied between main cohorts (17.5% IORRA, 18.9% CORRONA, 24.7% NOAR, 27.7% CORRONA International, and 36.8% SRR), with IORRA, CORRONA, and CORRONA International including more prevalent cases of RA; the differences were smaller for the subcohort. Prevalence of comorbidities varied across registries (e.g., coronary artery disease ranged from 1.5% in IORRA to 7.9% in SRR), partly due to the way comorbidity data were captured and general cultural differences; the pattern was similar for the subcohorts. Conclusion. Despite different inclusion criteria for the individual RA registries, it is possible to improve the comparability and interpretability of differences across RA registries by applying well-defined cohort definitions.
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| 20. |
- Yamanaka, H., et al.
(författare)
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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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Ingår i: RMD Open. - : BMJ. - 2056-5933. ; 3:2
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Tidskriftsartikel (refereegranskat)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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| 21. |
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| 22. |
- Bhat, N. D. R., et al.
(författare)
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Observations of Low-frequency Radio Emission from Millisecond Pulsars and Multipath Propagation in the Interstellar Medium
- 2018
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Ingår i: Astrophysical Journal, Supplement Series. - : American Astronomical Society. - 1538-4365 .- 0067-0049. ; 238:1
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Tidskriftsartikel (refereegranskat)abstract
- Studying the gravitational-wave sky with pulsar timing arrays (PTAs) is a key science goal for the Square Kilometre Array (SKA) and its pathfinder telescopes. With current PTAs reaching sub-microsecond timing precision, making accurate measurements of interstellar propagation effects and mitigating them effectively has become increasingly important to realize PTA goals. As these effects are much stronger at longer wavelengths, low-frequency observations are most appealing for characterizing the interstellar medium (ISM) along the sight lines toward PTA pulsars. The Murchison Widefield Array (MWA) and the Engineering Development Array (EDA), which utilizes MWA technologies, present promising opportunities for undertaking such studies, particularly for PTA pulsars located in the southern sky. Such pulsars are also the prime targets for PTA efforts planned with the South African MeerKAT, and eventually with the SKA. In this paper we report on observations of two bright southern millisecond pulsars, PSR J0437-4715 and PSR J2145-0750, made with these facilities; MWA observations sampled multiple frequencies across the 80-250 MHz frequency range, while the EDA provided direct-sampled baseband data to yield a large instantaneous usable bandwidth of similar to 200 MHz. Using these exploratory observations, we investigate various aspects relating to pulsar emission and ISM properties, such as spectral evolution of the mean pulse shape, scintillation as a function of frequency, chromaticity in interstellar dispersion, and flux density spectra at low frequencies. Systematic and regular monitoring observations will help ascertain the role of low-frequency measurements in PTA experiments, while simultaneously providing a detailed characterization of the ISM toward the pulsars, which will be useful in devising optimal observing strategies for future PTA experiments.
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| 23. |
- Bomfim, I L, et al.
(författare)
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The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene-environment interaction.
- 2017
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Ingår i: Genes and immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 18, s. 75-81
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Tidskriftsartikel (refereegranskat)abstract
- The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA- along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene-environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.Genes and Immunity advance online publication, 23 March 2017; doi:10.1038/gene.2017.1.
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| 24. |
- Cole, S. G., et al.
(författare)
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Arctic games : An analytical framework for identifying options for sustainable natural resource governance
- 2016
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Ingår i: The Polar Journal. - : Taylor and Francis Ltd.. - 2154-896X .- 2154-8978. ; 6:1
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Tidskriftsartikel (refereegranskat)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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| 25. |
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| 26. |
- Glicksberg, Benjamin S., et al.
(författare)
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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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Ingår i: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12
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Tidskriftsartikel (refereegranskat)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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| 27. |
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| 28. |
- Israeli-Korn, SD, et al.
(författare)
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Intersegmental coordination patterns are differently affected in Parkinson's disease and cerebellar ataxia
- 2019
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Ingår i: Journal of neurophysiology. - : American Physiological Society. - 1522-1598 .- 0022-3077. ; 121:2, s. 672-689
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Tidskriftsartikel (refereegranskat)abstract
- The law of intersegmental coordination (Borghese et al. 1996) may be altered in pathological conditions. Here we investigated the contribution of the basal ganglia (BG) and the cerebellum to lower limb intersegmental coordination by inspecting the plane’s orientation and other parameters pertinent to this law in patients with idiopathic Parkinson’s disease (PD) or cerebellar ataxia (CA). We also applied a mathematical model that successfully accounts for the intersegmental law of coordination observed in control subjects (Barliya et al. 2009). In the present study, we compared the planarity index (PI), covariation plane (CVP) orientation, and CVP orientation predicted by the model in 11 PD patients, 8 CA patients, and two groups of healthy subjects matched for age, height, weight, and gender to each patient group (Ctrl_PD and Ctrl_CA). Controls were instructed to alter their gait speed to match those of their respective patient group. PD patients were examined after overnight withdrawal of anti-parkinsonian medications (PD-off-med) and then on medication (PD-on-med). PI was above 96% in all gait conditions in all groups suggesting that the law of intersegmental coordination is preserved in both BG and cerebellar pathology. However, the measured and predicted CVP orientations rotated in PD-on-med and PD-off-med compared with Ctrl_PD and in CA vs. Ctrl_CA. These rotations caused by PD and CA were in opposite directions suggesting differences in the roles of the BG and cerebellum in intersegmental coordination during human locomotion. NEW & NOTEWORTHY Kinematic and muscular synergies may have a role in overcoming motor redundancies, which may be reflected in intersegmental covariation. Basal ganglia and cerebellar networks were suggested to be involved in crafting and modulating synergies. We thus compared intersegmental coordination in Parkinson’s disease and cerebellar disease patients and found opposite effects in some aspects. Further research integrating muscle activities as well as biomechanical and neural control modeling are needed to account for these findings.
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| 29. |
- Nyberg, Fredrik, 1961, et al.
(författare)
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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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Ingår i: Pharmacoepidemiology and Drug Safety. - : Wiley. - 1053-8569 .- 1099-1557. ; 24:11, s. 1121-1132
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Tidskriftsartikel (refereegranskat)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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| 30. |
- Nystrom, T., et al.
(författare)
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PCI Versus CABG in Patients With Type 1 Diabetes and Multivessel Disease
- 2017
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 70:12, s. 1441-1451
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND It is unknown if coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) may offer a survival benefit in patients with type 1 diabetes (T1D) in need of multivessel revascularization. OBJECTIVES This study sought to determine if patients with T1D and multivessel disease may benefit from CABG compared with PCI. METHODS In an observational cohort study, the authors included all patients with T1D who underwent a first multivessel revascularization in Sweden from 1995 to 2013. The authors used the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) register, the Swedish National Diabetes Register, and the Swedish National Patient Register to retrieve information about patient characteristics and outcomes. They estimated hazard ratios (HRs) adjusted for confounders with 95% confidence intervals (CIs) for all-cause and coronary heart disease mortality, myocardial infarction, repeat revascularization, stroke, and heart failure using inverse probability of treatment weighting based on propensity scores. RESULTS In total, 683 patients whounderwent CABGand 1,863 patientswho underwent PCI were included. During a mean follow-up of 10.6 years, 53% of patients in the CABG group and 45% in the PCI group died. PCI, compared with CABG, was associated with a similar risk of all-cause mortality (HR: 1.14; 95% CI: 0.99 to 1.32), but higher risks of death from coronary heart disease (HR: 1.45; 95% CI: 1.21 to 1.74), myocardial infarction (HR: 1.47; 95% CI: 1.23 to 1.78), and repeat revascularization (HR: 5.64; 95% CI: 4.67 to 6.82). No differences in risks of stroke or heart failure were found. CONCLUSIONS Notwithstanding the inclusion of patients with T1D who might not have been able to undergo CABG in the PCI group we found that PCI, compared with CABG, was associated with higher rates and risks of coronary heart disease mortality, myocardial infarction, and repeat revascularizations. Our findings indicate that CABG may be the preferred strategy in patients with T1D in need of multivessel revascularization. (J Am Coll Cardiol 2017; 70: 1441-51) (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 31. |
- Ochaya, S, et al.
(författare)
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Characterization of Evolutionarily Conserved Trypanosoma cruzi NatC and NatA-N-Terminal Acetyltransferase Complexes
- 2019
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Ingår i: Journal of parasitology research. - : Hindawi Limited. - 2090-0023 .- 2090-0031. ; 2019, s. 6594212-
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Tidskriftsartikel (refereegranskat)abstract
- Protein N-terminal acetylation is a co- and posttranslational modification, conserved among eukaryotes. It determines the functional fate of many proteins including their stability, complex formation, and subcellular localization. N-terminal acetyltransferases (NATs) transfer an acetyl group to the N-termini of proteins, and the major NATs in yeast and humans are NatA, NatB, and NatC. In this study, we characterized the Trypanosoma cruzi (T. cruzi) NatC and NatA protein complexes, each consisting of one catalytic subunit and predicted auxiliary subunits. The proteins were found to be expressed in the three main life cycle stages of the parasite, formed stable complexes in vivo, and partially cosedimented with the ribosome in agreement with a cotranslational function. An in vitro acetylation assay clearly demonstrated that the acetylated substrates of the NatC catalytic subunit from T. cruzi were similar to those of yeast and human NatC, suggesting evolutionary conservation of function. An RNAi knockdown of the Trypanosoma brucei (T. brucei) NatC catalytic subunit indicated that reduced NatC-mediated N-terminal acetylation of target proteins reduces parasite growth.
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| 32. |
- Ooki, S., et al.
(författare)
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Hydrological study of Lyngmossen bog, Sweden: Isotopic tracers (H-3, delta H-2 and delta O-18) imply three waters with different mobilities
- 2018
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 199, s. 97-107
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Tidskriftsartikel (refereegranskat)abstract
- The H-3 concentration and stable isotope ratio of hydrogen and oxygen, delta H-2 and delta O-18, of waters extracted from a Sphagnum-dominant raised bog in Lyngmossen, Sweden, were measured in order to understand where the precipitation is retained and how mobile it is. Three types of waters, which were defined by extractability, were collected from the peat. Two waters were extracted by compressing samples with different pressures (SQW1 and SQW2). The other water was obtained by distilling the compressed samples (DW). H-3 was detected in all types of water from depths of 0-50 cm: the concentrations in SQW1, SQW2 and DW ranged 1.17-3.07 Bq/L, 0.98-2.03 Bq/L, and 1.02-1.54 Bq/L, respectively. The maximum H-3 concentrations of SQW1, SQW2 and DW were all detected at a depth of around 15 cm, whose C-14 age covers the year of the atomic bomb experiments. The H-3 results of SQW1/2 indicate that SQW consists of at least two waters of different mobility, water flowing rapidly downward and immobile water. Sphagnum hyaline cells may be responsible for the immobile water. The delta O-18 and delta H-2 relationship exhibited independent trends between SQW and DW. The distinct difference observed between the two waters at the surface (0-5 cm) indicates that the two waters may be supplied by precipitation at different times of the year, or alternatively that DW comprises plant water taken in from hyaline cells. The delta O-18 and delta H-2 values of both SQW and DW in the shallow layer increased with increasing depth, and in the layer around 30 cm depth, those of SQW showed a distinct decrease with depth. Isotope fractionation caused by evaporation and/or plant utilization of water at the surface layer are considered to be the main causes of such isotopic variation at the surface. Evaporation is likely to take place in much drier conditions for DW than for SQW, probably through stems by capillary action. In SQW freezing may be a possible cause for the decrease of delta O-18 and delta H-2 around 30 cm depth. DW is isotopically very well separated from two SQW1/2. Integrating all isotopic information, we conclude the presence of three different waters: least mobile water at shallow depth perhaps in hyaline cells, which can be extracted by squeezing peat with low pressure; most mobile water in a deeper layer than 30 cm, extracted also by squeezing peat; mobile but least extractable water, which is likely water inside plant tissues. (C) 2018 Elsevier Ltd. All rights reserved.
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| 33. |
- Rawshani, Araz, 1986, et al.
(författare)
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Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: a nationwide, register-based cohort study
- 2018
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Ingår i: The Lancet. - : Elsevier BV. - 0140-6736. ; 392:10146, s. 477-486
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Tidskriftsartikel (refereegranskat)abstract
- Background People with type 1 diabetes are at elevated risk of mortality and cardiovascular disease, yet current guidelines do not consider age of onset as an important risk stratifier. We aimed to examine how age at diagnosis of type 1 diabetes relates to excess mortality and cardiovascular risk. Methods We did a nationwide, register-based cohort study of individuals with type 1 diabetes in the Swedish National Diabetes Register and matched controls from the general population. We included patients with at least one registration between Jan 1, 1998, and Dec 31, 2012. Using Cox regression, and with adjustment for diabetes duration, we estimated the excess risk of all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, acute myocardial infarction, stroke, cardiovascular disease (a composite of acute myocardial infarction and stroke), coronary heart disease, heart failure, and atrial fibrillation. Individuals with type 1 diabetes were categorised into five groups, according to age at diagnosis: 0-10 years, 11-15 years, 16-20 years, 21-25 years, and 26-30 years. Findings 27 195 individuals with type 1 diabetes and 135 178 matched controls were selected for this study. 959 individuals with type 1 diabetes and 1501 controls died during follow-up (median follow-up was 10 years). Patients who developed type 1 diabetes at 0-10 years of age had hazard ratios of 4.11 (95% CI 3.24-5.22) for all-cause mortality, 7.38 (3.65-14.94) for cardiovascular mortality, 3.96 (3.06-5.11) for non-cardiovascular mortality, 11.44 (7.95-16.44) for cardiovascular disease, 30.50 (19.98-46.57) for coronary heart disease, 30.95 (17.59-54.45) for acute myocardial infarction, 6.45 (4.04-10.31) for stroke, 12.90 (7.39-22.51) for heart failure, and 1.17 (0.62-2.20) for atrial fibrillation. Corresponding hazard ratios for individuals who developed type 1 diabetes aged 26-30 years were 2.83 (95% CI 2.38-3.37) for all-cause mortality, 3.64 (2.34-5.66) for cardiovascular mortality, 2.78 (2.29-3.38) for non-cardiovascular mortality, 3.85 (3.05-4.87) for cardiovascular disease, 6.08 (4.71-7.84) for coronary heart disease, 5.77 (4.08-8.16) for acute myocardial infarction, 3.22 (2.35-4.42) for stroke, 5.07 (3.55-7.22) for heart failure, and 1.18 (0.79-1.77) for atrial fibrillation; hence the excess risk differed by up to five times across the diagnosis age groups. The highest overall incidence rate, noted for all-cause mortality, was 1.9 (95% CI 1.71-2.11) per 100 000 person-years for people with type 1 diabetes. Development of type 1 diabetes before 10 years of age resulted in a loss of 17.7 life-years (95% CI 14.5-20.4) for women and 14.2 life-years (12.1-18.2) for men. Interpretation Age at onset of type 1 diabetes is an important determinant of survival, as well as all cardiovascular outcomes, with highest excess risk in women. Greater focus on cardioprotection might be warranted in people with early-onset type 1 diabetes. Funding Swedish Heart and Lung Foundation. Copyright (c) 2018 Elsevier Ltd. All rights reserved.
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| 34. |
- Taimour, S., et al.
(författare)
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Survival, cardiovascular morbidity, and reinterventions after elective endovascular aortic aneurysm repair in patients with and without diabetes: A nationwide propensity-adjusted analysis
- 2019
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Ingår i: Vascular Medicine. - : SAGE Publications. - 1358-863X .- 1477-0377. ; 24:6, s. 539-546
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological data indicate decreased risk for development and growth of abdominal aortic aneurysm (AAA) among patients with diabetes mellitus (DM). On the other hand, DM adds to increased cardiovascular (CV) morbidity and mortality. In a nationwide observational cohort study of patients registered in the Swedish Vascular Register and the Swedish National Diabetes Register, we evaluated potential effects of DM on total mortality, CV morbidity, and the need for reintervention after elective endovascular aneurysm repair (EVAR) for AAA. We compared 748 patients with and 2630 without DM with propensity score-adjusted analysis, during a median 4.22 years of follow-up for patients with DM, and 4.05 years for those without. In adjusted analysis, diabetic patients showed higher rates of acute myocardial infarction (AMI) during follow-up (relative risk (RR) 1.44, 95% CI 1.06-1.95; p = 0.02), but lower need for reintervention (RR 0.12, CI 0.02-0.91; p = 0.04). There were no differences in total (RR 0.88, CI 0.74-1.05; p = 0.15) or CV (RR 1.58, CI 0.87-2.86; p = 0.13) mortality, or stroke (RR 0.95, CI 0.68-1.32; p = 0.75) during follow-up. In conclusion, patients with DM had higher rates of AMI and lower need for reintervention after elective EVAR than those without DM, whereas neither total nor CV mortality differed between groups. The putative protective effects of DM towards further AAA enlargement and late sac rupture may help explain the lower need for reintervention and absence of excess mortality.
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| 35. |
- Wadensten, T., et al.
(författare)
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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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Ingår i: Neurourology and Urodynamics. - : John Wiley & Sons. - 0733-2467 .- 1520-6777. ; 38, s. S361-S363
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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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| 36. |
- Wadensten, T., et al.
(författare)
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Development and Use of an algorithm For Identifying Women With Urgency Or Mixed Urinary Incontinence Suitable For E-Health Treatment
- 2018
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Ingår i: Neurourology and Urodynamics. - : John Wiley & Sons. - 0733-2467 .- 1520-6777. ; 37:S5, s. S72-S74
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hypothesis / aims of study One of the challenges in health care today is providing affordable care for those in need, and identifying a reasonable level of care for care-seekers. Many women with urinary incontinence might be reluctant to seek care for various reasons. Recent reviews propose lifestyle advice, pelvic floor muscle training (PFMT) and, in some cases, behavioural changes as first-line treatment for urgency (UUI) and mixed (MUI) urinary incontinence in women (1). Treatment via a smartphone app containing lifestyle advice and PFMT has been shown to be effective for, and appreciated by, women with stress urinary incontinence (SUI) (2). A smartphone app could also be a way to make treatment available to more women with UUI and MUI. The traditional recommendation of an extensive examination, on the other hand, has been described as a potential barrier to offering diagnosis and treatment to women with those conditions (3). The results of one study support the use of an algorithm combined with dipstick urinalysis for diagnosing women with urgency-predominant incontinence suitable for pharmacological treatment (3). The first aim of this study was to develop and use an extensive algorithm intended for women with UUI or MUI, to identify those with symptoms that would motivate a physical examination within usual care. The algorithm was intended for women interested in treatment via a smartphone app. To our knowledge, this is the first attempt to identify this target group in this way. The second aim was to estimate the proportion of the people interested that might be suitable for smartphone app treatment, based on the algorithm. Study design, materials and methods This report is part of a larger RCT study aimed at evaluating smartphone app treatment for women with UUI and MUI. As part of the preparations for the RCT study, a team of experienced general practitioners (GP), a Specialist Continence nurse, a urologist and a urogynecologist together developed an algorithm with questions regarding symptoms for which an examination would be judged important within usual care. The team included both researchers and clinicians. The RCT study was approved by a regional ethics board and registered in the Clinical Trials register. Recruitment was carried out via conventional methods (press releases, information to midwives, advertisements in media) as well as via Facebook advertisements. The advertisements directed interested people to the homepage of the research project, where additional information about the study and a link to a web-based screening questionnaire was provided. The screening questionnaire included questions on inclusion criteria and some background information, before presenting the questions related to the algorithm (figure 1). People who did not meet the inclusion criteria (woman, ≥18 years, ≥2 leakages/week, ≥12 month symptom duration, urgency or mixed urinary incontinence), or those who were pregnant or used another PFMT app or antimuscarinic drugs could not proceed further with the questionnaire. If a respondent gave a positive answer on any symptom from the algorithm, she was excluded and recommended to contact her normal health care provider for further assessment. Any respondent who passed the screening questionnaire in full was asked to provide her email address and thereafter received an informed consent form and a bladder diary to complete. Once these were returned, the respondent received another questionnaire and was thereafter contacted via telephone by a Specialist Continence nurse or GP. The purpose of this telephone interview was to give the diagnosis and to verify the answers to the algorithm questions. Results Following a year of meetings and discussions in the research team, a final algorithm was decided via consensus, based on previous literature on the subject as well as clinical experience. The symptoms and conditions included in the algorithm were painful urges; pyelonephritis; three or more urinary tract infections (UTI) in the last 12 months; dysuria (burning upon urination); visible haematuria; non-investigated bladder emptying difficulties; metrorrhagia; cancer in the pelvic area, bladder or bowels; decreased mobility or sensibility in the legs or pelvic area; previous stroke; neurological disease and diabetes (figure 1). The algorithm was used in the web-based screening questionnaire as described above. Out of 765 women with UUI or MUI with ≥2 leakages/week and ≥12 month duration, 523 were identified as eligible to be offered e-health treatment after exclusions. The 238 women who were excluded for symptoms in the algorithm were automatically advised to contact their normal health care provider for further assessment (figure 1). A further four women left the questionnaire before completion of all questions and were therefore not included. Of the 523 eligible women, 142 women chose to complete all the successive steps and were interviewed via telephone. In the interviews, nine women presented algorithm-related symptoms. In five cases, those symptoms were neurological (i.e. a diffuse sense of numbness in regions of the lower limbs), one woman, aged 51, also had painful urges. Another woman, aged 45, had painful urges as her only symptom. One woman, aged 64, reported having recurring visible haematuria and dysuria three months prior to the interview and had earlier been examined with cystoscopy. Another woman, aged 70, had current dysuria and was being treated for a UTI. One woman had metrorrhagia and was being investigated in usual care. All of these cases were discussed with an experienced GP and/or urogynecologist and were excluded and redirected to their normal health care provider as an extra precaution. Interpretation of results It is possible to develop an algorithm as described above via consensus within a team of experienced clinicians and researchers. Approximately two-thirds of women with UUI or MUI with ≥2 leakages/week and ≥12 month duration who are interested in an e-health intervention might be suited to this kind of treatment. An algorithm such as the one described here might be one way to identify suitable women and redirect those who should contact usual care for an assessment of specific symptoms. However, we do not know whether the respondents who were redirected to usual care had already been examined for these symptoms and/or had relevant underlying pathology. Nonetheless, our view was that the occurrence of any of the other symptoms should motivate precaution, and was a reason for the patient to contact their normal health care provider. Concluding message An algorithm such as the one described here might both help the patient (or health care personnel) to choose a reasonable level of care, and possibly also identify women who had not previously considered seeking care for certain symptoms. In the long term an algorithm might help lessen the burden of ordinary health care providers by directing interested and eligible women to suitable e-health options. We are currently evaluating the efficacy of an app treatment for women with UUI/MUI, both in the short and long term. The results will include information from registers regarding diagnosis and care for relevant conditions.
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