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| 4. |
- van Haarlem, M. P., et al.
(författare)
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LOFAR : The LOw-Frequency ARray
- 2013
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 556, s. 1-53
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Tidskriftsartikel (refereegranskat)abstract
- LOFAR, the LOw-Frequency ARray, is a new-generation radio interferometer constructed in the north of the Netherlands and across europe. Utilizing a novel phased-array design, LOFAR covers the largely unexplored low-frequency range from 10–240 MHz and provides a number of unique observing capabilities. Spreading out from a core located near the village of Exloo in the northeast of the Netherlands, a total of 40 LOFAR stations are nearing completion. A further five stations have been deployed throughout Germany, and one station has been built in each of France, Sweden, and the UK. Digital beam-forming techniques make the LOFAR system agile and allow for rapid repointing of the telescope as well as the potential for multiple simultaneous observations. With its dense core array and long interferometric baselines, LOFAR achieves unparalleled sensitivity and angular resolution in the low-frequency radio regime. The LOFAR facilities are jointly operated by the International LOFAR Telescope (ILT) foundation, as an observatory open to the global astronomical community. LOFAR is one of the first radio observatories to feature automated processing pipelines to deliver fully calibrated science products to its user community. LOFAR’s new capabilities, techniques and modus operandi make it an important pathfinder for the Square Kilometre Array (SKA). We give an overview of the LOFAR instrument, its major hardware and software components, and the core science objectives that have driven its design. In addition, we present a selection of new results from the commissioning phase of this new radio observatory.
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| 6. |
- De Gasperin, F., et al.
(författare)
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M 87 at metre wavelengths: the LOFAR picture
- 2012
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 547, s. article no. 56-
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Tidskriftsartikel (refereegranskat)abstract
- Context. M87 is a giant elliptical galaxy located in the centre of the Virgo cluster, which harbours a supermassive black hole of mass 6.4x10(9) M-circle dot, whose activity is responsible for the extended (80 kpc) radio lobes that surround the galaxy. The energy generated by matter falling onto the central black hole is ejected and transferred to the intra-cluster medium via a relativistic jet and morphologically complex systems of buoyant bubbles, which rise towards the edges of the extended halo. Aims. To place constraints on past activity cycles of the active nucleus, images of M 87 were produced at low radio frequencies never explored before at these high spatial resolution and dynamic range. To disentangle different synchrotron models and place constraints on source magnetic field, age and energetics, we also performed a detailed spectral analysis of M 87 extended radio-halo. Methods. We present the first observations made with the new Low-Frequency Array (LOFAR) of M 87 at frequencies down to 20 MHz. Three observations were conducted, at 15-30 MHz, 30-77 MHz and 116-162 MHz. We used these observations together with archival data to produce a low-frequency spectral index map and to perform a spectral analysis in the wide frequency range 30 MHz-10 GHz. Results. We do not find any sign of new extended emissions; on the contrary the source appears well confined by the high pressure of the intra-cluster medium. A continuous injection of relativistic electrons is the model that best fits our data, and provides a scenario in which the lobes are still supplied by fresh relativistic particles from the active galactic nuclei. We suggest that the discrepancy between the low-frequency radio-spectral slope in the core and in the halo implies a strong adiabatic expansion of the plasma as soon as it leaves the core area. The extended halo has an equipartition magnetic field strength of similar or equal to 10 mu G, which increases to similar or equal to 13 mu G in the zones where the particle flows are more active. The continuous injection model for synchrotron ageing provides an age for the halo of similar or equal to 40 Myr, which in turn provides a jet kinetic power of 6-10 x 10(44) erg s(-1).
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| 7. |
- Bar, N., et al.
(författare)
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A reference map of potential determinants for the human serum metabolome
- 2020
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Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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| 8. |
- Offringa, A. R., et al.
(författare)
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The LOFAR radio environment
- 2012
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 549
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Tidskriftsartikel (refereegranskat)abstract
- Aims. This paper discusses the spectral occupancy for performing radio astronomy with the Low-Frequency Array (LOFAR), with a focus on imaging observations.Methods. We have analysed the radio-frequency interference (RFI) situation in two 24-h surveys with Dutch LOFAR stations, covering 30-78 MHz with low-band antennas and 115-163 MHz with high-band antennas. This is a subset of the full frequency range of LOFAR. The surveys have been observed with a 0.76 kHz/1 s resolution.Results. We measured the RFI occupancy in the low and high frequency sets to be 1.8% and 3.2% respectively. These values are found to be representative values for the LOFAR radio environment. Between day and night, there is no significant difference in the radio environment. We find that lowering the current observational time and frequency resolutions of LOFAR results in a slight loss of flagging accuracy. At LOFAR's nominal resolution of 0.76 kHz and 1 s, the false-positives rate is about 0.5%. This rate increases approximately linearly when decreasing the data frequency resolution.Conclusions. Currently, by using an automated RFI detection strategy, the LOFAR radio environment poses no perceivable problems for sensitive observing. It remains to be seen if this is still true for very deep observations that integrate over tens of nights, but the situation looks promising. Reasons for the low impact of RFI are the high spectral and time resolution of LOFAR; accurate detection methods; strong filters and high receiver linearity; and the proximity of the antennas to the ground. We discuss some strategies that can be used once low-level RFI starts to become apparent. It is important that the frequency range of LOFAR remains free of broadband interference, such as DAB stations and windmills.
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| 9. |
- Wilman, H. R., et al.
(författare)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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| 10. |
- Ashizawa, T., et al.
(författare)
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Consensus-based care recommendations for adults with myotonic dystrophy type 1
- 2018
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Ingår i: Neurology-Clinical Practice. - : Ovid Technologies (Wolters Kluwer Health). - 2163-0402 .- 2163-0933. ; 8:6, s. 507-520
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Forskningsöversikt (refereegranskat)abstract
- Purpose of review Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.
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| 11. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 12. |
- Koopman, J J E, et al.
(författare)
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Senescence rates in patients with end-stage renal disease: a critical appraisal of the Gompertz model.
- 2011
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Ingår i: Aging Cell. - : Wiley. - 1474-9726 .- 1474-9718. ; Dec, s. 233-238
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Tidskriftsartikel (refereegranskat)abstract
- The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age-specific mortality rates for European patients on dialysis (n=274,221; follow-up=594,767 person-years), for European patients with a functioning kidney transplant (n=61,286; follow-up=345,024 person-years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmical mortality curve for patients on dialysis compared to both patients with a functioning kidney transplant and the general population (p<0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation.
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| 14. |
- Bonamy, AKE, et al.
(författare)
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Wide variation in severe neonatal morbidity among very preterm infants in European regions
- 2019
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Ingår i: Archives of disease in childhood. Fetal and neonatal edition. - : BMJ. - 1468-2052 .- 1359-2998. ; 104:1, s. F36-F45
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the variation in severe neonatal morbidity among very preterm (VPT) infants across European regions and whether morbidity rates are higher in regions with low compared with high mortality rates.DesignArea-based cohort study of all births before 32 weeks of gestational age.Setting16 regions in 11 European countries in 2011/2012.PatientsSurvivors to discharge from neonatal care (n=6422).Main outcome measuresSevere neonatal morbidity was defined as intraventricular haemorrhage grades III and IV, cystic periventricular leukomalacia, surgical necrotizing enterocolitis and retinopathy of prematurity grades ≥3. A secondary outcome included severe bronchopulmonary dysplasia (BPD), data available in 14 regions. Common definitions for neonatal morbidities were established before data abstraction from medical records. Regional severe neonatal morbidity rates were correlated with regional in-hospital mortality rates for live births after adjustment on maternal and neonatal characteristics.Results10.6% of survivors had a severe neonatal morbidity without severe BPD (regional range 6.4%–23.5%) and 13.8% including severe BPD (regional range 10.0%–23.5%). Adjusted inhospital mortality was 13.7% (regional range 8.4%–18.8%). Differences between regions remained significant after consideration of maternal and neonatal characteristics (P<0.001) and severe neonatal morbidity rates were not correlated with mortality rates (P=0.50).ConclusionSevere neonatal morbidity rates for VPT survivors varied widely across European regions and were independent of mortality rates.
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| 15. |
- Cuttini, M, et al.
(författare)
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Breastfeeding outcomes in European NICUs: impact of parental visiting policies
- 2019
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Ingår i: Archives of disease in childhood. Fetal and neonatal edition. - : BMJ. - 1468-2052 .- 1359-2998. ; 104:2, s. F151-
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Tidskriftsartikel (refereegranskat)abstract
- The documented benefits of maternal milk for very preterm infants have raised interest in hospital policies that promote breastfeeding. We investigated the hypothesis that more liberal parental policies are associated with increased breastfeeding at discharge from the neonatal unit.DesignProspective area-based cohort study.SettingNeonatal intensive care units (NICUs) in 19 regions of 11 European countries.PatientsAll very preterm infants discharged alive in participating regions in 2011–2012 after spending >70% of their hospital stay in the same NICU (n=4407).Main outcome measuresWe assessed four feeding outcomes at hospital discharge: any and exclusive maternal milk feeding, independent of feeding method; any and exclusive direct breastfeeding, defined as sucking at the breast. We computed a neonatal unit Parental Presence Score (PPS) based on policies regarding parental visiting in the intensive care area (range 1–10, with higher values indicating more liberal policies), and we used multivariable multilevel modified Poisson regression analysis to assess the relation between unit PPS and outcomes.ResultsPolicies regarding visiting hours, duration of visits and possibility for parents to stay during medical rounds and spend the night in unit differed within and across countries. After adjustment for potential confounders, infants cared for in units with liberal parental policies (PPS≥7) were about twofold significantly more likely to be discharged with exclusive maternal milk feeding and exclusive direct breastfeeding.ConclusionUnit policies promoting parental presence and involvement in care may increase the likelihood of successful breastfeeding at discharge for very preterm infants.
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| 16. |
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| 17. |
- Ade, Peter, et al.
(författare)
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The Simons Observatory : science goals and forecasts
- 2019
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :2
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Tidskriftsartikel (refereegranskat)abstract
- The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial con figuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping approximate to 10% of the sky to a white noise level of 2 mu K-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of sigma(r) = 0.003. The large aperture telescope will map approximate to 40% of the sky at arcminute angular resolution to an expected white noise level of 6 mu K-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
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| 19. |
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| 20. |
- Koopman, M., et al.
(författare)
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Differential Outcomes Following 4 Weeks of Aclidinium/Formoterol in Patients with COPD: A Reanalysis of the ACTIVATE Study
- 2022
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Ingår i: International Journal of Chronic Obstructive Pulmonary Disease. - 1178-2005. ; 17, s. 517-533
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: It is difficult to predict the effects of long-acting bronchodilators (LABD) on lung function, exercise capacity and physical activity in patients with chronic obstructive pulmonary disease (COPD). Therefore, the multidimensional response to LABD was profiled in COPD patients participating in the ACTIVATE study and randomized to LABD. Methods: In the ACTIVATE study, patients were randomized to aclidinium bromide/formoterol fumarate ( AB/FF) or placebo for four weeks. The primary outcomes included (1) lung function as measured by functional residual capacity (FRC), residual volume (RV), and spirometric outcomes; (2) exercise performance as measured by a constant work rate cycle ergometry test (CWRT); and (3) physical activity (PA) using an activity monitor. Self-organizing maps (SOMs) were used to create an ordered representation of the patients who were randomly assigned to four weeks of AB/FF and cluster them into different outcome groups. Results: A total of 250 patients were randomized to AB/FF (n = 126) or placebo (n = 124). Patients in the AB/FF group (39.6% women) had moderate-to-severe COPD, static hyperinflation (FRC: 151.4 (27.7)% predicted) and preserved exercise capacity. Six clusters with differential outcomes were identified. Patients in clusters 1 and 2 had significant improvements in lung function compared to the remaining AB/FF-treated patients. Patients in clusters 1 and 3 had significant improvements in CWRT time, and patients in clusters 2, 3 and 6 had significant improvements in PA compared to the remaining AB/FF-treated patients. Conclusion: Individual responses to 4 weeks of AB/FF-treatment in COPD are differential and the degree of change differs across domains of lung function, exercise capacity and PA. These results indicate that clinical response to LABD therapy is difficult to predict and is non-linear, and show doctors that it is important to look at multiple outcomes simultaneously when evaluating the clinical response to LABD therapy.
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| 21. |
- Obura, M., et al.
(författare)
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Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time : An IMI-DIRECT study
- 2021
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 38:2
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. Methods: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. Results: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1–4. Participants in Subgroups 2–4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (β = 0.36, 95% CI 0.13–0.58), Subgroup 3 (β = 0.30; 95% CI 0.10–0.50) and Subgroup 2 (β = 0.18; 95% CI 0.04–0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. Conclusions: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.
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| 22. |
- Smith, P B, et al.
(författare)
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Cultural values, sources of guidance, and their relevance to managerial behavior - A 47-nation study
- 2002
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Ingår i: Journal of Cross-Cultural Psychology. - : Sage Publications. - 0022-0221 .- 1552-5422. ; 33:2, s. 188-208
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Tidskriftsartikel (refereegranskat)abstract
- Data are presented showing how middle managers in 47 countries report handling eight specific work events. The data are used to test the ability of cultural value dimensions derived from the work of Hofstede. Trompenaars, and Schwartz to predict the specific sources of guidance on which managers rely. Focusing on sources of guidance is expected to provide a more precise basis than do generalized measures of values for understanding the behaviors that prevail within different cultures. Values are strongly predictive of reliance on those sources of guidance that are relevant to vertical relationships within organizations. Hock ever, values are less successful in predicting reliance on peers and on more tacit sources of guidance. Explaining national differences in these neglected aspects of organizational processes will require greater sensitivity to the culture-specific contexts within which they occur.
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| 23. |
- Koivula, Robert W., et al.
(författare)
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium
- 2019
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:9, s. 1601-1615
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
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| 24. |
- Koopman, M., et al.
(författare)
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Effects of Non-Invasive Ventilation Combined with Oxygen Supplementation on Exercise Performance in COPD Patients with Static Lung Hyperinflation and Exercise-Induced Oxygen Desaturation: A Single Blind, Randomized Cross-Over Trial
- 2019
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Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- The effects of non-invasive ventilation (NIV) in addition to supplemental oxygen on exercise performance in patients with chronic obstructive pulmonary disease (COPD) with hyperinflation and exercise-induced desaturation (EID) remain unclear. We hypothesized that these patients would benefit from NIV and that this effect would be an add-on to oxygen therapy. Thirteen COPD patients with a residual volume >150% of predicted, normal resting arterial oxygen pressure (PaO2) and carbon-dioxide pressure (PaCO2) and EID during a six-minute walk test were included. Patients performed four constant work-rate treadmill tests, each consisting of two exercise bouts with a recovery period in between, wearing an oronasal mask connected to a ventilator and oxygen supply. The ventilator was set to the following settings in fixed order with clockwise rotation: Sham (continuous positive airway pressure (CPAP) 2 cm H2O, FiO(2) 21%), oxygen (CPAP 2 cm H2O, FiO(2) 35%), NIV and oxygen (inspiratory positive airway pressure (IPAP) 14 cm H2O/expiratory positive airway pressure (EPAP) 6 cm H2O, inspired oxygen fraction (FiO(2)) 35%), intermittent (walking: Sham setting, recovery: NIV and oxygen setting). During the first exercise, bout patients walked further with the oxygen setting compared to the sham setting (225 +/- 107 vs 120 +/- 50 meters, p < 0.05), but even further with the oxygen/NIV setting (283 +/- 128 meters; p < 0.05). Recovery time between two exercise bouts was shortest with NIV and oxygen. COPD patients with severe static hyperinflation and EID benefit significantly from NIV in addition to oxygen during exercise and recovery.
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| 25. |
- Boon, Hanneke, 1981-, et al.
(författare)
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Substrate Source Use in Older, Trained Males after Decades of Endurance Training
- 2007
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Ingår i: Medicine & Science in Sports & Exercise. - Philadelphia, PA : Lippincott Williams & Wilkins. - 0195-9131 .- 1530-0315. ; 39:12, s. 2160-2170
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The purpose of this study was to compare substrate source use in older, long-term exercising, endurance-trained males with sedentary controls. METHODS: [U-C]palmitate and [6,6-H2]glucose tracers were applied to assess plasma free fatty acid (FFA) and glucose oxidation rates, and to estimate muscle- and/or lipoprotein-derived triacylglycerol (TG) and muscle glycogen use. Subjects were 10 long-term exercising, endurance-trained males and 10 sedentary controls (age 57 +/- 1 and 60 +/- 2 yr, respectively). Muscle biopsy samples were collected before and after exercise to assess muscle fiber type-specific intramyocellular lipid and glycogen content. RESULTS: During exercise, plasma palmitate Ra, Rd, and Rox were significantly greater in the trained subjects compared with the controls (Ra: 0.36 +/- 0.02 and 0.25 +/- 0.02; Rd: 0.36 +/- 0.03 and 0.24 +/- 0.02; Rox: 0.31 +/- 0.02 and 0.20 +/- 0.02 mmol.min, respectively, P < 0.01). This resulted in greater plasma FFA and total fat oxidation rates in the trained versus sedentary subjects (P < 0.001). Muscle- and/or lipoprotein-derived TG use contributed 10 +/- 2 and 11 +/- 3% in the trained and control groups, respectively (NS). No significant net changes in muscle fiber lipid content were observed. CONCLUSIONS: Older, endurance-trained males oxidize more fat during moderate-intensity exercise than do sedentary controls. This greater total fat oxidation rate is attributed to a higher plasma FFA release, uptake, and oxidation rate. In contrast, intramyocellular triacylglycerol does not seem to represent a major substrate source during 1 h of moderate-intensity exercise in older trained or sedentary men. ©2007 The American College of Sports Medicine.
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| 27. |
- Lend, K., et al.
(författare)
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Sex differences in remission rates over 24 weeks among three different biological treatments compared to conventional therapy in patients with early rheumatoid arthritis (NORD-STAR): a post-hoc analysis of a randomised controlled trial
- 2023
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Ingår i: The Lancet Rheumatology. - 2665-9913. ; 4:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rheumatoid arthritis is a chronic inflammatory disease with a well-recognised female preponderance. In this post-hoc analysis of the NORD-STAR trial, we aimed to examine sex differences in remission rates with three different biological treatments combined with methotrexate versus active conventional treatment over 24 weeks, in patients with early rheumatoid arthritis. Methods: NORD-STAR was a multicentre, investigator-initiated, assessor-blinded, phase 4, randomised, controlled trial of early rheumatoid arthritis, done in Denmark, Finland, Iceland, Norway, Sweden, and the Netherlands. Newly diagnosed patients, naive to disease-modifying antirheumatic drugs, aged 18 years or older with early rheumatoid arthritis and with a symptom duration less than 24 months were randomly assigned (1:1:1:1) to receive active conventional treatment, certolizumab-pegol, abatacept, or tocilizumab. Sex was reported in case report forms by study physicians or by study nurses. Data on gender were not collected. Remission outcomes were analysed with logistic generalised estimating equations (GEE), using a logit link and exchangeable correlation matrix. The model included treatment, time, sex, and the relevant interactions. For this post-hoc analysis, the co-primary outcomes were differences in Clinical Disease Activity Index (CDAI) remission (CDAI score ≤2·8) between sexes over time and at week 24, assessed with interaction terms (men vs women within each treatment comparison) and using active conventional treatment as the reference. We present adjusted average marginal differences in remission rates (risk differences) with 95% CIs. Findings: Between Dec 14, 2012, and Dec 11, 2018, 812 patients were enrolled and randomly assigned; 217 received active conventional treatment, 203 received certolizumab-pegol, 204 received abatacept, and 188 received tocilizumab. All 812 patients were included in this analysis; 561 (69%) were women and 251 (31%) were men. Observed CDAI remission rates at 24 weeks were numerically higher among men than among women despite comparable disease activity at baseline (55% vs 50% with active conventional treatment, 57% vs 52% with certolizumab-pegol, 65% vs 51% with abatacept, and 61% vs 40% with tocilizumab). In the adjusted analysis, with active conventional treatment as the reference, the only significant difference between men and women was in the tocilizumab group (pinteraction=0·015); men in the tocilizumab group had a higher probability of CDAI remission, on average over time, than did men in the active conventional treatment group (0·12; 95% CI 0·00 to 0·23), whereas women in the tocilizumab group had a lower probability of remission than did women in the active conventional treatment group (–0·05, 95% CI –0·13 to 0·02). Interpretation: Numerically higher remission rates were observed in men than in women in all four treatment groups at week 24, suggesting that this generalised sex difference is not related to the treatment. The difference between men and women was significantly greater with tocilizumab, an interleukin (IL)-6 inhibitor, than with active conventional treatment, suggesting a possible additional sex-based effect specific for IL-6 blockade. Funding: None. © 2022 Elsevier Ltd
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| 28. |
- Sator, Lea, et al.
(författare)
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Overdiagnosis of COPD in Subjects With Unobstructed Spirometry A BOLD Analysis
- 2019
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Ingår i: Chest. - : Elsevier BV. - 0012-3692 .- 1931-3543. ; 156:2, s. 277-288
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012.METHODS: A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV1/FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV1/FVC < 0.7).RESULTS: Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication.CONCLUSIONS: False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.
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| 29. |
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| 30. |
- Studnicka, Michael, et al.
(författare)
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COPD : Should Diagnosis Match Physiology?
- 2020
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Ingår i: Chest. - : Elsevier BV. - 0012-3692 .- 1931-3543. ; 157:2, s. 473-475
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 31. |
- Hagerling, Catharina, et al.
(författare)
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LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target
- 2020
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Ingår i: Bmc Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Novel biomarkers are required to discern between breast tumors that should be targeted for treatment from those that would never become clinically apparent and/or life threatening for patients. Moreover, therapeutics that specifically target breast cancer (BC) cells with tumor-initiating capacity to prevent recurrence are an unmet need. We investigated the clinical importance of LGR5 in BC and ductal carcinoma in situ (DCIS) to explore LGR5 as a biomarker and a therapeutic target. Methods We stained BC (n = 401) and DCIS (n = 119) tissue microarrays with an antibody against LGR5. We examined anLGR5knockdown ER(-)cell line that was orthotopically transplanted and used for in vitro colony assays. We also determined the tumor-initiating role of Lgr5 in lineage-tracing experiments. Lastly, we transplanted ER(-)patient-derived xenografts into mice that were subsequently treated with a LGR5 antibody drug conjugate (anti-LGR5-ADC). Results LGR5 expression correlated with small tumor size, lower grade, lymph node negativity, and ER-positivity. ER(+)patients with LGR5(high)tumors rarely had recurrence, while high-grade ER(-)patients with LGR5(high)expression recurred and died due to BC more often. Intriguingly, all the DCIS patients who later died of BC had LGR5-positive tumors. Colony assays and xenograft experiments substantiated a role for LGR5 in ER(-)tumor initiation and subsequent growth, which was further validated by lineage-tracing experiments in ER-/triple-negative BC mouse models. Importantly, by utilizing LGR5(high)patient-derived xenografts, we showed that anti-LGR5-ADC should be considered as a therapeutic for high-grade ER-BC. Conclusion LGR5 has distinct roles in ER(-)vs. ER+BC with potential clinical applicability as a biomarker to identify patients in need of therapy and could serve as a therapeutic target for high-grade ER-BC.
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| 35. |
- Persson Waye, Kerstin, 1959, et al.
(författare)
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Assessing the exposure-response relationship of sleep disturbance and vibration in field and laboratory settings
- 2019
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Ingår i: Environmental Pollution. - : Elsevier BV. - 0269-7491. ; 245, s. 558-567
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to nocturnal freight train vibrations may impact sleep, but exposure-response relationships are lacking. The European project CargoVibes evaluated sleep disturbance both in the field and in the laboratory and provides unique data, as measures of response and exposure metrics are comparable. This paper therefore provides data on exposure-response relationships of vibration and sleep disturbance and compares the relationships evaluated in the laboratory and the field. Two field studies (one in Poland and one in the Netherlands) with 233 valid respondents in total, and three laboratory studies in Sweden with a total of 59 subjects over 350 person-nights were performed. The odds ratios (OR) of sleep disturbance were analyzed in relation to nighttime vibration exposure by ordinal logit regression, adjusting for moderating factors common for the studies. Outcome specific fractions were calculated for eleven sleep outcomes and supported comparability between the field and laboratory settings. Vibration exposure was significantly associated with sleep disturbance, OR = 3.51 (95% confidence interval 2.6–4.73) denoting a three and a half times increase in the odds of sleep disturbance with one unit increased 8 h nighttime log10 Root Mean Square vibration. The results suggest no significant difference between field and laboratory settings OR = 1.37 (0.59–3.19). However, odds of sleep disturbance were higher in the Netherlands as compared to Sweden, indicating unexplained differences between study populations or countries, possibly related to cultural and contextual differences and uncertainties in exposure assessments. Future studies should be carefully designed to record explanatory factors in the field and enhance ecological validity in the laboratory. Nevertheless, the presented combined data set provides a first set of exposure response relationships for vibration-induced sleep disturbance, which are useful when considering public health outcomes among exposed populations. Exposure-response relationships of vibration exposure from trains and sleep disturbance were derived from laboratory studies and field studies, with no significant differences between the settings. © 2018 The Authors
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