| 1. |
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| 2. |
- Glasbey, JC, et al.
(author)
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- 2021
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swepub:Mat__t
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| 3. |
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| 4. |
- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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| 5. |
- Tabiri, S, et al.
(author)
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- 2021
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swepub:Mat__t
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| 6. |
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| 7. |
- Khatri, C, et al.
(author)
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Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
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In: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Journal article (peer-reviewed)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
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| 8. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 9. |
- Adams, C. B., et al.
(author)
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Observation of the Gamma-Ray Binary HESS J0632+057 with the HESS, MAGIC, and VERITAS Telescopes
- 2021
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In: Astrophysical Journal. - : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 923:2
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Journal article (peer-reviewed)abstract
- The results of gamma-ray observations of the binary system HESS J0632 + 057 collected during 450 hr over 15 yr, between 2004 and 2019, are presented. Data taken with the atmospheric Cherenkov telescopes H.E.S.S., MAGIC, and VERITAS at energies above 350 GeV were used together with observations at X-ray energies obtained with Swift-XRT, Chandra, XMM-Newton, NuSTAR, and Suzaku. Some of these observations were accompanied by measurements of the H alpha emission line. A significant detection of the modulation of the very high-energy gamma-ray fluxes with a period of 316.7 +/- 4.4 days is reported, consistent with the period of 317.3 +/- 0.7 days obtained with a refined analysis of X-ray data. The analysis of data from four orbital cycles with dense observational coverage reveals short-timescale variability, with flux-decay timescales of less than 20 days at very high energies. Flux variations observed over a timescale of several years indicate orbit-to-orbit variability. The analysis confirms the previously reported correlation of X-ray and gamma-ray emission from the system at very high significance, but cannot find any correlation of optical H alpha parameters with fluxes at X-ray or gamma-ray energies in simultaneous observations. The key finding is that the emission of HESS J0632 + 057 in the X-ray and gamma-ray energy bands is highly variable on different timescales. The ratio of gamma-ray to X-ray flux shows the equality or even dominance of the gamma-ray energy range. This wealth of new data is interpreted taking into account the insufficient knowledge of the ephemeris of the system, and discussed in the context of results reported on other gamma-ray binary systems.
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| 10. |
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| 11. |
- Acharyya, A., et al.
(author)
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Multiwavelength Observations of the Blazar PKS 0735+178 in Spatial and Temporal Coincidence with an Astrophysical Neutrino Candidate IceCube-211208A
- 2023
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In: Astrophysical Journal. - : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 954:1
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Journal article (peer-reviewed)abstract
- We report on multiwavelength target-of-opportunity observations of the blazar PKS 0735+178, located 2 degrees .2 away from the best -fit position of the IceCube neutrino event IceCube-211208A detected on 2021 December 8. The source was in a high -flux state in the optical, ultraviolet, X-ray, and GeV ?-ray bands around the time of the neutrino event, exhibiting daily variability in the soft X-ray flux. The X-ray data from Swift-XRT and NuSTAR characterize the transition between the low-energy and high-energy components of the broadband spectral energy distribution (SED), and the ?-ray data from Fermi-LAT, VERITAS, and H.E.S.S. require a spectral cutoff near 100 GeV. Both the X-ray and ?-ray measurements provide strong constraints on the leptonic and hadronic models. We analytically explore a synchrotron self-Compton model, an external Compton model, and a lepto-hadronic model. Models that are entirely based on internal photon fields face serious difficulties in matching the observed SED. The existence of an external photon field in the source would instead explain the observed ?-ray spectral cutoff in both the leptonic and lepto-hadronic models and allow a proton jet power that marginally agrees with the Eddington limit in the lepto-hadronic model. We show a numerical lepto-hadronic model with external target photons that reproduces the observed SED and is reasonably consistent with the neutrino event despite requiring a high jet power.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Beal, Jacob, et al.
(author)
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Robust estimation of bacterial cell count from optical density
- 2020
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In: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Journal article (peer-reviewed)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 16. |
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| 17. |
- Maron, David J., et al.
(author)
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Initial Invasive or Conservative Strategy for Stable Coronary Disease
- 2020
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 382:15, s. 1395-1407
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Journal article (peer-reviewed)abstract
- Background: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.Methods: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.Results: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).Conclusions: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, .) Patients with stable coronary disease were randomly assigned to an initial invasive strategy with angiography and revascularization if appropriate or to medical therapy alone. At 3.2 years, there was no significant difference between the groups with respect to the estimated rate of ischemic events. The findings were sensitive to the definition of myocardial infarction.
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| 18. |
- Ovaskainen, Otso, et al.
(author)
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Global Spore Sampling Project: A global, standardized dataset of airborne fungal DNA
- 2024
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In: Scientific Data. - 2052-4463. ; 11
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Journal article (peer-reviewed)abstract
- Novel methods for sampling and characterizing biodiversity hold great promise for re-evaluating patterns of life across the planet. The sampling of airborne spores with a cyclone sampler, and the sequencing of their DNA, have been suggested as an efficient and well-calibrated tool for surveying fungal diversity across various environments. Here we present data originating from the Global Spore Sampling Project, comprising 2,768 samples collected during two years at 47 outdoor locations across the world. Each sample represents fungal DNA extracted from 24 m3 of air. We applied a conservative bioinformatics pipeline that filtered out sequences that did not show strong evidence of representing a fungal species. The pipeline yielded 27,954 species-level operational taxonomic units (OTUs). Each OTU is accompanied by a probabilistic taxonomic classification, validated through comparison with expert evaluations. To examine the potential of the data for ecological analyses, we partitioned the variation in species distributions into spatial and seasonal components, showing a strong effect of the annual mean temperature on community composition.
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Feng, Shaohong, et al.
(author)
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Dense sampling of bird diversity increases power of comparative genomics
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 587:7833
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Journal article (peer-reviewed)abstract
- Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity(1-4). Sparse taxon sampling has previously been proposed to confound phylogenetic inference(5), and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species. A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.
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| 23. |
- Grossmann, Igor, et al.
(author)
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Insights into the accuracy of social scientists' forecasts of societal change
- 2023
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In: Nature Human Behaviour. - : Springer Nature. - 2397-3374. ; 7, s. 484-501
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Journal article (peer-reviewed)abstract
- How well can social scientists predict societal change, and what processes underlie their predictions? To answer these questions, we ran two forecasting tournaments testing the accuracy of predictions of societal change in domains commonly studied in the social sciences: ideological preferences, political polarization, life satisfaction, sentiment on social media, and gender-career and racial bias. After we provided them with historical trend data on the relevant domain, social scientists submitted pre-registered monthly forecasts for a year (Tournament 1; N = 86 teams and 359 forecasts), with an opportunity to update forecasts on the basis of new data six months later (Tournament 2; N = 120 teams and 546 forecasts). Benchmarking forecasting accuracy revealed that social scientists' forecasts were on average no more accurate than those of simple statistical models (historical means, random walks or linear regressions) or the aggregate forecasts of a sample from the general public (N = 802). However, scientists were more accurate if they had scientific expertise in a prediction domain, were interdisciplinary, used simpler models and based predictions on prior data. How accurate are social scientists in predicting societal change, and what processes underlie their predictions? Grossmann et al. report the findings of two forecasting tournaments. Social scientists' forecasts were on average no more accurate than those of simple statistical models.
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| 24. |
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| 25. |
- Morabito, L., et al.
(author)
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Sub-arcsecond imaging with the International LOFAR Telescope: I. Foundational calibration strategy and pipeline
- 2022
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 658
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Journal article (peer-reviewed)abstract
- The International LOFAR Telescope is an interferometer with stations spread across Europe. With baselines of up to ∼2000 km, LOFAR has the unique capability of achieving sub-arcsecond resolution at frequencies below 200 MHz. However, it is technically and logistically challenging to process LOFAR data at this resolution. To date only a handful of publications have exploited this capability. Here we present a calibration strategy that builds on previous high-resolution work with LOFAR. It is implemented in a pipeline using mostly dedicated LOFAR software tools and the same processing framework as the LOFAR Two-metre Sky Survey (LoTSS). We give an overview of the calibration strategy and discuss the special challenges inherent to enacting high-resolution imaging with LOFAR, and describe the pipeline, which is publicly available, in detail. We demonstrate the calibration strategy by using the pipeline on P205+55, a typical LoTSS pointing with an 8 h observation and 13 international stations. We perform in-field delay calibration, solution referencing to other calibrators in the field, self-calibration of these calibrators, and imaging of example directions of interest in the field. We find that for this specific field and these ionospheric conditions, dispersive delay solutions can be transferred between calibrators up to ∼1.5° away, while phase solution transferral works well over ∼1°. We also demonstrate a check of the astrometry and flux density scale with the in-field delay calibrator source. Imaging in 17 directions, we find the restoring beam is typically ∼0.3″ ×0.2″ although this varies slightly over the entire 5 deg2 field of view. We find we can achieve ∼80-300 μJy bm-1 image rms noise, which is dependent on the distance from the phase centre; typical values are ∼90 μJy bm-1 for the 8 h observation with 48 MHz of bandwidth. Seventy percent of processed sources are detected, and from this we estimate that we should be able to image roughly 900 sources per LoTSS pointing. This equates to ∼ 3 million sources in the northern sky, which LoTSS will entirely cover in the next several years. Future optimisation of the calibration strategy for efficient post-processing of LoTSS at high resolution makes this estimate a lower limit.
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| 26. |
- Reynolds, Harmony R., et al.
(author)
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Association of Sex With Severity of Coronary Artery Disease, Ischemia, and Symptom Burden in Patients With Moderate or Severe Ischemia Secondary Analysis of the ISCHEMIA Randomized Clinical Trial
- 2020
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In: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 5:7, s. 773-786
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Journal article (peer-reviewed)abstract
- Key PointsQuestion When considering patients who have obstructive coronary artery disease and ischemia on stress testing, are there sex differences in severity of coronary artery disease, ischemia, and/or symptoms?Findings In this secondary analysis of the ISCHEMIA randomized clinical trial of 5179 patients, women had more frequent angina, less extensive coronary artery disease, and less severe ischemia than men. On multivariate analysis, female sex was independently associated with greater angina frequency.Meaning There may be inherent sex differences in the complex relationships between angina, ischemia, and atherosclerosis that may have implications for testing and treatment of patients with suspected coronary artery disease.AbstractImportance While many features of stable ischemic heart disease vary by sex, differences in ischemia, coronary anatomy, and symptoms by sex have not been investigated among patients with moderate or severe ischemia. The enrolled ISCHEMIA trial cohort that underwent coronary computed tomographic angiography (CCTA) was required to have obstructive coronary artery disease (CAD) for randomization.Objective To describe sex differences in stress testing, CCTA findings, and symptoms in ISCHEMIA trial participants.Design, Setting, and Participants This secondary analysis of the multicenter ISCHEMIA randomized clinical trial analyzed baseline characteristics of patients with stable ischemic heart disease. Individuals were enrolled from July 2012 to January 2018 based on local reading of moderate or severe ischemia on a stress test, after which blinded CCTA was performed in most. Core laboratories reviewed stress tests and CCTAs. Participants with no obstructive CAD or with left main CAD of 50% or greater were excluded. Those who met eligibility criteria including CCTA (if performed) were randomized to a routine invasive or a conservative management strategy (N = 5179). Angina was assessed using the Seattle Angina Questionnaire. Analysis began October 1, 2018.Interventions CCTA and angina assessment.Main Outcomes and Measures Sex differences in stress test, CCTA findings, and symptom severity.Results Of 8518 patients enrolled, 6256 (77%) were men. Women were more likely to have no obstructive CAD (<50% stenosis in all vessels on CCTA) (353 of 1022 [34.4%] vs 378 of 3353 [11.3%]). Of individuals who were randomized, women had more angina at baseline than men (median [interquartile range] Seattle Angina Questionnaire Angina Frequency score: 80 [70-100] vs 90 [70-100]). Women had less severe ischemia on stress imaging (383 of 919 [41.7%] vs 1361 of 2972 [45.9%] with severe ischemia; 386 of 919 [42.0%] vs 1215 of 2972 [40.9%] with moderate ischemia; and 150 of 919 [16.4%] vs 394 of 2972 [13.3%] with mild or no ischemia). Ischemia was similar by sex on exercise tolerance testing. Women had less extensive CAD on CCTA (205 of 568 women [36%] vs 1142 of 2418 men [47%] with 3-vessel disease; 184 of 568 women [32%] vs 754 of 2418 men [31%] with 2-vessel disease; and 178 of 568 women [31%] vs 519 of 2418 men [22%] with 1-vessel disease). Female sex was independently associated with greater angina frequency (odds ratio, 1.41; 95% CI, 1.13-1.76).Conclusions and Relevance Women in the ISCHEMIA trial had more frequent angina, independent of less extensive CAD, and less severe ischemia than men. These findings reflect inherent sex differences in the complex relationships between angina, atherosclerosis, and ischemia that may have implications for testing and treatment of patients with suspected stable ischemic heart disease.
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| 27. |
- Sallee, J. B., et al.
(author)
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Southern ocean carbon and heat impact on climate
- 2023
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In: Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. - 1364-503X .- 1471-2962. ; 381:2249
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Journal article (peer-reviewed)abstract
- The Southern Ocean greatly contributes to the regulation of the global climate by controlling important heat and carbon exchanges between the atmosphere and the ocean. Rates of climate change on decadal timescales are therefore impacted by oceanic processes taking place in the Southern Ocean, yet too little is known about these processes. Limitations come both from the lack of observations in this extreme environment and its inherent sensitivity to intermittent processes at scales that are not well captured in current Earth system models. The Southern Ocean Carbon and Heat Impact on Climate programme was launched to address this knowledge gap, with the overall objective to understand and quantify variability of heat and carbon budgets in the Southern Ocean through an investigation of the key physical processes controlling exchanges between the atmosphere, ocean and sea ice using a combination of observational and modelling approaches. Here, we provide a brief overview of the programme, as well as a summary of some of the scientific progress achieved during its first half. Advances range from new evidence of the importance of specific processes in Southern Ocean ventilation rate (e.g. storm-induced turbulence, sea-ice meltwater fronts, wind-induced gyre circulation, dense shelf water formation and abyssal mixing) to refined descriptions of the physical changes currently ongoing in the Southern Ocean and of their link with global climate.This article is part of a discussion meeting issue 'Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities'.
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| 28. |
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| 29. |
- Vallée, Tanja C, et al.
(author)
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Wiskott-Aldrich Syndrome: A study on 577 patients defining the genotype as a predictive biomarker for disease severity.
- 2024
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In: Blood. - 1528-0020.
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Journal article (peer-reviewed)abstract
- WAS is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% CI 78-87) at 15 years and 70% (61-80) at 30 years of age. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hotspot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared to 71% (62-81) and 48% (34-68) in patients with any other variant (class II; p<0.0001). The cumulative incidence rates of disease-related complications such as severe bleeding (p=0.007), life-threatening infection (p<0.0001), and autoimmunity (p=0.004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (p=0.6) was not different between classes I and II. This study represents the largest cohort of WAS patients studied so far. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of variant is a biomarker to predict the outcome for WAS patients.
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| 30. |
- Wallsten, Daniel, et al.
(author)
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Treating co-morbid insomnia and social anxiety disorder with sequential CBT protocols : a single-case experimental study
- 2021
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In: Behavioural and Cognitive Psychotherapy. - : Cambridge University Press. - 1352-4658 .- 1469-1833. ; 49:6, s. 641-657
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Journal article (peer-reviewed)abstract
- BACKGROUND: Although insomnia disorder and social anxiety disorder are among the most prevalent psychiatric disorders, no studies have yet evaluated the use of sequential evidence-based treatment protocols in the population with co-morbid social anxiety disorder and insomnia disorder.AIMS: This study aimed to investigate the effects of sequential treatments on co-morbid insomnia disorder and social anxiety disorder. As depression is a common co-morbid syndrome for both insomnia and social anxiety, a secondary aim was to examine depressive symptoms.METHOD: A single-case repeated crossover AB design was used. Ten participants between 18 and 59 years of age with co-morbid DSM-5 diagnoses of insomnia disorder and social anxiety disorder received sequential treatments with cognitive behavioural therapy (CBT). Seven participants completed the treatment course. The primary outcomes were symptoms of insomnia and social anxiety, and the secondary outcome was symptoms of depression.RESULTS: The effects of CBT on people with co-morbid social anxiety disorder and insomnia disorder were mixed. The majority of participants improved their sleep quality and lessened symptoms of social anxiety and depression. However, participants differed in their degree of improvement concerning all three disorders.CONCLUSIONS: Sequential CBT treatments are potentially effective at decreasing symptoms of social anxiety and insomnia for people with co-morbid social anxiety disorder and insomnia disorder. The variation in outcome across participants makes firm conclusions about the treatment efficacy difficult to draw.
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| 31. |
- Carnicelli, Anthony P., et al.
(author)
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Premature permanent discontinuation of apixaban or warfarin in patients with atrial fibrillation
- 2021
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In: Heart. - : BMJ Publishing Group Ltd. - 1355-6037 .- 1468-201X. ; 107:9, s. 713-720
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Journal article (peer-reviewed)abstract
- Aims The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug.Methods/Results We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by <= 30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events <= 30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation.Conclusion Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation.
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| 34. |
- Hanna, E., et al.
(author)
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Short- and long-term variability of the Antarctic and Greenland ice sheets
- 2024
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In: Nature Reviews Earth & Environment. - : Springer Nature. - 2662-138X. ; 5, s. 193-210
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Research review (peer-reviewed)abstract
- The variability of the Antarctic and Greenland ice sheets occurs on various timescales and is important for projections of sea level rise; however, there are substantial uncertainties concerning future ice-sheet mass changes. In this Review, we explore the degree to which short-term fluctuations and extreme glaciological events reflect the ice sheets’ long-term evolution and response to ongoing climate change. Short-term (decadal or shorter) variations in atmospheric or oceanic conditions can trigger amplifying feedbacks that increase the sensitivity of ice sheets to climate change. For example, variability in ocean-induced and atmosphere-induced melting can trigger ice thinning, retreat and/or collapse of ice shelves, grounding-line retreat, and ice flow acceleration. The Antarctic Ice Sheet is especially prone to increased melting and ice sheet collapse from warm ocean currents, which could be accentuated with increased climate variability. In Greenland both high and low melt anomalies have been observed since 2012, highlighting the influence of increased interannual climate variability on extreme glaciological events and ice sheet evolution. Failing to adequately account for such variability can result in biased projections of multi-decadal ice mass loss. Therefore, future research should aim to improve climate and ocean observations and models, and develop sophisticated ice sheet models that are directly constrained by observational records and can capture ice dynamical changes across various timescales.
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| 35. |
- Hathazi, D., et al.
(author)
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Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
- 2020
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In: Embo Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 39:23
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Journal article (peer-reviewed)abstract
- Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only similar to 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
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| 36. |
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| 39. |
- Micke, Patrick, et al.
(author)
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The prognostic impact of the tumour stroma fraction : A machine learning-based analysis in 16 human solid tumour types
- 2021
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In: EBioMedicine. - : Elsevier. - 2352-3964. ; 65
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Journal article (peer-reviewed)abstract
- Background: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed.Methods: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns.Findings: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR (95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59 (1.49-8.62)) associations of the tumour stroma fraction with survival.Interpretation: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance.
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| 40. |
- Ossenkoppele, Rik, et al.
(author)
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Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease : A Head-to-Head Comparison against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging
- 2021
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In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:8, s. 961-971
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Journal article (peer-reviewed)abstract
- Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P <.001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P <.001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P <.001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P =.71). Age (t = -2.28; P =.02), but not sex (t = 0.92; P =.36) or APOE genotype (t = 1.06; P =.29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
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| 41. |
- Ossenkoppele, Rik, et al.
(author)
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The impact of demographic, clinical, genetic, and imaging variables on tau PET status
- 2021
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2245-2258
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Journal article (peer-reviewed)abstract
- Purpose: A substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) are tau PET–negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET–positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status. Methods: We included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model. Results: Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan. Conclusion: We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.
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| 42. |
- Piec, I., et al.
(author)
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Gestational hypercalcemia: Prevalence and biochemical profile
- 2020
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In: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 199
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Journal article (peer-reviewed)abstract
- © 2020 Elsevier Ltd Gestational hypercalcemia is associated with an increased risk of maternal, fetal and neonatal morbidity and mortality. Hypercalcemia may develop during pregnancy in individuals who were previously asymptomatic. The increased sensitivity during pregnancy may be related to physiological, gestational alterations in vitamin D and calcium metabolism and may be influenced by gene variants. The prevalence is unknown. We investigated the prevalence of hypercalcemia in trimester 3 (T3) in a population representative prospective cohort study (n = 1832) in South-West Sweden. Women with serum albumin (Alb) adjusted calcium (CaAlb) ≥ 2.65 mmol/L in T3 (n = 30) were matched to normo-calcemic controls, and markers of calcium and vitamin D metabolism were investigated in trimester 1 (T1) and T3. Serum concentrations of Ca, phosphate (P), Magnesium (Mg), Alb and creatinine (Cr), parathyroid hormone (PTH; T3 only), vitamin D metabolites (total 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, and free 25(OH)D) were analysed in T1 and T3. CaAlb (Payne; inter-laboratory difference: UEA = 0.15 + 0.9*UGOT; UEA 2.54 = UGOT 2.65) and estimated glomerular filtration rate (eGFR; modified 4-variable MDRD) and vitamin D metabolites ratios (VMR) were calculated. Normally and non-normally distributed data were presented as mean (SD) or median (95 %CI). Group differences in relationships between vitamin D metabolites and with PTH were investigated with multiple regression analyses. Hypercalcemia in T3 was found in 1.7 % of women. PTH concentrations suggestive of primary hyperparathyroidism was found in 1 woman and none had 25(OH)D or 24,25(OH)2D concentrations in the toxicity range or suggestive of mutations in the CYP24A1 gene. CaAlb was significantly higher in hypercalcemic cases compared to controls in T1 (2.44 (2.30–2.80) vs 2.37 (2.25–2.49) mmol/L) and T3 (2.63 (2.52–2.78) vs 2.46 (2.31–2.58) mmol/L). Serum P was higher among cases than controls in T3 (1.12 (0.16) vs 1.07 (0.18) mmol/L) but not in T1 (1.12 (0.18) and 1.12 (0.16) mmol/L). PTH in T3 was lower in cases (1.6 (1.6–2.8) vs 2.3 (2.1–2.8) pmol/L) but 1,25(OH)2D concentrations were similar. There were no significant group differences in serum 25(OH)D, free 25(OH)D, 24,25(OH)2D, Mg, Alb, Cr and eGFR. Regression analyses did not show significant differences between cases and controls in relationships between vitamin D metabolites and with PTH, except for the free 25(OH)D-PTH relationship and a higher free:total 25(OH)D ratio in cases at T1. In conclusion, most common causes of hypercalcemia were excluded in the majority of women. Hypercalcemic women had a relatively high serum 1,25(OH)2D concentration despite an appropriately suppressed PTH, suggestive of abnormal gestational adaptions.
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| 43. |
- Prudencio, Mercedes, et al.
(author)
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Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3
- 2020
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:566
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Journal article (peer-reviewed)abstract
- Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
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| 44. |
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| 45. |
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| 46. |
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| 47. |
- Siemann, Gesa R., et al.
(author)
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Spin-orbit coupled spin-polarised hole gas at the CrSe2-terminated surface of AgCrSe2
- 2023
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In: npj Quantum Materials. - 2397-4648. ; 8:1
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Journal article (peer-reviewed)abstract
- In half-metallic systems, electronic conduction is mediated by a single spin species, offering enormous potential for spintronic devices. Here, using microscopic-area angle-resolved photoemission, we show that a spin-polarised two-dimensional hole gas is naturally realised in the polar magnetic semiconductor AgCrSe2 by an intrinsic self-doping at its CrSe2-terminated surface. Through comparison with first-principles calculations, we unveil a striking role of spin-orbit coupling for the surface hole gas, unlocked by both bulk and surface inversion symmetry breaking, suggesting routes for stabilising complex magnetic textures in the surface layer of AgCrSe2.
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| 48. |
- Watts, Eleanor L., et al.
(author)
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Circulating free testosterone and risk of aggressive prostate cancer : Prospective and Mendelian randomisation analyses in international consortia
- 2022
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In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 151:7, s. 1033-1046
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Journal article (peer-reviewed)abstract
- Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet =.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.
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| 49. |
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| 50. |
- Aguilera, Anabella, et al.
(author)
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Ecophysiological analysis reveals distinct environmental preferences in closely related Baltic Sea picocyanobacteria
- 2023
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In: Environmental Microbiology. - Chichester : John Wiley & Sons. - 1462-2912 .- 1462-2920. ; 25:9, s. 1674-1695
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Journal article (peer-reviewed)abstract
- Cluster 5 picocyanobacteria significantly contribute to primary productivity in aquatic ecosystems. Estuarine populations are highly diverse and consist of many co-occurring strains, but their physiology remains largely understudied. In this study, we characterized 17 novel estuarine picocyanobacterial strains. Phylogenetic analysis of the 16S rRNA and pigment genes (cpcBandcpeBA) uncovered multiple estuarine and freshwater-related clusters and pigment types. Assays with five representative strains (three phycocyanin rich and two phycoerythrin rich) under temperature (10–30°C), light(10–190 μmol photons m-2s-1), and salinity (2–14 PSU) gradients revealed distinct growth optima and tolerance, indicating that genetic variability was accompanied by physiological diversity. Adaptability to environmental conditions was associated with differential pigment content and photosynthetic performance. Amplicon sequence variants at a coastal and an offshore station linked population dynamics with phylogenetic clusters, supporting that strains isolated in this study represent key ecotypes within the Baltic Sea picocyanobacterial community. The functional diversity found within strains with the same pigment type suggests that understanding estuarine picocyanobacterial ecology requires analysis beyond the phycocyanin and phycoerythrin divide. This new knowledge of the environmental preferences in estuarine picocyanobacteria is important for understanding and evaluating productivity in current and future ecosystems.
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