| 1. |
- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 4. |
- Khatri, C, et al.
(författare)
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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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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Tidskriftsartikel (refereegranskat)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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| 5. |
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| 6. |
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| 7. |
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| 8. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 9. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Akkoyun, S., et al.
(författare)
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AGATA - Advanced GAmma Tracking Array
- 2012
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Ingår i: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002 .- 0167-5087 .- 1872-9576. ; 668, s. 26-58
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced GAmma Tracking Array (AGATA) is a European project to develop and operate the next generation γ-ray spectrometer. AGATA is based on the technique of γ-ray energy tracking in electrically segmented high-purity germanium crystals. This technique requires the accurate determination of the energy, time and position of every interaction as a γ ray deposits its energy within the detector volume. Reconstruction of the full interaction path results in a detector with very high efficiency and excellent spectral response. The realisation of γ-ray tracking and AGATA is a result of many technical advances. These include the development of encapsulated highly segmented germanium detectors assembled in a triple cluster detector cryostat, an electronics system with fast digital sampling and a data acquisition system to process the data at a high rate. The full characterisation of the crystals was measured and compared with detector- response simulations. This enabled pulse-shape analysis algorithms, to extract energy, time and position, to be employed. In addition, tracking algorithms for event reconstruction were developed. The first phase of AGATA is now complete and operational in its first physics campaign. In the future AGATA will be moved between laboratories in Europe and operated in a series of campaigns to take advantage of the different beams and facilities available to maximise its science output. The paper reviews all the achievements made in the AGATA project including all the necessary infrastructure to operate and support the spectrometer. © 2011 Elsevier B.V. All rights reserved.
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| 11. |
- Clement, E., et al.
(författare)
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Conceptual design of the AGATA 1 π array at GANIL
- 2017
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 855, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced GAmma Tracking Array (AGATA) has been installed at the GANIL facility, Caen-France. This setup exploits the stable and radioactive heavy-ions beams delivered by the cyclotron accelerator complex of GANIL. Additionally, it benefits from a large palette of ancillary detectors and spectrometers to address in-beam γ-ray spectroscopy of exotic nuclei. The set-up has been designed to couple AGATA with a magnetic spectrometer, charged-particle and neutron detectors, scintillators for the detection of high-energy γ rays and other devices such as a plunger to measure nuclear lifetimes. In this paper, the design and the mechanical characteristics of the set-up are described. Based on simulations, expected performances of the AGATA l π array are presented.
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| 12. |
- Siciliano, M., et al.
(författare)
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Pairing-quadrupole interplay in the neutron-deficient tin nuclei : First lifetime measurements of low-lying states in Sn-106,Sn-108
- 2020
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Ingår i: Physics Letters B. - : ELSEVIER. - 0370-2693 .- 1873-2445. ; 806
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Tidskriftsartikel (refereegranskat)abstract
- The lifetimes of the low-lying excited states 2(+) and 4(+) have been directly measured in the neutron-deficient Sn-106,Sn-108 isotopes. The nuclei were populated via a deep-inelastic reaction and the lifetime measurement was performed employing a differential plunger device. The emitted gamma rays were detected by the AGATA array, while the reaction products were uniquely identified by the VAMOS++ magnetic spectrometer. Large-Scale Shell-Model calculations with realistic forces indicate that, independently of the pairing content of the interaction, the quadrupole force is dominant in the B(E2; 2(1)(+) -> 0(g.s)(+)) values and it describes well the experimental pattern for Sn104-114 ; the B(E2;(+)(4) -> 2(1)(+)) values, measured here for the first time, depend critically on a delicate pairing-quadrupole balance, disclosed by the very precise results in Sn-108.
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| 13. |
- Modamio, V., et al.
(författare)
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Digital pulse-timing technique for the neutron detector array NEDA
- 2015
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 775, s. 71-76
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Tidskriftsartikel (refereegranskat)abstract
- A new digital pulse-timing algorithm, to be used with the future neutron detector array NEDA, has been developed and tested. The time resolution of four 5 in diameter photomultiplier tubes (XP4512, R4144, R11833-100, and ET9390-kb), coupled to a cylindrical 5 in by 5 in BC501A liquict scintillator detector was measured by employing digital sampling electronics and a constant fraction discriminator (CFD) algorithm. The zero crossing of the CM algorithm was obtained with a cubic spline interpolation, which was continuous up to the second derivative. The performance of the algorithm was studied at sampling rates of 500 MS/s and 200 MS/s. The time resolution obtained with the digital electronics was compared to the values acquired with a standard analog CFD. The result of this comparison shows that the time resolution from the analog and the digital measurements at 500 MS/s and at 200 MS/s are within 15% for all the tested photomultiplier tubes.
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| 14. |
- Valiente-Dobon, J. J., et al.
(författare)
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NEDA-NEutron Detector Array
- 2019
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 927, s. 81-86
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Tidskriftsartikel (refereegranskat)abstract
- The NEutron Detector Array, NEDA, will form the next generation neutron detection system that has been designed to be operated in conjunction with gamma-ray arrays, such as the tracking-array AGATA, to aid nuclear spectroscopy studies. NEDA has been designed to be a versatile device, with high-detection efficiency, excellent neutron-gamma discrimination, and high rate capabilities. It will be employed in physics campaigns in order to maximise the scientific output, making use of the different stable and radioactive ion beams available in Europe. The first implementation of the neutron detector array NEDA with AGATA 1 pi was realised at GANIL. This manuscript reviews the various aspects of NEDA.
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| 15. |
- Jaworski, G., et al.
(författare)
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Monte Carlo simulation of a single detector unit for the neutron detector array NEDA
- 2012
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 673, s. 64-72
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Tidskriftsartikel (refereegranskat)abstract
- A study of the dimensions and performance of a single detector of the future neutron detector array NEDA was performed by means of Monte Carlo simulations, using GEANT4. Two different liquid scintillators were evaluated: the hydrogen based BC501A and the deuterated BC537. The efficiency and the probability that one neutron will trigger a signal in more than one detector were investigated as a function of the detector size. The simulations were validated comparing the results to experimental measurements performed with two existing neutron detectors, with different geometries, based on the liquid scintillator BC501
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| 16. |
- Jaworski, G., et al.
(författare)
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The New Neutron Multiplicity Filter NEDA and Its First Physics Campaign with AGATA
- 2019
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Ingår i: Acta Physica Polonica B. - 0587-4254 .- 1509-5770. ; 50:3, s. 585-590
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Tidskriftsartikel (refereegranskat)abstract
- A new neutron multiplicity filter NEDA, after a decade of design, R&D and construction, was employed in its first physics campaign with the AGATA spectrometer. Properties and performance of the array are discussed.
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| 17. |
- Luo, X. L., et al.
(författare)
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Pulse pile-up identification and reconstruction for liquid scintillator based neutron detectors
- 2018
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : ELSEVIER SCIENCE BV. - 0168-9002 .- 1872-9576. ; 897, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- The issue of pulse pile-up is frequently encountered in nuclear experiments involving high counting rates, which will distort the pulse shapes and the energy spectra. A digital method of off-line processing of pile-up pulses is presented. The pile-up pulses were firstly identified by detecting the downward-going zero-crossings in the first-order derivative of the original signal, and then the constituent pulses were reconstructed based on comparing the pile-up pulse with four models that are generated by combining pairs of neutron and.. standard pulses together with a controllable time interval. The accuracy of this method in resolving the pile-up events was investigated as a function of the time interval between two pulses constituting a pile-up event. The obtained results show that the method is capable of disentangling two pulses with a time interval among them down to 20 ns, as well as classifying them as neutrons or gamma rays. Furthermore, the error of reconstructing pile-up pulses could be kept below 6% when successive peaks were separated by more than 50 ns. By applying the method in a high counting rate of pile-up events measurement of the NEutron Detector Array (NEDA), it was empirically found that this method can reconstruct the pile-up pulses and perform neutron-gamma discrimination quite accurately. It can also significantly correct the distorted pulse height spectrum due to pile-up events.
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| 18. |
- Luo, X. L., et al.
(författare)
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Test of digital neutron-gamma discrimination with four different photomultiplier tubes for the NEutron Detector Array (NEDA)
- 2014
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 767, s. 83-91
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Tidskriftsartikel (refereegranskat)abstract
- A comparative study of the neutron-gamma discrimination performance of a liquid scintillator detector BC501A coupled to four different 5 in photomultiplier tubes (ET9390kb, R11833-100, XP4512 and R4144) was carried out Both the Charge Comparison method and the Integrated Rise-Time method were implemented digitally to discriminate between neutrons and gamma rays emitted by a Cf-252 source. In both methods, the neutron-gamma discrimination capabilities of the four photomultiplier tubes were quantitatively compared by evaluating their figure-of-merit values at different energy regions between 50 keVee and 1000 keVee. Additionally, the results were further verified qualitatively using time-of-flight to distinguish gamma rays and neutrons. The results consistently show that photomultiplier tubes R11833-100 and ET9390kb generally perform best regarding neutron-gamma discrimination with only slight differences in figure-of-merit values. This superiority can be explained by their relatively higher photoelectron yield, which indicates that a scintillator detector coupled to a photomultiplier tube with higher photoelectron yield tends to result in better neutron-gamma discrimination performance. The results of this work will provide reference for the choice of photomultiplier tubes for future neutron detector arrays like NEDA.
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| 19. |
- Söderström, Pär-Anders, 1980-, et al.
(författare)
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Neutron detection and gamma-ray suppression using artificial neural networks with the liquid scintillators BC-501A and BC-537
- 2019
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : ELSEVIER SCIENCE BV. - 0168-9002 .- 1872-9576. ; 916, s. 238-245
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Tidskriftsartikel (refereegranskat)abstract
- In this work we present a comparison between the two liquid scintillators BC-501A and BC-537 in terms of their performance regarding the pulse-shape discrimination between neutrons and gamma rays. Special emphasis is put on the application of artificial neural networks. The results show a systematically higher gamma-ray rejection ratio for BC-501A compared to BC-537 applying the commonly used charge comparison method. Using the artificial neural network approach the discrimination quality was improved to more than 95% rejection efficiency of gamma rays over the energy range 150 to 1000 keV for both BC-501A and BC-537. However, due to the larger light output of BC-501A compared to BC-537, neutrons could be identified in BC-501A using artificial neural networks down to a recoil proton energy of 800 keV compared to a recoil deuteron energy of 1200 keV for BC-537. We conclude that using artificial neural networks it is possible to obtain the same gamma-ray rejection quality from both BC-501A and BC-537 for neutrons above a low-energy threshold. This threshold is, however, lower for BC-501A, which is important for nuclear structure spectroscopy experiments of rare reaction channels where low-energy interactions dominates.
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| 20. |
- Egea Canet, F. J., et al.
(författare)
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A New Front-End High-Resolution Sampling Board for the New-Generation Electronics of EXOGAM2 and NEDA Detectors
- 2015
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Ingår i: IEEE Transactions on Nuclear Science. - 0018-9499 .- 1558-1578. ; 62:3, s. 1056-1062
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents the final design and results of the FADC Mezzanine for the EXOGAM (EXOtic GAMma array spectrometer) and NEDA (Neutron Detector Array) detectors. The measurements performed include those of studying the effective number of bits, the energy resolution using HP-Ge detectors, as well as timing histograms and discrimination performance. Finally, the conclusion shows how a common digitizing device has been integrated in the experimental environment of two very different detectors which combine both low-noise acquisition and fast sampling rates. Not only the integration fulfilled the expected specifications on both systems, but it also showed how a study of synergy between detectors could lead to the reduction of resources and time by applying a common strategy.
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| 21. |
- Egea Canet, F. J., et al.
(författare)
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Digital Front-End Electronics for the Neutron Detector NEDA
- 2015
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Ingår i: IEEE Transactions on Nuclear Science. - 0018-9499 .- 1558-1578. ; 62:3, s. 1063-1069
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents the design of the NEDA (Neutron Detector Array) electronics, a first attempt to involve the use of digital electronics in large neutron detector arrays. Starting from the front-end modules attached to the PMTs (PhotoMultiplier Tubes) and ending up with the data processing workstations, a comprehensive electronic system capable of dealing with the acquisition and pre-processing of the neutron array is detailed. Among the electronic modules required, we emphasize the front-end analog processing, the digitalization, digital pre-processing and communications firmware, as well as the integration of the GTS (Global Trigger and Synchronization) system, already used successfully in AGATA (Advanced Gamma Tracking Array). The NEDA array will be available for measurements in 2016.
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| 22. |
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| 23. |
- De las Cuevas, Carlos, et al.
(författare)
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Revealing the reporting disparity : VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK
- 2024
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Ingår i: Schizophrenia Research. - : Elsevier. - 0920-9964 .- 1573-2509. ; 268, s. 175-188
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs).Objective: In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality.Methods: VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions.Results: The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label “death” was the top cause in the world (46 %) and in the UK (33 %). “Pneumonia” was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1–10 % of the UK clozapine fatal outcome number.Conclusions: Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.
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| 24. |
- Javier Egea, Francisco, et al.
(författare)
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Design and Test of a High-Speed Flash ADC Mezzanine Card for High-Resolution and Timing Performance in Nuclear Structure Experiments
- 2013
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Ingår i: IEEE Transactions on Nuclear Science. - 0018-9499 .- 1558-1578. ; 60:5, s. 3526-3531
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Tidskriftsartikel (refereegranskat)abstract
- This work describes new electronics for the EX-OGAM2 (HP-Ge detector array) and NEDA (BC501A-based neutron detector array). A new digitizing card with high resolution has been designed for gamma-ray and neutron spectroscopy experiments. The higher bandwidth requirement of the NEDA signals, together with the necessity for accuracy, require a high sampling rate in order to preserve the shape for real-time Pulse Shape Analysis (PSA). The PSA is of paramount importance for the NEDA to discriminate between neutrons and gamma-ray signals. Both high resolution and high speed parameters are often difficult to achieve in a single electronic unit. These constraints, together with the need to build new digitizing electronics to improve performance and flexibility of signal analysis in nuclear physics experiments, led to the development a new FADC mezzanine card. In this work, the design and development are described, including the characterization procedure and the preliminary measurement results.
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| 25. |
- Liddelow, S. A., et al.
(författare)
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Mechanisms That Determine the Internal Environment of the Developing Brain: A Transcriptomic, Functional and Ultrastructural Approach
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- We provide comprehensive identification of embryonic (E15) and adult rat lateral ventricular choroid plexus transcriptome, with focus on junction-associated proteins, ionic influx transporters and channels. Additionally, these data are related to new structural and previously published permeability studies. Results reveal that most genes associated with intercellular junctions are expressed at similar levels at both ages. In total, 32 molecules known to be associated with brain barrier interfaces were identified. Nine claudins showed unaltered expression, while two claudins (6 and 8) were expressed at higher levels in the embryo. Expression levels for most cytoplasmic/regulatory adaptors (10 of 12) were similar at the two ages. A few junctional genes displayed lower expression in embryos, including 5 claudins, occludin and one junctional adhesion molecule. Three gap junction genes were enriched in the embryo. The functional effectiveness of these junctions was assessed using blood-delivered water-soluble tracers at both the light and electron microscopic level: embryo and adult junctions halted movement of both 286Da and 3kDa molecules into the cerebrospinal fluid (CSF). The molecular identities of many ion channel and transporter genes previously reported as important for CSF formation and secretion in the adult were demonstrated in the embryonic choroid plexus (and validated with immunohistochemistry of protein products), but with some major age-related differences in expression. In addition, a large number of previously unidentified ion channel and transporter genes were identified for the first time in plexus epithelium. These results, in addition to data obtained from electron microscopical and physiological permeability experiments in immature brains, indicate that exchange between blood and CSF is mainly transcellular, as well-formed tight junctions restrict movement of small water-soluble molecules from early in development. These data strongly indicate the brain develops within a well-protected internal environment and the exchange between the blood, brain and CSF is transcellular and not through incomplete barriers.
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| 26. |
- Moreno-Càceres, J, et al.
(författare)
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Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17
- 2014
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Transforming growth factor-beta (TGF-β) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-β in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-β receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-β-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1(-/-) hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-β, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-β-induced survival signals in Cav1(-/-) hepatocytes, such as AKT and ERK1/2 phosphorylation and NFκ-B activation. Transactivation of the EGFR pathway by TGF-β was impaired in Cav1(-/-) hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1(-/-) hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1(+/+) cells, which was not the case in Cav1(-/-) cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-β treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-β-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-β pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-β in liver cancer cells.
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| 27. |
- Moretti, R., et al.
(författare)
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Melatonin reduces excitotoxic blood-brain barrier breakdown in neonatal rats
- 2015
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522. ; 311, s. 382-397
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Tidskriftsartikel (refereegranskat)abstract
- The blood-brain barrier (BBB) is a complex structure that protects the central nervous system from peripheral insults. Understanding the molecular basis of BBB function and dysfunction holds significant potential for future strategies to prevent and treat neurological damage. The aim of our study was (1) to investigate BBB alterations following excitotoxicity and (2) to test the protective properties of melatonin.Ibotenate, a glutamate analog, was injected intracerebrally in postnatal day 5 (P5) rat pups to mimic excitotoxic injury. Animals were than randomly divided into two groups, one receiving intraperitoneal (i.p.) melatonin injections (5. mg/kg), and the other phosphate buffer saline (PBS) injections. Pups were sacrificed 2, 4 and 18. h after ibotenate injection. We determined lesion size at 5. days by histology, the location and organization of tight junction (TJ) proteins by immunohistochemical studies, and BBB leakage by dextran extravasation. Expression levels of BBB genes (TJs, efflux transporters and detoxification enzymes) were determined in the cortex and choroid plexus by quantitative PCR.Dextran extravasation was seen 2. h after the insult, suggesting a rapid BBB breakdown that was resolved by 4. h. Extravasation was significantly reduced in melatonin-treated pups. Gene expression and immunohistochemical assays showed dynamic BBB modifications during the first 4. h, partially prevented by melatonin. Lesion-size measurements confirmed white matter neuroprotection by melatonin.Our study is the first to evaluate BBB structure and function at a very early time point following excitotoxicity in neonates. Melatonin neuroprotects by preventing TJ modifications and BBB disruption at this early phase, before its previously demonstrated anti-inflammatory, antioxidant and axonal regrowth-promoting effects. © 2015 IBRO.
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| 28. |
- Segura-Egea, J. J., et al.
(författare)
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Antibiotics in Endodontics: a review
- 2017
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Ingår i: International Endodontic Journal. - : Wiley. - 0143-2885. ; 50:12, s. 1169-1184
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Forskningsöversikt (refereegranskat)abstract
- The overuse of antibiotics and the emergence of antibiotic-resistant bacterial strains is a global concern. This concern is also of importance in terms of the oral microbiota and the use of antibiotics to deal with oral and dental infections. The aim of this paper was to review the current literature on the indications and use of antibiotics and to make recommendations for their prescription in endodontic patients. Odontogenic infections, including endodontic infections, are polymicrobial, and in most cases, the prescription of antibiotics is empirical. This has led to the increasing use of broad-spectrum antibiotics even in cases where antibiotics are not indicated, such as symptomatic irreversible pulpitis, necrotic pulps and localized acute apical abscesses. In case of discrete and localized swelling, the primary aim is to achieve drainage without additional antibiotics. Adjunctive antibiotic treatment may be necessary in the prevention of the spread of infection, in acute apical abscesses with systemic involvement and in progressive and persistent infections. Medically compromised patients are more susceptible to complication arising from odontogenic infections and antimicrobials have a more specific role in their treatment. Therefore, antibiotics should be considered in patients having systemic diseases with compromised immunity or in patients with a localized congenital or acquired altered defence capacity, such as patients with infective endocarditis, prosthetic cardiac valves or recent prosthetic joint replacement. Penicillin VK, possibly combined with metronidazole to cover anaerobic strains, is still effective in most cases. However, amoxicillin (alone or together with clavulanic acid) is recommended because of better absorption and lower risk of side effects. In case of confirmed penicillin allergy, lincosamides such as clindamycin are the drug of choice. BOTT PV, 1989, ENDODONTICS & DENTAL TRAUMATOLOGY, V5, P92 BOTT PV, 1990, AUSTRALIAN DENTAL JOURNAL, V35, P50
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| 29. |
- Segura-Egea, J. J., et al.
(författare)
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European Society of Endodontology position statement: the use of antibiotics in endodontics
- 2018
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Ingår i: International Endodontic Journal. - : Wiley. - 0143-2885 .- 1365-2591. ; 51:1, s. 20-25
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Forskningsöversikt (refereegranskat)abstract
- This position statement represents a consensus of an expert committee convened by the European Society of Endodontology (ESE) on Antibiotics in Endodontics. The statement is based on current scientific evidence as well as the expertise of the committee. The goal is to provide dentists and other healthcare workers with evidence-based criteria for when to use antibiotics in the treatment of endodontic infections, traumatic injuries of the teeth, revascularization procedures in immature teeth with pulp necrosis, and in prophylaxis for medically compromised patients. It also highlights the role that dentists and others can play in preventing the overuse of antibiotics. A recent review article provides the basis for this position statement and more detailed background information (International Endodontic Journal, 2017, https://doi.org/10.1111/iej.12741). Given the dynamic nature of research in this area, this position statement will be updated at appropriate intervals.
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| 30. |
- Ausili, A., et al.
(författare)
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Membrane docking mode of the C2 domain of PKCε: An infrared spectroscopy and FRET study
- 2013
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Ingår i: Biochimica et Biophysica Acta - Biomembranes. - : Elsevier BV. - 0005-2736. ; 1828:2, s. 552-560
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Tidskriftsartikel (refereegranskat)abstract
- The C2 domain of PKCε binds to negatively charged phospholipids but little is known so far about the docking orientation of this domain when it is bound. By using a FRET assay we have studied the binding of this domain to model membranes. We have also used ATR-Fourier transform infrared spectroscopy with polarized light (ATR-FTIR) to determine the docking mode by calculating the β-sandwich orientation when the domain is bound to different types of model membranes. The vesicle lipid compositions were: POPC/POPE/POPA (22:36:42) imitating the inner leaflet of a plasma membrane, POPC/POPA (50:50) in which POPE has been eliminated with respect to the former composition and POPC/POPE/CL (43:36:21) imitating the inner mitochondrial membrane. Results show that the β-sandwich of the PKCα-C2 domain is inclined at an angle α close to 45 to the membrane normal. Some differences were found with respect to the extent of binding as a function of phospholipid composition and small changes on secondary structure were only evident when the domain was bound to model membranes of POPC/POPA: in this case, the percentage of β-sheet of the C2 domain increases if compared with the secondary structure of the domain in the absence of vesicles. With respect to the β-sandwich orientation, when the domain is bound to POPC/POPE/CL membranes it forms an angle with the normal to the surface of the lipid bilayer (39) smaller than that one observed when the domain interacts with vesicles of POPC/POPA (49). © 2012 Elsevier B.V. All rights reserved.
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| 31. |
- Chavarría, Teresa, et al.
(författare)
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Differential, age-dependent MEK-ERK and PI3K-Akt activation by insulin acting as a survival factor during embryonic retinal development
- 2007
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Ingår i: Developmental Neurobiology. - : Wiley. - 1932-8451 .- 1932-846X. ; 67:13, s. 1777-1788
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Tidskriftsartikel (refereegranskat)abstract
- Programmed cell death is a genuine developmental process of the nervous system, affecting not only projecting neurons but also proliferative neuroepithelial cells and young neuroblasts. The embryonic chick retina has been employed to correlate in vivo and in vitro studies on cell death regulation. We characterize here the role of two major signaling pathways, PI3K-Akt and MEK-ERK, in controlled retinal organotypic cultures from embryonic day 5 (E5) and E9, when cell death preferentially affects proliferating neuroepithelial cells and ganglion cell neurons, respectively. The relative density of programmed cell death in vivo was much higher in the proliferative and early neurogenic stages of retinal development (E3-E5) than during neuronal maturation and synaptogenesis (E8-E19). In organotypic cultures from E5 and E9 retinas, insulin, as the only growth factor added, was able to completely prevent cell death induced by growth factor deprivation. Insulin activated both the PI3K-Akt and the MEK-ERK pathways. Insulin survival effect, however, was differentially blocked at the two stages. At E5, the effect was blocked by MEK inhibitors, whereas at E9 it was blocked by PI3K inhibitors. The cells which were found to be dependent on insulin activation of the MEK-ERK pathway at E5 were mostly proliferative neuroepithelial cells. These observations support a remarkable specificity in the regulation of early neural cell death.
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| 32. |
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| 33. |
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| 34. |
- Guillén, Yolanda, et al.
(författare)
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Genomics of ecological adaptation in cactophilic Drosophila.
- 2014
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Ingår i: Genome Biology and Evolution. - : Oxford University Press (OUP). - 1759-6653. ; 7:1, s. 349-66
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Tidskriftsartikel (refereegranskat)abstract
- Cactophilic Drosophila species provide a valuable model to study gene-environment interactions and ecological adaptation. Drosophila buzzatii and Drosophila mojavensis are two cactophilic species that belong to the repleta group, but have very different geographical distributions and primary host plants. To investigate the genomic basis of ecological adaptation, we sequenced the genome and developmental transcriptome of D. buzzatii and compared its gene content with that of D. mojavensis and two other noncactophilic Drosophila species in the same subgenus. The newly sequenced D. buzzatii genome (161.5 Mb) comprises 826 scaffolds (>3 kb) and contains 13,657 annotated protein-coding genes. Using RNA sequencing data of five life-stages we found expression of 15,026 genes, 80% protein-coding genes, and 20% noncoding RNA genes. In total, we detected 1,294 genes putatively under positive selection. Interestingly, among genes under positive selection in the D. mojavensis lineage, there is an excess of genes involved in metabolism of heterocyclic compounds that are abundant in Stenocereus cacti and toxic to nonresident Drosophila species. We found 117 orphan genes in the shared D. buzzatii-D. mojavensis lineage. In addition, gene duplication analysis identified lineage-specific expanded families with functional annotations associated with proteolysis, zinc ion binding, chitin binding, sensory perception, ethanol tolerance, immunity, physiology, and reproduction. In summary, we identified genetic signatures of adaptation in the shared D. buzzatii-D. mojavensis lineage, and in the two separate D. buzzatii and D. mojavensis lineages. Many of the novel lineage-specific genomic features are promising candidates for explaining the adaptation of these species to their distinct ecological niches.
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| 35. |
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| 36. |
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| 37. |
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| 38. |
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| 39. |
- Mottahedin, Amin, et al.
(författare)
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N-acetylcysteine inhibits bacterial lipopeptide-mediated neutrophil transmigration through the choroid plexus in the developing brain
- 2020
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The etiology of neurological impairments associated with prematurity and other perinatal complications often involves an infectious or pro-inflammatory component. The use of antioxidant molecules have proved useful to protect the neonatal brain from injury. The choroid plexuses-CSF system shapes the central nervous system response to inflammation at the adult stage, but little is known on the neuroimmune interactions that take place at the choroidal blood-CSF barrier during development. We previously described that peripheral administration to neonatal mice of the TLR2 ligand PAM3CSK4 (P3C), a prototypic Gram-positive bacterial lipopeptide, induces the migration of innate immune cells to the CSF. Here we showed in neonatal rats exposed to P3C that the migration of neutrophils into the CSF, which occurred through the choroid plexuses, is abolished following administration of the antioxidant drug N-acetylcysteine. Combining light sheet microscopy imaging of choroid plexus, a differentiated model of the blood-CSF barrier, and multiplex cytokine assays, we showed that the choroidal epithelium responds to the bacterial insult by a specific pattern of cytokine secretion, leading to a selective accumulation of neutrophils in the choroid plexus and to their trafficking into CSF. N-acetylcysteine acted by blocking neutrophil migration across both the endothelium of choroidal stromal vessels and the epithelium forming the blood-CSF barrier, without interfering with neutrophil blood count, neutrophil tropism for choroid plexus, and choroidal chemokine-driven chemotaxis. N-acetylcysteine reduced the injury induced by hypoxia-ischemia in P3C-sensitized neonatal rats. Overall, the data show that a double endothelial and epithelial check point controls the transchoroidal migration of neutrophils into the developing brain. They also point to the efficacy of N-acetylcysteine in reducing the deleterious effects of inflammation-associated perinatal injuries by a previously undescribed mechanism, i.e. the inhibition of innate immune cell migration across the choroid plexuses, without interfering with the systemic inflammatory response to infection.
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| 40. |
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