62 research outputs found
Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. Here, we describe the first two patients with biallelic BUB1 germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features. The identified mutations cause variable degrees of reduced total protein level and kinase activity, leading to distinct mitotic defects. Both patients' cells show prolonged mitosis duration, chromosome segregation errors, and an overall functional spindle assembly checkpoint. However, while BUB1 levels mostly affect BUBR1 kinetochore recruitment, impaired kinase activity prohibits centromeric recruitment of Aurora B, SGO1, and TOP2A, correlating with anaphase bridges, aneuploidy, and defective sister chromatid cohesion. We do not observe accelerated cohesion fatigue. We hypothesize that unresolved DNA catenanes increase cohesion strength, with concomitant increase in anaphase bridges. In conclusion, BUB1 mutations cause a neurodevelopmental disorder, with clinical and cellular phenotypes that partially resemble previously described syndromes, including autosomal recessive primary microcephaly, mosaic variegated aneuploidy, and cohesinopathies.info:eu-repo/semantics/publishedVersio
A multicomponent prehabilitation pathway to reduce the incidence of delirium in elderly patients in need of major abdominal surgery
__Background:__ Due to the increase in elderly patients who undergo major abdominal surgery there is a subsequent
increase in postoperative complications, prolonged hospital stays, health-care costs and mortality rates. Delirium is
Assessing the Dutch energy transition policy: how does it deal with dilemmas of managing transitions?
ABSTRACT In the Netherlands, the national government is committed towards altering the systems of energy, transport and agriculture in the name of sustainable development. A process of deliberation and change was started\xe2\x80\x94aimed at achieving \xe2\x80\x98transitions\xe2\x80\x99\xe2\x80\x94using a model of transition management. This paper examines how the new arrangements of governance for energy transition deal with six problems of steering: ambivalence about goals, uncertainty about cause\xe2\x80\x93effect relations, distributed power of control, political myopia, determination of short-term steps for long-term change and the danger of lock-in to new systems. The Dutch experience shows that transition management is applied in ways different from the original model (established players play a too great role) but it appears a useful model of reflexive governance, combining advantages of incremental politics with those of planning. It helps to orientate innovation policy and sectoral policies to sustainable development goals and to exploit business interests in system innovations in a prudent manner
Observer variability of absolute and relative thrombus density measurements in patients with acute ischemic stroke
Introduction: Thrombus density may be a predictor for acute ischemic stroke treatment success. However, only limited data on observer variability for thrombus density measurements exist. This study assesses the variability and bias of four common thrombus density measurement methods by expert and non-expert observers. Methods: For 132 consecutive patients with acute ischemic stroke, three experts and two trained observers determined thrombus density by placing three standardized regions of interest (ROIs) in the thrombus and corresponding contralateral arterial segment. Subsequently, absolute and relative thrombus densities were determined using either one or three ROIs. Intraclass correlation coefficient (ICC) was determined, and BlandâAltman analysis was performed to evaluate interobserver and intermethod agreement. Accuracy of the trained observer was evaluated with a reference expert observer using the same statistical analysis. Results: The highest interobserver agreement was obtained for absolute thrombus measurements using three ROIs (ICCs ranging from 0.54 to 0.91). In general, interobserver agreement was lower for relative measurements, and for using one instead of three ROIs. Interobserver agreement of trained non-experts and experts was similar. Accuracy of the trained observer measurements was comparable to the expert interobserver agreement and was better for absolute measurements and with three ROIs. The agreement between the one ROI and three ROI methods was good. Conclusion: Absolute thrombus density measurement has superior interobserver agreement compared to relative density measurement. Interobserver variation is smaller when multiple ROIs are used. Trained non-expert observers can accurately and reproducibly assess absolute thrombus densities using three ROIs
Two-year clinical follow-up of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN): Design and statistical analysis plan of the extended follow-up study
Background: MR CLEAN was the first randomized trial to demonstrate the short-term clinical effectiveness of endovascular treatment in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation. Several other trials confirmed that endovascular treatment improves clinical outcome at three months. However, limited data are available on long-term clinical outcome. We aimed to estimate the effect of endovascular treatment on functional outcome at two-year follow-up in patients with acute ischemic stroke. Secondly, we aimed to assess the effect of endovascular treatment on major vascular events and mortality during two years of follow-up. Methods: MR CLEAN is a multicenter clinical trial with randomized treatment allocation, open-label treatment, and blinded endpoint evaluation. Patients included were 18 years or older with acute ischemic stroke caused by a proven anterior proximal artery occlusion who could be treated within six hours after stroke onset. The intervention contrast was endovascular treatment and usual care versus no endovascular treatment and usual care. The current study extended the follow-up duration from three months to two years. The primary outcome is the score on the modified Rankin scale at two years. Secondary outcomes include all-cause mortality and the occurrence of major vascular events within two years of follow-up. Discussion: The results of our study provide information on the long-term clinical effectiveness of endovascular treatment, which may have implications for individual treatment decisions and estimates of cost-effectiveness. Trial registration:NTR1804. Registered on 7 May 2009; ISRCTN10888758. Registered on 24 July 2012 (main MR CLEAN trial); NTR5073. Registered on 26 February 2015 (extended follow-up study)
Automated entire thrombus density measurements for robust and comprehensive thrombus characterization in patients with acute ischemic stroke
Background and Purpose: In acute ischemic stroke (AIS) management, CT-based thrombus density has been associated with treatment success. However, currently used thrombus measurements are prone to inter-observer variability and oversimplify the heterogeneous thrombus composition. Our aim was first to introduce an automated method to assess the entire thrombus density and then to compare the measured entire thrombus density with respect to current standard manual measurements. Materials and Method: In 135 AIS patients, the density distribution of the entire thrombus was determined. Density distributions were described usingmedians, interquartile ranges (IQR), kurtosis, and skewedness. Differences between themedian of entire thrombusmeasurements and commonly applied manualmeasurements using 3 regions of interest were determined using linear regression. Results: Density distributions varied considerably with medians ranging from 20.0 to 62.8 HU and IQRs ranging from 9.3 to 55.8 HU. The average median of the thrombus density distributions (43.5 ± 10.2 HU) was lower than the manual assessment (49.6 ± 8.0 HU) (p<0.05). The difference between manual measurements and median density of entire thrombus decreased with increasing density (r = 0.64; p<0.05), revealing relatively higher manual measurements for low density thrombi such that manual density measurement tend overestimates the real thrombus density. Conclusions: Automatic measurements of the full thrombus expose a wide variety of thrombi density distribution, which is not grasped with currently used manual measurement. Furthermore, d
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Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers.
BACKGROUND: The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. METHODS: Eye-tracking data were collected from 486 6-to-30-year-old autistic (Nâ=â282) and non-autistic control (Nâ=â204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). RESULTS: The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. LIMITATIONS: The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. CONCLUSIONS: Biological motion preference elicits small-to-medium-sized case-control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear
Differences in Intrinsic Gray-Matter Connectivity and their genomic underpinnings in Autism Spectrum Disorder
Patterns of connectome variability in autism across five functional activation tasks:Findings from the LEAP project
Joint Constraints on Galactic Diffuse Neutrino Emission from the ANTARES and IceCube Neutrino Telescopes
[EN] The existence of diffuse Galactic neutrino production is expected from cosmic-ray interactions with Galactic gas and radiation Âżelds. Thus, neutrinos are a unique messenger offering the opportunity to test the products of Galactic cosmic-ray interactions up to energies of hundreds of TeV. Here we present a search for this production using ten years of Astronomy with a Neutrino Telescope and Abyss environmental RESearch (ANTARES) track and shower data, as well as seven years of IceCube track data. The data are combined into a joint likelihood test for neutrino emission according to the KRAg model assuming a 5 PeV per nucleon Galactic cosmic-ray cutoff. No signiÂżcant excess is found. As a consequence, the limits presented in this Letter start constraining the model parameter space for Galactic cosmic-ray production and transport.Albert, A.; Andre, M.; Anghinolfi, M.; Ardid RamĂrez, M.; Aubert, J-.; Aublin, J.; Avgitas, T.... (2018). Joint Constraints on Galactic Diffuse Neutrino Emission from the ANTARES and IceCube Neutrino Telescopes. The Astrophysical Journal. 868(2):1-7. https://doi.org/10.3847/2041-8213/aaeecfS178682Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., ⊠Anderson, T. (2017). Search for Astrophysical Sources of Neutrinos Using Cascade Events in IceCube. The Astrophysical Journal, 846(2), 136. doi:10.3847/1538-4357/aa8508Aartsen, M. G., Abraham, K., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., ⊠Archinger, M. (2015). A COMBINED MAXIMUM-LIKELIHOOD ANALYSIS OF THE HIGH-ENERGY ASTROPHYSICAL NEUTRINO FLUX MEASURED WITH ICECUBE. The Astrophysical Journal, 809(1), 98. doi:10.1088/0004-637x/809/1/98Aartsen, M. G., Abraham, K., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., ⊠Anderson, T. (2017). All-sky Search for Time-integrated Neutrino Emission from Astrophysical Sources with 7 yr of IceCube Data. The Astrophysical Journal, 835(2), 151. doi:10.3847/1538-4357/835/2/151Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., ⊠Anderson, T. (2017). Constraints on Galactic Neutrino Emission with Seven Years of IceCube Data. The Astrophysical Journal, 849(1), 67. doi:10.3847/1538-4357/aa8dfbAartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., ⊠Ansseau, I. (2017). The IceCube Neutrino Observatory: instrumentation and online systems. Journal of Instrumentation, 12(03), P03012-P03012. doi:10.1088/1748-0221/12/03/p03012Ackermann, M., Ajello, M., Atwood, W. B., Baldini, L., Ballet, J., Barbiellini, G., ⊠Berenji, B. (2012). FERMI-LAT OBSERVATIONS OF THE DIFFUSE Îł-RAY EMISSION: IMPLICATIONS FOR COSMIC RAYS AND THE INTERSTELLAR MEDIUM. The Astrophysical Journal, 750(1), 3. doi:10.1088/0004-637x/750/1/3AdriĂĄn-MartĂnez, S., Ageron, M., Aguilar, J. A., Samarai, I. A., Albert, A., AndrĂ©, M., ⊠Ardid, M. (2012). The positioning system of the ANTARES Neutrino Telescope. Journal of Instrumentation, 7(08), T08002-T08002. doi:10.1088/1748-0221/7/08/t08002Ageron, M., Aguilar, J. A., Al Samarai, I., Albert, A., Ameli, F., AndrĂ©, M., ⊠Ardid, M. (2011). ANTARES: The first undersea neutrino telescope. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 656(1), 11-38. doi:10.1016/j.nima.2011.06.103Ahn, H. S., Allison, P., Bagliesi, M. G., Beatty, J. J., Bigongiari, G., Childers, J. T., ⊠Zinn, S. Y. (2010). DISCREPANT HARDENING OBSERVED IN COSMIC-RAY ELEMENTAL SPECTRA. The Astrophysical Journal, 714(1), L89-L93. doi:10.1088/2041-8205/714/1/l89Albert, A., AndrĂ©, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., ⊠Basa, S. (2017). New constraints on all flavor Galactic diffuse neutrino emission with the ANTARES telescope. Physical Review D, 96(6). doi:10.1103/physrevd.96.062001Antoni, T., Apel, W. D., Badea, A. F., Bekk, K., Bercuci, A., BlĂŒmer, J., ⊠Zabierowski, J. (2005). KASCADE measurements of energy spectra for elemental groups of cosmic rays: Results and open problems. Astroparticle Physics, 24(1-2), 1-25. doi:10.1016/j.astropartphys.2005.04.001Apel, W. D., Arteaga-VelĂĄzquez, J. C., Bekk, K., Bertaina, M., BlĂŒmer, J., Bozdog, H., ⊠Cossavella, F. (2013). KASCADE-Grande measurements of energy spectra for elemental groups of cosmic rays. Astroparticle Physics, 47, 54-66. doi:10.1016/j.astropartphys.2013.06.004Gaggero, D., Grasso, D., Marinelli, A., Taoso, M., & Urbano, A. (2017). Diffuse Cosmic Rays Shining in the Galactic Center: A Novel Interpretation of H.E.S.S. and Fermi-LAT
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-Ray Data. Physical Review Letters, 119(3). doi:10.1103/physrevlett.119.031101Gaggero, D., Grasso, D., Marinelli, A., Urbano, A., & Valli, M. (2015). THE GAMMA-RAY AND NEUTRINO SKY: A CONSISTENT PICTURE OF
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-LAT, MILAGRO, AND ICECUBE RESULTS. The Astrophysical Journal, 815(2), L25. doi:10.1088/2041-8205/815/2/l25Gaggero, D., Urbano, A., Valli, M., & Ullio, P. (2015). Gamma-ray sky points to radial gradients in cosmic-ray transport. Physical Review D, 91(8). doi:10.1103/physrevd.91.083012Vladimirov, A. E., Digel, S. W., Jóhannesson, G., Michelson, P. F., Moskalenko, I. V., Nolan, P. L., ⊠Strong, A. W. (2011). GALPROP WebRun: An internet-based service for calculating galactic cosmic ray propagation and associated photon emissions. Computer Physics Communications, 182(5), 1156-1161. doi:10.1016/j.cpc.2011.01.01
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