| 1. |
- de Jong, R. S., et al.
(författare)
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4MOST : Project overview and information for the First Call for Proposals
- 2019
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Ingår i: The Messenger. - : European Southern Observatory. - 0722-6691. ; 175, s. 3-11
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We introduce the 4-metre Multi-Object Spectroscopic Telescope (4MOST), a new high-multiplex, wide-field spectroscopic survey facility under development for the four-metre-class Visible and Infrared Survey Telescope for Astronomy (VISTA) at Paranal. Its key specifications are: a large field of view (FoV) of 4.2 square degrees and a high multiplex capability, with 1624 fibres feeding two low-resolution spectrographs (R = λ/Δλ ~ 6500), and 812 fibres transferring light to the high-resolution spectrograph (R ~ 20 000). After a description of the instrument and its expected performance, a short overview is given of its operational scheme and planned 4MOST Consortium science; these aspects are covered in more detail in other articles in this edition of The Messenger. Finally, the processes, schedules, and policies concerning the selection of ESO Community Surveys are presented, commencing with a singular opportunity to submit Letters of Intent for Public Surveys during the first five years of 4MOST operations.
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| 2. |
- Ackermann, M., et al.
(författare)
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SEARCH FOR COSMIC-RAY-INDUCED GAMMA-RAY EMISSION IN GALAXY CLUSTERS
- 2014
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 787:1
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Tidskriftsartikel (refereegranskat)abstract
- Current theories predict relativistic hadronic particle populations in clusters of galaxies in addition to the already observed relativistic leptons. In these scenarios hadronic interactions give rise to neutral pions which decay into gamma rays that are potentially observable with the Large Area Telescope (LAT) on board the Fermi space telescope. We present a joint likelihood analysis searching for spatially extended gamma-ray emission at the locations of 50 galaxy clusters in four years of Fermi-LAT data under the assumption of the universal cosmic-ray (CR) model proposed by Pinzke & Pfrommer. We find an excess at a significance of 2.7 sigma, which upon closer inspection, however, is correlated to individual excess emission toward three galaxy clusters: A400, A1367, and A3112. We discuss these cases in detail and conservatively attribute the emission to unmodeled background systems (for example, radio galaxies within the clusters). Through the combined analysis of 50 clusters, we exclude hadronic injection efficiencies in simple hadronic models above 21% and establish limits on the CR to thermal pressure ratio within the virial radius, R-200, to be below 1.25%-1.4% depending on the morphological classification. In addition, we derive new limits on the gamma-ray flux from individual clusters in our sample.
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| 3. |
- Ackermann, M., et al.
(författare)
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Search for extended gamma-ray emission from the Virgo Galaxy Cluster with Fermi-LAT
- 2015
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Ingår i: Astrophysical Journal. - : Institute of Physics (IOP). - 0004-637X .- 1538-4357. ; 812:2
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Tidskriftsartikel (refereegranskat)abstract
- Galaxy clusters are one of the prime sites to search for dark matter (DM) annihilation signals. Depending on the substructure of the DM halo of a galaxy cluster and the cross sections for DM annihilation channels, these signals might be detectable by the latest generation of gamma-ray telescopes. Here we use three years of Fermi-Large Area Telescope data, which are the most suitable for searching for very extended emission in the vicinity of the nearby Virgo galaxy cluster. Our analysis reveals statistically significant extended emission which can be well characterized by a uniformly emitting disk profile with a radius of 3 degrees that moreover is offset from the cluster center. We demonstrate that the significance of this extended emission strongly depends on the adopted interstellar emission model (IEM) and is most likely an artifact of our incomplete description of the IEM in this region. We also search for and find new point source candidates in the region. We then derive conservative upper limits on the velocity-averaged DM pair annihilation cross section from Virgo. We take into account the potential gamma-ray flux enhancement due to DM sub-halos and its complex morphology as a merging cluster. For DM annihilating into b (b) over bar, assuming a conservative sub-halo model setup, we find limits that are between 1 and 1.5 orders of magnitude above the expectation from the thermal cross section for m(DM) <= 100 GeV. In a more optimistic scenario, we exclude similar to 3 x 10(-26)cm(3)s(-1) for m(DM)less than or similar to 40 GeV for the same channel. Finally, we derive upper limits on the gamma-ray-flux produced by hadronic cosmic-ray interactions in the inter cluster medium. We find that the volume-averaged cosmic-ray-to-thermal pressure ratio is less than similar to 6%.
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| 4. |
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| 5. |
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| 6. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 7. |
- Körber, R., et al.
(författare)
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SQUIDs in biomagnetism: A roadmap towards improved healthcare
- 2016
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Ingår i: Superconductors Science and Technology. - : IOP Publishing. - 0953-2048 .- 1361-6668. ; 29:11
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Tidskriftsartikel (refereegranskat)abstract
- Globally, the demand for improved health care delivery while managing escalating costs is a major challenge. Measuring the biomagnetic fields that emanate from the human brain already impacts the treatment of epilepsy, brain tumours and other brain disorders. This roadmap explores how superconducting technologies are poised to impact health care. Biomagnetism is the study of magnetic fields of biological origin. Biomagnetic fields are typically very weak, often in the femtotesla range, making their measurement challenging. The earliest in vivo human measurements were made with room-temperature coils. In 1963, Baule and McFee (1963 Am. Heart J. 55 95-6) reported the magnetic field produced by electric currents in the heart ('magnetocardiography'), and in 1968, Cohen (1968 Science 161 784-6) described the magnetic field generated by alpha-rhythm currents in the brain ('magnetoencephalography'). Subsequently, in 1970, Cohen et al (1970 Appl. Phys. Lett. 16 278-80) reported the recording of a magnetocardiogram using a Superconducting QUantum Interference Device (SQUID). Just two years later, in 1972, Cohen (1972 Science 175 664-6) described the use of a SQUID in magnetoencephalography. These last two papers set the scene for applications of SQUIDs in biomagnetism, the subject of this roadmap. The SQUID is a combination of two fundamental properties of superconductors. The first is flux quantization - the fact that the magnetic flux Φ in a closed superconducting loop is quantized in units of the magnetic flux quantum, Φ0 ≡ h/2e, ≈ 2.07 × 10-15 Tm2 (Deaver and Fairbank 1961 Phys. Rev. Lett. 7 43-6, Doll R and Nabauer M 1961 Phys. Rev. Lett. 7 51-2). Here, h is the Planck constant and e the elementary charge. The second property is the Josephson effect, predicted in 1962 by Josephson (1962 Phys. Lett. 1 251-3) and observed by Anderson and Rowell (1963 Phys. Rev. Lett. 10 230-2) in 1963. The Josephson junction consists of two weakly coupled superconductors separated by a tunnel barrier or other weak link. A tiny electric current is able to flow between the superconductors as a supercurrent, without developing a voltage across them. At currents above the 'critical current' (maximum supercurrent), however, a voltage is developed. In 1964, Jaklevic et al (1964 Phys. Rev. Lett. 12 159-60) observed quantum interference between two Josephson junctions connected in series on a superconducting loop, giving birth to the dc SQUID. The essential property of the SQUID is that a steady increase in the magnetic flux threading the loop causes the critical current to oscillate with a period of one flux quantum. In today's SQUIDs, using conventional semiconductor readout electronics, one can typically detect a change in Φ corresponding to 10-6 Φ0 in one second. Although early practical SQUIDs were usually made from bulk superconductors, for example, niobium or Pb-Sn solder blobs, today's devices are invariably made from thin superconducting films patterned with photolithography or even electron lithography. An extensive description of SQUIDs and their applications can be found in the SQUID Handbooks (Clarke and Braginski 2004 Fundamentals and Technology of SQUIDs and SQUID Systems vol I (Weinheim, Germany: Wiley-VCH), Clarke and Braginski 2006 Applications of SQUIDs and SQUID Systems vol II (Weinheim, Germany: Wiley-VCH)). The roadmap begins (chapter 1) with a brief review of the state-of-the-art of SQUID-based magnetometers and gradiometers for biomagnetic measurements. The magnetic field noise referred to the pick-up loop is typically a few fT Hz-1/2, often limited by noise in the metallized thermal insulation of the dewar rather than by intrinsic SQUID noise. The authors describe a pathway to achieve an intrinsic magnetic field noise as low as 0.1 fT Hz-1/2, approximately the Nyquist noise of the human body. They also descibe a technology to defeat dewar noise. Chapter 2 reviews the neuroscientific and clinical use of magnetoencephalography (MEG), by far the most widespread application of biomagnetism with systems containing ty ically 300 sensors cooled to liquid-helium temperature, 4.2 K. Two important clinical applications are presurgical mapping of focal epilepsy and of eloquent cortex in brain-tumor patients. Reducing the sensor-to-brain separation and the system noise level would both improve spatial resolution. The very recent commercial innovation that replaces the need for frequent manual transfer of liquid helium with an automated system that collects and liquefies the gas and transfers the liquid to the dewar will make MEG systems more accessible. A highly promising means of placing the sensors substantially closer to the scalp for MEG is to use high-transition-temperature (high-T c) SQUID sensors and flux transformers (chapter 3). Operation of these devices at liquid-nitrogen temperature, 77 K, enables one to minimize or even omit metallic thermal insulation between the sensors and the dewar. Noise levels of a few fT Hz-1/2 have already been achieved, and lower values are likely. The dewars can be made relatively flexible, and thus able to be placed close to the skull irrespective of the size of the head, potentially providing higher spatial resolution than liquid-helium based systems. The successful realization of a commercial high-T c MEG system would have a major commercial impact. Chapter 4 introduces the concept of SQUID-based ultra-low-field magnetic resonance imaging (ULF MRI) operating at typically several kHz, some four orders of magnitude lower than conventional, clinical MRI machines. Potential advantages of ULF MRI include higher image contrast than for conventional MRI, enabling methodologies not currently available. Examples include screening for cancer without a contrast agent, imaging traumatic brain injury (TBI) and degenerative diseases such as Alzheimer's, and determining the elapsed time since a stroke. The major current problem with ULF MRI is that its signal-to-noise ratio (SNR) is low compared with high-field MRI. Realistic solutions to this problem are proposed, including implementing sensors with a noise level of 0.1 fT Hz-1/2. A logical and exciting prospect (chapter 5) is to combine MEG and ULF MRI into a single system in which both signal sources are detected with the same array of SQUIDs. A prototype system is described. The combination of MEG and ULF MRI allows one to obtain structural images of the head concurrently with the recording of brain activity. Since all MEG images require an MRI to determine source locations underlying the MEG signal, the combined modality would give a precise registration of the two images; the combination of MEG with high-field MRI can produce registration errors as large as 5 mm. The use of multiple sensors for ULF MRI increases both the SNR and the field of view. Chapter 6 describes another potentially far-reaching application of ULF MRI, namely neuronal current imaging (NCI) of the brain. Currently available neuronal imaging techniques include MEG, which is fast but has relatively poor spatial resolution, perhaps 10 mm, and functional MRI (fMRI) which has a millimeter resolution but is slow, on the order of seconds, and furthermore does not directly measure neuronal signals. NCI combines the ability of direct measurement of MEG with the spatial precision of MRI. In essence, the magnetic fields generated by neural currents shift the frequency of the magnetic resonance signal at a location that is imaged by the three-dimensional magnetic field gradients that form the basis of MRI. The currently achieved sensitivity of NCI is not quite sufficient to realize its goal, but it is close. The realization of NCI would represent a revolution in functional brain imaging. Improved techniques for immunoassay are always being sought, and chapter 7 introduces an entirely new topic, magnetic nanoparticles for immunoassay. These particles are bio-funtionalized, for example with a specific antibody which binds to its corresponding antigen, if it is present. Any resulting changes in the properties of the nanoparticles are detected with a SQUID. For liquid-phase detection, there are three ba ic methods: AC susceptibility, magnetic relaxation and remanence measurement. These methods, which have been successfully implemented for both in vivo and ex vivo applications, are highly sensitive and, although further development is required, it appears highly likely that at least some of them will be commercialized. © 2016 IOP Publishing Ltd.
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| 8. |
- Dankiewicz, Josef, et al.
(författare)
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Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
- 2021
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Ingår i: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 384:24, s. 2283-2294
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Tidskriftsartikel (refereegranskat)abstract
- Hypothermia or Normothermia after Cardiac Arrest This trial randomly assigned patients with coma after out-of-hospital cardiac arrest to undergo targeted hypothermia at 33 degrees C or normothermia with treatment of fever. At 6 months, there were no significant between-group differences regarding death or functional outcomes. Background Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. Methods In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33 degrees C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, >= 37.8 degrees C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. Results A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P=0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score >= 4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. Conclusions In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, .)
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| 9. |
- Walcher, C.~J., et al.
(författare)
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4MOST Scientific Operations
- 2019
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Ingår i: Messenger. - 0722-6691. ; 175, s. 12-16
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The 4MOST instrument is a multi-object spectrograph that will address Galactic and extragalactic science cases simultaneously by observing targets from a large number of different surveys within each science exposure. This parallel mode of operation and the survey nature of 4MOST require some distinct 4MOST- specific operational features within the overall operations model of ESO. The main feature is that the 4MOST Consortium will deliver, not only the instrument, but also contractual services to the user community, which is why 4MOST is also described as a facility. This white paper concentrates on information particularly useful to answering the forthcoming Call for Letters of Intent.
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| 10. |
- Tempel, E., et al.
(författare)
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An optimized tiling pattern for multiobject spectroscopic surveys : Application to the 4MOST survey
- 2020
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 497:4, s. 4626-4643
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Tidskriftsartikel (refereegranskat)abstract
- Large multiobject spectroscopic surveys require automated algorithms to optimize their observing strategy. One of the most ambitious upcoming spectroscopic surveys is the 4MOST survey. The 4MOST survey facility is a fibre-fed spectroscopic instrument on the VISTA telescope with a large enough field of view to survey a large fraction of the southern sky within a few years. Several Galactic and extragalactic surveys will be carried out simultaneously, so the combined target density will strongly vary. In this paper, we describe a new tiling algorithm that can naturally deal with the large target density variations on the sky and which automatically handles the different exposure times of targets. The tiling pattern is modelled as a marked point process, which is characterized by a probability density that integrates the requirements imposed by the 4MOST survey. The optimal tilling pattern with respect to the defined model is estimated by the tiles configuration that maximizes the proposed probability density. In order to achieve this maximization a simulated annealing algorithm is implemented. The algorithm automatically finds an optimal tiling pattern and assigns a tentative sky brightness condition and exposure time for each tile, while minimizing the total execution time that is needed to observe the list of targets in the combined input catalogue of all surveys. Hence, the algorithm maximizes the long-term observing efficiency and provides an optimal tiling solution for the survey. While designed for the 4MOST survey, the algorithm is flexible and can with simple modifications be applied to any other multiobject spectroscopic survey.
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| 11. |
- Tempel, E., et al.
(författare)
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Probabilistic fibre-to-target assignment algorithm for multi-object spectroscopic surveys
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 635
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Tidskriftsartikel (refereegranskat)abstract
- Context. Several new multi-object spectrographs are currently planned or under construction that are capable of observing thousands of Galactic and extragalactic objects simultaneously. Aims. In this paper we present a probabilistic fibre-to-target assignment algorithm that takes spectrograph targeting constraints into account and is capable of dealing with multiple concurrent surveys. We present this algorithm using the 4-m Multi-Object Spectroscopic Telescope (4MOST) as an example. Methods. The key idea of the proposed algorithm is to assign probabilities to fibre-target pairs. The assignment of probabilities takes the fibre positioner's capabilities and constraints into account. Additionally, these probabilities include requirements from surveys and take the required exposure time, number density variation, and angular clustering of targets across each survey into account. The main advantage of a probabilistic approach is that it allows for accurate and easy computation of the target selection function for the different surveys, which involves determining the probability of observing a target, given an input catalogue. Results. The probabilistic fibre-to-target assignment allows us to achieve maximally uniform completeness within a single field of view. The proposed algorithm maximises the fraction of successfully observed targets whilst minimising the selection bias as a function of exposure time. In the case of several concurrent surveys, the algorithm maximally satisfies the scientific requirements of each survey and no specific survey is penalised or prioritised. Conclusions. The algorithm presented is a proposed solution for the 4MOST project that allows for an unbiased targeting of many simultaneous surveys. With some modifications, the algorithm may also be applied to other multi-object spectroscopic surveys.
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| 12. |
- Kamps, M. J. A., et al.
(författare)
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Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature
- 2013
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Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 39:10, s. 1671-1682
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Forskningsöversikt (refereegranskat)abstract
- To assess the sensitivity and false positive rate (FPR) of neurological examination and somatosensory evoked potentials (SSEPs) to predict poor outcome in adult patients treated with therapeutic hypothermia after cardiopulmonary resuscitation (CPR). MEDLINE and EMBASE were searched for cohort studies describing the association of clinical neurological examination or SSEPs after return of spontaneous circulation with neurological outcome. Poor outcome was defined as severe disability, vegetative state and death. Sensitivity and FPR were determined. A total of 1,153 patients from ten studies were included. The FPR of a bilaterally absent cortical N20 response of the SSEP could be calculated from nine studies including 492 patients. The SSEP had an FPR of 0.007 (confidence interval, CI, 0.001-0.047) to predict poor outcome. The Glasgow coma score (GCS) motor response was assessed in 811 patients from nine studies. A GCS motor score of 1-2 at 72 h had a high FPR of 0.21 (CI 0.08-0.43). Corneal reflex and pupillary reactivity at 72 h after the arrest were available in 429 and 566 patients, respectively. Bilaterally absent corneal reflexes had an FPR of 0.02 (CI 0.002-0.13). Bilaterally absent pupillary reflexes had an FPR of 0.004 (CI 0.001-0.03). At 72 h after the arrest the motor response to painful stimuli and the corneal reflexes are not a reliable tool for the early prediction of poor outcome in patients treated with hypothermia. The reliability of the pupillary response to light and the SSEP is comparable to that in patients not treated with hypothermia.
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| 13. |
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| 14. |
- Dankiewicz, Josef, et al.
(författare)
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Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial - Rationale and design
- 2019
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 217, s. 23-31
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Tidskriftsartikel (refereegranskat)abstract
- Background: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. Methods: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4–6) at 180 days after arrest. Discussion: The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest. © 2019
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| 15. |
- Guiglion, G., et al.
(författare)
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4MOST Survey Strategy Plan
- 2019
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Ingår i: Messenger. - 0722-6691. ; 175, s. 17-21
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The current status of and motivation for the 4MOST survey strategy, as developed by the Consortium science team, are presented here. Key elements of the strategy are described, such as sky coverage, number of visits and total exposure times in different parts of the sky, and how to deal with different observing conditions. The task of organising the strategy is not simple, with many different surveys that have vastly different target brightnesses and densities, sample completeness levels, and signal-to-noise requirements. We introduce here a number of concepts that we will use to ensure all surveys are optimised. Astronomers who are planning to submit a Participating Survey proposal are strongly encouraged to read this article and any relevant 4MOST Survey articles in this issue of The Messenger such that they can optimally complement and benefit from the planned surveys of the 4MOST Consortium.
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| 16. |
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| 17. |
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| 18. |
- Allemani, Claudia, et al.
(författare)
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Breast cancer survival in the US and Europe: a CONCORD high-resolution study
- 2013
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 132:5, s. 1170-1181
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study (CONCORD) found wide international differences in age-standardized survival. The aim of this study is to explain these survival differences. Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were collected for about 20,000 women diagnosed with breast cancer aged 15-99 years during 1996-98 in 7 US states and 12 European countries. Age-standardized net survival and the excess hazard of death up to 5 years after diagnosis were estimated by jurisdiction (registry, country, European region), age and stage with flexible parametric models. Breast cancers were generally less advanced in the US than in Europe. Stage also varied less between US states than between European jurisdictions. Early, node-negative tumors were more frequent in the US (39%) than in Europe (32%), while locally advanced tumors were twice as frequent in Europe (8%), and metastatic tumors of similar frequency (5-6%). Net survival in Northern, Western and Southern Europe (81-84%) was similar to that in the US (84%), but lower in Eastern Europe (69%). For the first 3 years after diagnosis the mean excess hazard was higher in Eastern Europe than elsewhere: the difference was most marked for women aged 70-99 years, and mainly confined to women with locally advanced or metastatic tumors. Differences in breast cancer survival between Europe and the US in the late 1990s were mainly explained by lower survival in Eastern Europe, where low healthcare expenditure may have constrained the quality of treatment.
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| 19. |
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| 20. |
- Basten, B., et al.
(författare)
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Modular language implementation in Rascal - experience report
- 2015
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Ingår i: Science of Computer Programming. - : Elsevier BV. - 0167-6423. ; 114, s. 7-19
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Tidskriftsartikel (refereegranskat)abstract
- All software evolves, and programming languages and programming language tools are no exception. And just like in ordinary software construction, modular implementations can help ease the process of changing a language implementation and its dependent tools. However, the syntactic and semantic dependencies between language features make this a challenging problem. In this paper we detail how programming languages can be implemented in a modular fashion using the RASCAL meta-programming language. RASCAL supports extensible definition of concrete syntax, abstract syntax and operations on concrete and abstract syntax trees like matching, traversal and transformation. As a result, new language features can be added without having to change existing code. As a case study, we detail our solution of the LDTA'11 Tool Challenge: a modular implementation of OBERON-0, a relatively simple imperative programming language. The approach we sketch can be applied equally well to the implementation of domain-specific languages.
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| 21. |
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| 22. |
- Burke, Adam, et al.
(författare)
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InAs Nanowire Transistors with Multiple, Independent Wrap-Gate Segments.
- 2015
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6992 .- 1530-6984. ; 15:5, s. 2836-2843
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Tidskriftsartikel (refereegranskat)abstract
- We report a method for making horizontal wrap-gate nanowire transistors with up to four independently controllable wrap-gated segments. While the step up to two independent wrap-gates requires a major change in fabrication methodology, a key advantage to this new approach, and the horizontal orientation more generally, is that achieving more than two wrap-gate segments then requires no extra fabrication steps. This is in contrast to the vertical orientation, where a significant subset of the fabrication steps needs to be repeated for each additional gate. We show that cross-talk between adjacent wrap-gate segments is negligible despite separations less than 200 nm. We also demonstrate the ability to make multiple wrap-gate transistors on a single nanowire using the exact same process. The excellent scalability potential of horizontal wrap-gate nanowire transistors makes them highly favorable for the development of advanced nanowire devices and possible integration with vertical wrap-gate nanowire transistors in 3D nanowire network architectures.
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| 23. |
- Carrad, Damon J., et al.
(författare)
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Electron-Beam Patterning of Polymer Electrolyte Films To Make Multiple Nanoscale Gates for Nanowire Transistors
- 2014
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6992 .- 1530-6984. ; 14:1, s. 94-100
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Tidskriftsartikel (refereegranskat)abstract
- We report an electron-beam based method for the nanoscale patterning of the poly(ethylene oxide)/LiClO4 polymer electrolyte. We use the patterned polymer electrolyte as a high capacitance gate dielectric in single nanowire transistors and obtain subthreshold swings comparable to conventional metal/oxide wrap-gated nanowire transistors. Patterning eliminates gate/contact overlap, which reduces parasitic effects and enables multiple, independently controllable gates. The method's simplicity broadens the scope for using polymer electrolyte gating in studies of nanowires and other nanoscale devices.
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| 24. |
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| 25. |
- Endisch, Christian, et al.
(författare)
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Hypoxic-Ischemic Encephalopathy Evaluated by Brain Autopsy and Neuroprognostication after Cardiac Arrest
- 2020
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 77:11, s. 1430-1439
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Neuroprognostication studies are potentially susceptible to a self-fulfilling prophecy as investigated prognostic parameters may affect withdrawal of life-sustaining therapy. Objective: To compare the results of prognostic parameters after cardiac arrest (CA) with the histopathologically determined severity of hypoxic-ischemic encephalopathy (HIE) obtained from autopsy results. Design, Setting, and Participants: In a retrospective, 3-center cohort study of all patients who died following cardiac arrest during their intensive care unit stay and underwent autopsy between 2003 and 2015, postmortem brain histopathologic findings were compared with post-CA brain computed tomographic imaging, electroencephalographic (EEG) findings, somatosensory-evoked potentials, and serum neuron-specific enolase levels obtained during the intensive care unit stay. Data analysis was conducted from 2015 to 2020. Main Outcomes and Measures: The severity of HIE was evaluated according to the selective eosinophilic neuronal death (SEND) classification and patients were dichotomized into categories of histopathologically severe and no/mild HIE. Results: Of 187 included patients, 117 were men (63%) and median age was 65 (interquartile range, 58-74) years. Severe HIE was found in 114 patients (61%) and no/mild HIE was identified in 73 patients (39%). Severe HIE was found in all 21 patients with bilaterally absent somatosensory-evoked potentials, all 15 patients with gray-white matter ratio less than 1.10 on brain computed tomographic imaging, all 9 patients with suppressed EEG, 15 of 16 patients with burst-suppression EEG, and all 29 patients with neuron-specific enolase levels greater than 67 μg/L more than 48 hours after CA without confounders. Three of 7 patients with generalized periodic discharges on suppressed background and 1 patient with burst-suppression EEG had a SEND 1 score (<30% dead neurons) in the cerebral cortex, but higher SEND scores (>30% dead neurons) in other oxygen-sensitive brain regions. Conclusions and Relevance: In this study, histopathologic findings suggested severe HIE after cardiac arrest in patients with bilaterally absent cortical somatosensory-evoked potentials, gray-white matter ratio less than 1.10, highly malignant EEG, and serum neuron-specific enolase concentration greater than 67 μg/L.
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| 26. |
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| 27. |
- Kia, Richard, et al.
(författare)
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MicroRNA-122 : a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity
- 2015
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Ingår i: Toxicological Sciences. - : Oxford University Press. - 1096-6080 .- 1096-0929. ; 144:1, s. 173-185
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Tidskriftsartikel (refereegranskat)abstract
- Emerging hepatic models for the study of drug-induced toxicity include pluripotent stem cell-derived hepatocyte-like cells (HLCs) and complex hepatocyte-non-parenchymal cellular coculture to mimic the complex multicellular interactions that recapitulate the niche environment in the human liver. However, a specific marker of hepatocyte perturbation, required to discriminate hepatocyte damage from non-specific cellular toxicity contributed by non-hepatocyte cell types or immature differentiated cells is currently lacking, as the cytotoxicity assays routinely used in in vitro toxicology research depend on intracellular molecules which are ubiquitously present in all eukaryotic cell types. In this study, we demonstrate that microRNA-122 (miR-122) detection in cell culture media can be used as a hepatocyte-enriched in vitro marker of drug-induced toxicity in homogeneous cultures of hepatic cells, and a cell-specific marker of toxicity of hepatic cells in heterogeneous cultures such as HLCs generated from various differentiation protocols and pluripotent stem cell lines, where conventional cytotoxicity assays using generic cellular markers may not be appropriate. We show that the sensitivity of the miR-122 cytotoxicity assay is similar to conventional assays that measure lactate dehydrogenase activity and intracellular adenosine triphosphate when applied in hepatic models with high levels of intracellular miR-122, and can be multiplexed with other assays. MiR-122 as a biomarker also has the potential to bridge results in in vitro experiments to in vivo animal models and human samples using the same assay, and to link findings from clinical studies in determining the relevance of in vitro models being developed for the study of drug-induced liver injury.
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| 28. |
- Medin, T, et al.
(författare)
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Dopamine D5 receptors are localized at asymmetric synapses in the rat hippocampus.
- 2011
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Ingår i: Neuroscience. - : Elsevier. - 0306-4522 .- 1873-7544. ; 192, s. 164-171
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Tidskriftsartikel (refereegranskat)abstract
- Functional studies indicate that the dopamine D5 receptor is involved in synaptic transmission in the hippocampus. However, previous anatomical studies have detected D5 receptor labelling primarily on the soma and main dendrites of CA1 pyramidal cells and on dendritic spines in monkey but not in rats. In order to get a better understanding of putative dopamine function in the hippocampus, we quantified the D5 receptor immunoreactivity on the pyramidal cell somas and on spines and dendrites in stratum radiatum and stratum oriens in the hippocampal CA1 region of rats by quantitative immunofluorescence and immunogold electron microscopy. The quantitative immunogold results revealed a higher labelling density on dendritic spines, notably at their synaptic membranes, compared to pyramidal cell somas and dendrites. Hence, dopamine could have effects on spines as well as on somas and dendrites. The labelling density was similar on spines in stratum oriens and stratum radiatum, but the presence of labelling varied between the spines within each stratum, indicating that the effect of dopamine could be diverse between different spines.
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| 29. |
- Mörck, Catarina, 1972, et al.
(författare)
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Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:43, s. 18285-90
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Tidskriftsartikel (refereegranskat)abstract
- Statins are compounds prescribed to lower blood cholesterol in millions of patients worldwide. They act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that leads to the synthesis of farnesyl pyrophosphate, a precursor for cholesterol synthesis and the source of lipid moieties for protein prenylation. The nematode Caenorhabditis elegans possesses a mevalonate pathway that lacks the branch leading to cholesterol synthesis, and thus represents an ideal organism to specifically study the noncholesterol roles of the pathway. Inhibiting HMG-CoA reductase in C. elegans using statins or RNAi leads to developmental arrest and loss of membrane association of a GFP-based prenylation reporter. The unfolded protein response (UPR) is also strongly activated, suggesting that impaired prenylation of small GTPases leads to the accumulation of unfolded proteins and ER stress. UPR induction was also observed upon pharmacological inhibition of farnesyl transferases or RNAi inhibition of a specific isoprenoid transferase (M57.2) and found to be dependent on both ire-1 and xbp-1 but not on pek-1 or atf-6, which are all known regulators of the UPR. The lipid stores and fatty acid composition were unaffected in statin-treated worms, even though they showed reduced staining with Nile red. We conclude that inhibitors of HMG-CoA reductase or of farnesyl transferases induce the UPR by inhibiting the prenylation of M57.2 substrates, resulting in developmental arrest in C. elegans. These results provide a mechanism for the pleiotropic effects of statins and suggest that statins could be used clinically where UPR activation may be of therapeutic benefit.
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| 30. |
- Nilsson, Emma C, 1979-, et al.
(författare)
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The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis (Letter)
- 2011
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 17:1, s. 105-109
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Tidskriftsartikel (refereegranskat)abstract
- Adenovirus type 37 (Ad37) is a leading cause of epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular disease. Whereas most other adenoviruses infect cells by engaging CD46 or the coxsackie and adenovirus receptor (CAR), Ad37 binds previously unknown sialic acid-containing cell surface molecules. By glycan array screening, we show here that the receptor-recognizing knob domain of the Ad37 fiber protein specifically binds a branched hexasaccharide that is present in the GD1a ganglioside and that features two terminal sialic acids. Soluble GD1a glycan and GD1a-binding antibodies efficiently prevented Ad37 virions from binding and infecting corneal cells. Unexpectedly, the receptor is constituted by one or more glycoproteins containing the GD1a glycan motif rather than the ganglioside itself, as shown by binding, infection and flow cytometry experiments. Molecular modeling, nuclear magnetic resonance and X-ray crystallography reveal that the two terminal sialic acids dock into two of three previously established sialic acid-binding sites in the trimeric Ad37 knob. Surface plasmon resonance analysis shows that the knob-GD1a glycan interaction has high affinity. Our findings therefore form a basis for the design and development of sialic acid-containing antiviral drugs for topical treatment of EKC.
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| 31. |
- Storm, Petter, et al.
(författare)
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Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis.
- 2011
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 30, s. 4765-4779
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Tidskriftsartikel (refereegranskat)abstract
- HAMLET is the first member of a new family of tumoricidal protein-lipid complexes that kill cancer cells broadly, while sparing healthy, differentiated cells. Many and diverse tumor cell types are sensitive to the lethal effect, suggesting that HAMLET identifies and activates conserved death pathways in cancer cells. Here, we investigated the molecular basis for the difference in sensitivity between cancer cells and healthy cells. Using a combination of small-hairpin RNA (shRNA) inhibition, proteomic and metabolomic technology, we identified the c-Myc oncogene as one essential determinant of HAMLET sensitivity. Increased c-Myc expression levels promoted sensitivity to HAMLET and shRNA knockdown of c-Myc suppressed the lethal response, suggesting that oncogenic transformation with c-Myc creates a HAMLET-sensitive phenotype. Furthermore, HAMLET sensitivity was modified by the glycolytic state of tumor cells. Glucose deprivation sensitized tumor cells to HAMLET-induced cell death and in the shRNA screen, hexokinase 1 (HK1), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 and hypoxia-inducible factor 1α modified HAMLET sensitivity. HK1 was shown to bind HAMLET in a protein array containing ∼8000 targets, and HK activity decreased within 15 min of HAMLET treatment, before morphological signs of tumor cell death. In parallel, HAMLET triggered rapid metabolic paralysis in carcinoma cells. Tumor cells were also shown to contain large amounts of oleic acid and its derivatives already after 15 min. The results identify HAMLET as a novel anti-cancer agent that kills tumor cells by exploiting unifying features of cancer cells such as oncogene addiction or the Warburg effect.
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| 32. |
- Van Der Woude, Auke M., et al.
(författare)
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Near-real-time CO2 fluxes from CarbonTracker Europe for high-resolution atmospheric modeling
- 2023
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Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3508 .- 1866-3516. ; 15:2, s. 579-605
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Tidskriftsartikel (refereegranskat)abstract
- We present the CarbonTracker Europe High-Resolution (CTE-HR) system that estimates carbon dioxide (CO2) exchange over Europe at high resolution (0.1 × 0.2° ) and in near real time (about 2 months' latency). It includes a dynamic anthropogenic emission model, which uses easily available statistics on economic activity, energy use, and weather to generate anthropogenic emissions with dynamic time profiles at high spatial and temporal resolution (0.1×0.2° hourly). Hourly net ecosystem productivity (NEP) calculated by the Simple Biosphere model Version 4 (SiB4) is driven by meteorology from the European Centre for Medium-Range Weather Forecasts (ECMWF) Reanalysis 5th Generation (ERA5) dataset. This NEP is downscaled to 0.1×0.2° using the high-resolution Coordination of Information on the Environment (CORINE) land-cover map and combined with the Global Fire Assimilation System (GFAS) fire emissions to create terrestrial carbon fluxes. Ocean CO2 fluxes are included in our product, based on Jena CarboScope ocean CO2 fluxes, which are downscaled using wind speed and temperature. Jointly, these flux estimates enable modeling of atmospheric CO2 mole fractions over Europe. We assess the skill of the CTE-HR CO2 fluxes (a) to reproduce observed anomalies in biospheric fluxes and atmospheric CO2 mole fractions during the 2018 European drought, (b) to capture the reduction of anthropogenic emissions due to COVID-19 lockdowns, (c) to match mole fraction observations at Integrated Carbon Observation System (ICOS) sites across Europe after atmospheric transport with the Transport Model, version 5 (TM5) and the Stochastic Time-Inverted Lagrangian Transport (STILT), driven by ECMWF-IFS, and (d) to capture the magnitude and variability of measured CO2 fluxes in the city center of Amsterdam (the Netherlands). We show that CTE-HR fluxes reproduce large-scale flux anomalies reported in previous studies for both biospheric fluxes (drought of 2018) and anthropogenic emissions (COVID-19 pandemic in 2020). After applying transport of emitted CO2, the CTE-HR fluxes have lower median root mean square errors (RMSEs) relative to mole fraction observations than fluxes from a non-informed flux estimate, in which biosphere fluxes are scaled to match the global growth rate of CO2 (poor person's inversion). RMSEs are close to those of the reanalysis with the CTE data assimilation system. This is encouraging given that CTE-HR fluxes did not profit from the weekly assimilation of CO2 observations as in CTE. We furthermore compare CO2 concentration observations at the Dutch Lutjewad coastal tower with high-resolution STILT transport to show that the high-resolution fluxes manifest variability due to different emission sectors in summer and winter. Interestingly, in periods where synoptic-scale transport variability dominates CO2 concentration variations, the CTE-HR fluxes perform similarly to low-resolution fluxes (5-10× coarsened). The remaining 10 % of the simulated CO2 mole fraction differs by >2 ppm between the low-resolution and high-resolution flux representation and is clearly associated with coherent structures ("plumes") originating from emission hotspots such as power plants. We therefore note that the added resolution of our product will matter most for very specific locations and times when used for atmospheric CO2 modeling. Finally, in a densely populated region like the Amsterdam city center, our modeled fluxes underestimate the magnitude of measured eddy covariance fluxes but capture their substantial diurnal variations in summertime and wintertime well. We conclude that our product is a promising tool for modeling the European carbon budget at a high resolution in near real time. The fluxes are freely available from the ICOS Carbon Portal (CC-BY-4.0) to be used for near-real-time monitoring and modeling, for example, as an a priori flux product in a CO2 data assimilation system. The data are available at 10.18160/20Z1-AYJ2 .
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| 33. |
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| 34. |
- Wild, CP, et al.
(författare)
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Cancer Prevention Europe
- 2019
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Ingår i: Molecular oncology. - : Wiley. - 1878-0261 .- 1574-7891. ; 13:3, s. 528-534
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Tidskriftsartikel (refereegranskat)
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Balabanski, Anna H., et al.
(författare)
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Incidence of stroke in indigenous populations of countries with a very high human development index : a systematic review
- 2024
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Ingår i: Neurology. - : American Academy of Neurology. - 0028-3878 .- 1526-632X. ; 102:5
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Forskningsöversikt (refereegranskat)abstract
- Background and objectives: Cardiovascular disease contributes significantly to disease burden among many Indigenous populations. However, data on stroke incidence in Indigenous populations are sparse. We aimed to investigate what is known of stroke incidence in Indigenous populations of countries with a very high Human Development Index (HDI), locating the research in the broader context of Indigenous health.Methods: We identified population-based stroke incidence studies published between 1990 and 2022 among Indigenous adult populations of developed countries using PubMed, Embase, and Global Health databases, without language restriction. We excluded non-peer-reviewed sources, studies with fewer than 10 Indigenous people, or not covering a 35- to 64-year minimum age range. Two reviewers independently screened titles, abstracts, and full-text articles and extracted data. We assessed quality using "gold standard" criteria for population-based stroke incidence studies, the Newcastle-Ottawa Scale for risk of bias, and CONSIDER criteria for reporting of Indigenous health research. An Indigenous Advisory Board provided oversight for the study.Results: From 13,041 publications screened, 24 studies (19 full-text articles, 5 abstracts) from 7 countries met the inclusion criteria. Age-standardized stroke incidence rate ratios were greater in Aboriginal and Torres Strait Islander Australians (1.7-3.2), American Indians (1.2), Sámi of Sweden/Norway (1.08-2.14), and Singaporean Malay (1.7-1.9), compared with respective non-Indigenous populations. Studies had substantial heterogeneity in design and risk of bias. Attack rates, male-female rate ratios, and time trends are reported where available. Few investigators reported Indigenous stakeholder involvement, with few studies meeting any of the CONSIDER criteria for research among Indigenous populations.Discussion: In countries with a very high HDI, there are notable, albeit varying, disparities in stroke incidence between Indigenous and non-Indigenous populations, although there are gaps in data availability and quality. A greater understanding of stroke incidence is imperative for informing effective societal responses to socioeconomic and health disparities in these populations. Future studies into stroke incidence in Indigenous populations should be designed and conducted with Indigenous oversight and governance to facilitate improved outcomes and capacity building.
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| 39. |
- Balabanski, Anna H., et al.
(författare)
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The Incidence of Stroke in Indigenous Populations of Countries With a Very High Human Development Index : A Systematic Review Protocol
- 2021
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Ingår i: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 12
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Forskningsöversikt (refereegranskat)abstract
- Background and Aims: Despite known Indigenous health and socioeconomic disadvantage in countries with a Very High Human Development Index, data on the incidence of stroke in these populations are sparse. With oversight from an Indigenous Advisory Board, we will undertake a systematic review of the incidence of stroke in Indigenous populations of developed countries or regions, with comparisons between Indigenous and non-Indigenous populations of the same region, though not between different Indigenous populations.Methods: Using PubMed, OVID-EMBASE, and Global Health databases, we will examine population-based incidence studies of stroke in Indigenous adult populations of developed countries published 1990-current, without language restriction. Non-peer-reviewed sources, studies including <10 Indigenous People, or with insufficient data to determine incidence, will be excluded. Two reviewers will independently validate the search strategies, screen titles and abstracts, and record reasons for rejection. Relevant articles will undergo full-text screening, with standard data extracted for all studies included. Quality assessment will include Sudlow and Warlow's criteria for population-based stroke incidence studies, the Newcastle-Ottawa Scale for risk of bias, and the CONSIDER checklist for Indigenous research.Results: Primary outcomes include crude, age-specific and/or age-standardized incidence of stroke. Secondary outcomes include overall stroke rates, incidence rate ratio and case-fatality. Results will be synthesized in figures and tables, describing data sources, populations, methodology, and findings. Within-population meta-analysis will be performed if, and where, methodologically sound and comparable studies allow this.Conclusion: We will undertake the first systematic review assessing disparities in stroke incidence in Indigenous populations of developed countries. Data outputs will be disseminated to relevant Indigenous stakeholders to inform public health and policy research.
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| 40. |
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| 41. |
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| 42. |
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| 43. |
- Campbell, Brittany B., et al.
(författare)
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Comprehensive Analysis of Hypermutation in Human Cancer
- 2017
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 171:5
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 Elsevier Inc. We present an extensive assessment of mutation burden through sequencing analysis of > 81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.
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| 44. |
- Caraballo, Rémi, et al.
(författare)
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Triazole linker-based trivalent sialic acid inhibitors of adenovirus type 37 infection of human corneal epithelial cells
- 2015
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Ingår i: Organic and biomolecular chemistry. - 1477-0520 .- 1477-0539. ; 13:35, s. 9194-9205
-
Tidskriftsartikel (refereegranskat)abstract
- Adenovirus type 37 (Ad37) is one of the principal agents responsible for epidemic keratoconjunctivitis (EKC), a severe ocular infection that remains without any available treatment. Recently, a trivalent sialic acid derivative (ME0322, Angew. Chem. Int. Ed., 2011, 50, 6519) was shown to function as a highly potent inhibitor of Ad37, efficiently preventing the attachment of the virion to the host cells and subsequent infection. Here, new trivalent sialic acid derivatives were designed, synthesized and their inhibitory properties against Ad37 infection of the human corneal epithelial cells were investigated. In comparison to ME0322, the best compound (17a) was found to be over three orders of magnitude more potent in a cell-attachment assay (IC50 = 1.4 nM) and about 140 times more potent in a cell-infection assay (IC50 = 2.9nM). X-ray crystallographic analysis demonstrated a trivalent binding mode of all compounds to the Ad37 fiber knob. For the most potent compound ophthalmic toxicity in rabbits was investigated and it was concluded that repeated eye administration did not cause any adverse effects.
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| 45. |
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| 46. |
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| 47. |
- Christensen, LH, et al.
(författare)
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Can the survival difference between breast cancer patients in Denmark and Sweden 1989 and 1994 be explained by patho-anatomical variables? - A population-based study
- 2004
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 40:8, s. 1233-1243
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of data from cancer registries have shown a 10% unit difference in 5-year relative survival between Danish and Swedish patients with breast cancer. This study investigates the effect of age and patho-anatomic variables on this survival difference. Hospital records were collected for women over 40 years of age diagnosed in 1989 or 1994 in east Denmark and south Sweden; patho-anatomical variables and survival were compared between 2289 Danish and 1715 Swedish women. Tumours were smaller, node-negative axillae more frequent and well-differentiated tumours almost 10% more frequent in Sweden. A superior 5-year relative survival in Sweden was found in the 50- to 79-year age group. The adjusted hazard rate ratio between countries was 1.7 in 1989 and 1.3 in 1994. Conditional survival after surviving the first 5 years was similar for the two countries. Adjusting for patho-anatomical variables reduced but did not eliminate the higher risk of death among the Danish patients. Higher population death rates could explain some but not all of the residual elevated risk for Danish women. (C) 2004 Elsevier Ltd. All rights reserved.
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| 48. |
- Christensen, L. H., et al.
(författare)
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Reduced mortality for women with mammography-detected breast cancer in east Denmark and south Sweden
- 2006
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 42:16, s. 2773-2780
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Tidskriftsartikel (refereegranskat)abstract
- The 5-year relative survival from breast cancer in Denmark is 10 percentage points lower than in Sweden. This difference has been demonstrated previously as being caused partly by more involved lymph nodes and larger tumours in Denmark. Sweden has had nationwide mammography-screening coverage since 1991, whereas this is still in its infancy in Denmark. In the search for an explanation for the remaining survival difference, patient delay was a likely candidate. This study compared patient delay and mammography-detection between two national regions. Data on patient delay and mammography were obtained from hospital records from 1989 and 1994, and analysed using Cox proportional hazard analysis of death within the first 5 years, with the factors age, country, delay/mammography detection and established patho-anatomic variables. A comparison of patient delay and mammography detection in 1989 and 1994 showed more mammography-detected tumours in south Sweden and more women with long delay in east Denmark. Mammography detection, but not long patient delay, had a significant effect on the death hazard when adjusting for patho-anatomic risk factors. The hazard ratio was not eliminated in 1989, but in 1994, the hazard ratio between east Denmark and south Sweden was reduced from 1.3 to 1.1. In conclusion, patient delay did not appear to have any effect on 5-year survival when adjusting for patho-anatomic factors, but tumour detection by mammography affected survival favourably and partly explained the survival difference between east Denmark and south Sweden. (c) 2006 Elsevier Ltd. All rights reserved.
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| 49. |
- da Silva, R., et al.
(författare)
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Oxygen, sulfur, and iron radial abundance gradients of classical Cepheids across the Galactic thin disk
- 2023
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 678, s. A195-A195
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Tidskriftsartikel (refereegranskat)abstract
- Context. Classical Cepheids (CCs) are solid distance indicators and tracers of young stellar populations. Dating back to the beginning of the 20th century, they have been safely adopted to trace the rotation, kinematics, and chemical enrichment history of the Galactic thin disk.Aims. The main aim of this investigation is to provide iron, oxygen, and sulfur abundances for the largest and most homogeneous sample of Galactic CCs analyzed so far (1118 spectra of 356 objects). The current sample, containing 70 CCs for which spectroscopic metal abundances are provided for the first time, covers a wide range in galactocentric distances, pulsation modes, and pulsation periods.Methods. Optical high-resolution spectra with a high signal-to-noise ratio that were collected with different spectrographs were adopted to provide homogeneous estimates of the atmospheric parameters (effective temperature, surface gravity, and microturbulent velocity) that are required to determine the abundance. Individual distances were based either on trigonometric parallaxes by the Gaia Data Release 3 (Gaia DR3) or on distances based on near-infrared period-luminosity relations.Results. We found that iron and α-element radial gradients based on CCs display a well-defined change in the slope for galactocentric distances larger than ~12 kpc. We also found that logarithmic regressions account for the variation in [X/H] abundances from the inner to the outer disk. Radial gradients for the same elements, but based on open clusters covering a wide range in cluster ages, display similar trends. This means that the flattening in the outer disk is an intrinsic feature of the radial gradients because it is independent of age. Empirical evidence indicates that the S radial gradient is steeper than the Fe radial gradient. The difference in the slope is a factor of two in the linear fit (−0.081 vs. −0.041 dex kpc−1) and changes from −1.62 to −0.91 in the logarithmic distance. Moreover, we found that S (explosive nucleosynthesis) is underabundant on average when compared with O (hydrostatic nucleosynthesis). The difference becomes clearer in the metal-poor regime and for the [O/Fe] and [S/Fe] abundance ratios. We performed a detailed comparison with Galactic chemical evolution models and found that a constant star formation efficiency for galactocentric distances larger than 12 kpc accounts for the flattening observed in both iron and α-elements. To further constrain the impact of the predicted S yields for massive stars on radial gradients, we adopted a toy model and found that the flattening in the outermost regions requires a decrease of a factor of four in the current S predictions.Conclusions. CCs are solid beacons for tracing the recent chemical enrichment of young stellar populations. Sulfur photospheric abundances, when compared with other α-elements, have the key advantage of being a volatile element. Therefore, stellar S abundances can be directly compared with nebular sulfur abundances in external galaxies.
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| 50. |
- Damas, J, et al.
(författare)
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Prevalence of HIV, Hepatitis C and its related risk behaviours among women who inject drugs in the Kathmandu Valley, Nepal: a cross-sectional study
- 2021
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Ingår i: Therapeutic advances in infectious disease. - : SAGE Publications. - 2049-9361 .- 2049-937X. ; 8, s. 20499361211062107-
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Tidskriftsartikel (refereegranskat)abstract
- People who inject drugs (PWID) are at great risk of HIV and Hepatitis C Virus (HCV). In order to properly design interventions and develop programmes for women who inject drugs, this study assessed the prevalence of HIV, Hepatitis B, Hepatitis C, and syphilis and its risk behaviours among women who inject drugs in the Kathmandu Valley, Nepal. Methods: Through modified network sampling in three districts in the Kathmandu Valley, Nepal, this cross-sectional study enrolled a total of 160 women who inject drugs. Participants’ serum samples were tested for HIV, HCV, Hepatitis B virus (HBV) and syphilis and risk behaviours were assessed through a structured questionnaire. Primary outcome variables were HIV, HCV, HBV and syphilis prevalence, and secondary outcome variables were sharing needles in the past month and using condom in last sexual intercourse. Stepwise logistic regression was used to determine micro- and macroenvironmental factors associated with secondary outcomes. Results: The prevalence of HIV, HCV, and HBV was 8.8%, 21.3%, and 1.9%, respectively. HIV-HCV co-infection rate was 5.6%. Fifteen percent of women who inject drugs reported transactional sex for drugs or money. One in four women who inject drugs (27.5%) reported that they were imprisoned or detained for drug related reasons. In multivariable analysis, women living with HIV who inject drugs were almost four times more likely to use a previously used needle/syringe than women who inject drugs who were HIV negative (aOR: 4.2 CI: 1.1-15.9, p = 0.03), but were almost four times more likely to use a condom during sexual intercourse (aOR: 3.5 CI: 1.1-28.9, p = 0.03). Enrolment in family planning was the main determinant for using condoms in last sexual intercourse (aOR 4.9 CI: 1.6-16.7, p = 0.006). Participants with access to HIV test and counselling (HTC) services were less likely to share needles (aOR: 0.3, 95% CI: 0.1–0.8, p = 0.01). Conclusion: Prevalence of HIV and HCV is high among women who inject drugs in Kathmandu valley of Nepal. Women who inject drugs enrolled in national programmes such as family planning and HTC were positively associated with condom use, and less likely to share needles.
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