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| 3. |
- Delabrouille, J., et al.
(author)
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Exploring cosmic origins with CORE : Survey requirements and mission design
- 2018
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In: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :4
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Journal article (peer-reviewed)abstract
- Future observations of cosmic microwave background (CMB) polarisation have the potential to answer some of the most fundamental questions of modern physics and cosmology, including: what physical process gave birth to the Universe we see today? What are the dark matter and dark energy that seem to constitute 95% of the energy density of the Universe? Do we need extensions to the standard model of particle physics and fundamental interactions? Is the ACDM cosmological scenario correct, or are we missing an essential piece of the puzzle? In this paper, we list the requirements for a future CMB polarisation survey addressing these scientific objectives, and discuss the design drivers of the CORE space mission proposed to ESA in answer to the M5 call for a medium-sized mission. The rationale and options, and the methodologies used to assess the mission's performance, are of interest to other future CMB mission design studies. CORE has 19 frequency channels, distributed over a broad frequency range, spanning the 60-600 GHz interval, to control astrophysical foreground emission. The angular resolution ranges from 2' to 18', and the aggregate CMB sensitivity is about 2 mu K.arcmin. The observations are made with a single integrated focal-plane instrument, consisting of an array of 2100 cryogenically-cooled, linearly-polarised detectors at the focus of a 1.2-m aperture cross-Dragone telescope. The mission is designed to minimise all sources of systematic effects, which must be controlled so that no more than 10(-4) of the intensity leaks into polarisation maps, and no more than about 1% of E-type polarisation leaks into B-type modes. CORE observes the sky from a large Lissajous orbit around the Sun-Earth L2 point on an orbit that offers stable observing conditions and avoids contamination from sidelobe pick-up of stray radiation originating from the Sun, Earth, and Moon. The entire sky is observed repeatedly during four years of continuous scanning, with a combination of three rotations of the spacecraft over different timescales. With about 50% of the sky covered every few days, this scan strategy provides the mitigation of systematic effects and the internal redundancy that are needed to convincingly extract the primordial B-mode signal on large angular scales, and check with adequate sensitivity the consistency of the observations in several independent data subsets. CORE is designed as a near-ultimate CMB polarisation mission which, for optimal complementarity with ground-based observations, will perform the observations that are known to be essential to CMB polarisation science and cannot be obtained by any other means than a dedicated space mission. It will provide well-characterised, highly-redundant multi-frequency observations of polarisation at all the scales where foreground emission and cosmic variance dominate the final uncertainty for obtaining precision CMB science, as well as 2' angular resolution maps of high-frequency foreground emission in the 300-600 GHz frequency range, essential for complementarity with future ground-based observations with large telescopes that can observe the CMB with the same beamsize.
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| 4. |
- Ederle, Joerg, et al.
(author)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
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In: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
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Journal article (peer-reviewed)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 6. |
- Natoli, P., et al.
(author)
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Exploring cosmic origins with CORE : Mitigation of systematic effects
- 2018
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In: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :4
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Journal article (peer-reviewed)abstract
- We present an analysis of the main systematic effects that could impact the measurement of CMB polarization with the proposed CORE space mission. We employ timeline to-map simulations to verify that the CORE instrumental set-up and scanning strategy allow us to measure sky polarization to a level of accuracy adequate to the mission science goals. We also show how the CORE observations can be processed to mitigate the level of contamination by potentially worrying systematics, including intensity-to-polarization leakage due to bandpass mismatch, asymmetric main beams, pointing errors and correlated noise. We use analysis techniques that are well validated on data from current missions such as Planck to demonstrate how the residual contamination of the measurements by these effects can be brought to a level low enough not to hamper the scientific capability of the mission, nor significantly increase the overall error budget. We also present a prototype of the CORE photometric calibration pipeline, based on that used for Planck, and discuss its robustness to systematics, showing how CORE can achieve its calibration requirements. While a fine-grained assessment of the impact of systematics requires a level of knowledge of the system that can only be achieved in a future study phase, the analysis presented here strongly suggests that the main areas of concern for the CORE mission can be addressed using existing knowledge, techniques and algorithms.
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| 7. |
- Dunham, I, et al.
(author)
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The DNA sequence of human chromosome 22
- 1999
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 402:6761, s. 489-495
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Journal article (peer-reviewed)
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| 8. |
- Kueppers, Michael, et al.
(author)
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Triple F-a comet nucleus sample return mission
- 2009
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In: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 23:3, s. 809-847
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Journal article (peer-reviewed)abstract
- The Triple F (Fresh From the Fridge) mission, a Comet Nucleus Sample Return, has been proposed to ESA's Cosmic Vision program. A sample return from a comet enables us to reach the ultimate goal of cometary research. Since comets are the least processed bodies in the solar system, the proposal goes far beyond cometary science topics (like the explanation of cometary activity) and delivers invaluable information about the formation of the solar system and the interstellar molecular cloud from which it formed. The proposed mission would extract three sample cores of the upper 50 cm from three locations on a cometary nucleus and return them cooled to Earth for analysis in the laboratory. The simple mission concept with a touch-and-go sampling by a single spacecraft was proposed as an M-class mission in collaboration with the Russian space agency ROSCOSMOS.
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| 9. |
- Weinstein, John N., et al.
(author)
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The cancer genome atlas pan-cancer analysis project
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Research review (peer-reviewed)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 10. |
- Moles, Angela T, et al.
(author)
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Correlations between physical and chemical defences in plants : tradeoffs, syndromes, or just many different ways to skin a herbivorous cat?
- 2013
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In: New Phytologist. - : Wiley-Blackwell. - 0028-646X .- 1469-8137. ; 198:1, s. 252-263
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Journal article (peer-reviewed)abstract
- Most plant species have a range of traits that deter herbivores. However, understanding of how different defences are related to one another is surprisingly weak. Many authors argue that defence traits trade off against one another, while others argue that they form coordinated defence syndromes. We collected a dataset of unprecedented taxonomic and geographic scope (261 species spanning 80 families, from 75 sites across the globe) to investigate relationships among four chemical and six physical defences. Five of the 45 pairwise correlations between defence traits were significant and three of these were tradeoffs. The relationship between species' overall chemical and physical defence levels was marginally nonsignificant (P=0.08), and remained nonsignificant after accounting for phylogeny, growth form and abundance. Neither categorical principal component analysis (PCA) nor hierarchical cluster analysis supported the idea that species displayed defence syndromes. Our results do not support arguments for tradeoffs or for coordinated defence syndromes. Rather, plants display a range of combinations of defence traits. We suggest this lack of consistent defence syndromes may be adaptive, resulting from selective pressure to deploy a different combination of defences to coexisting species.
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| 11. |
- Moles, A. T., et al.
(author)
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Putting plant resistance traits on the map : A test of the idea that plants are better defended at lower latitudes
- 2011
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In: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 191:3, s. 777-788
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Journal article (peer-reviewed)abstract
- It has long been believed that plant species from the tropics have higher levels of traits associated with resistance to herbivores than do species from higher latitudes. A meta-analysis recently showed that the published literature does not support this theory. However, the idea has never been tested using data gathered with consistent methods from a wide range of latitudes. • We quantified the relationship between latitude and a broad range of chemical and physical traits across 301 species from 75 sites world-wide. • Six putative resistance traits, including tannins, the concentration of lipids (an indicator of oils, waxes and resins), and leaf toughness were greater in high-latitude species. Six traits, including cyanide production and the presence of spines, were unrelated to latitude. Only ash content (an indicator of inorganic substances such as calcium oxalates and phytoliths) and the properties of species with delayed greening were higher in the tropics. • Our results do not support the hypothesis that tropical plants have higher levels of resistance traits than do plants from higher latitudes. If anything, plants have higher resistance toward the poles. The greater resistance traits of high-latitude species might be explained by the greater cost of losing a given amount of leaf tissue in low-productivity environments. © 2011 New Phytologist Trust.
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| 12. |
- Cauchoix, M., et al.
(author)
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The repeatability of cognitive performance : a meta-analysis
- 2018
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In: Philosophical Transactions of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8436 .- 1471-2970. ; 373:1756
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Journal article (peer-reviewed)abstract
- Behavioural and cognitive processes play important roles in mediating an individual's interactions with its environment. Yet, while there is a vast literature on repeatable individual differences in behaviour, relatively little is known about the repeatability of cognitive performance. To further our understanding of the evolution of cognition, we gathered 44 studies on individual performance of 25 species across six animal classes and used meta-analysis to assess whether cognitive performance is repeatable. We compared repeatability (R) in performance (1) on the same task presented at different times (temporal repeatability), and (2) on different tasks that measured the same putative cognitive ability (contextual repeatability). We also addressed whether R estimates were influenced by seven extrinsic factors (moderators): type of cognitive performance measurement, type of cognitive task, delay between tests, origin of the subjects, experimental context, taxonomic class and publication status. We found support for both temporal and contextual repeatability of cognitive performance, with mean R estimates ranging between 0.15 and 0.28. Repeatability estimates were mostly influenced by the type of cognitive performance measures and publication status. Our findings highlight the widespread occurrence of consistent inter-individual variation in cognition across a range of taxa which, like behaviour, may be associated with fitness outcomes. This article is part of the theme issue 'Causes and consequences of individual differences in cognitive abilities'.
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| 15. |
- Aurora, P., et al.
(author)
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Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis
- 2004
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In: Thorax. - : BMJ. - 0040-6376. ; 59:12, s. 1068-73
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Journal article (peer-reviewed)abstract
- BACKGROUND: Multiple breath inert gas washout (MBW) has been suggested as a tool for detecting early cystic fibrosis (CF) lung disease. A study was undertaken to compare the relative sensitivity of MBW and spirometry for detecting abnormal lung function in school age children with CF and to compare MBW results obtained from healthy children in the UK with those recently reported from Sweden. METHODS: Forced expiratory volume in 1 second (FEV1) and maximal expiratory flow when 25% of forced vital capacity remains to be expired (MEF25) were compared with the lung clearance index (LCI) derived from sulphur hexafluoride MBW in 22 children with CF aged 6-16 years and in 33 healthy controls. RESULTS: LCI was higher in children with CF than in healthy controls (mean difference 5.1 (95% CI of difference 4.1 to 6.1) and FEV1 and MEF25 z-scores were lower (mean difference -2.3 (95% CI -2.9 to -1.7) and -1.8 (95% CI -2.4 to -1.3), respectively; p<0.001 for all). There was a significant negative correlation between LCI and FEV1 (r2 = 0.62) and MEF25 (r2 = 0.46). However, while normal (> or =-1.96 z-scores) FEV1 and MEF25 results were seen in 11 (50%) and 12 (53%) children with CF, respectively, all but one of these children had an abnormally increased LCI. LCI was repeatable in both groups (within subject CV for three measurements 6% for CF and 5% for healthy children). In healthy subjects LCI was independent of age and virtually identical in the British and Swedish children (mean difference 0.1 (95% CI -0.1 to 0.4), p = 0.38) CONCLUSIONS: MBW is reproducible between laboratories, generates normal ranges which are constant over childhood, and is more frequently abnormal than spirometry in children with CF.
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| 16. |
- Aurora, P., et al.
(author)
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Multiple-breath washout as a marker of lung disease in preschool children with cystic fibrosis
- 2005
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In: Am J Respir Crit Care Med. - 1073-449X. ; 171:3, s. 249-56
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Journal article (peer-reviewed)abstract
- Sensitive measures of lung function applicable to young subjects are needed to detect early cystic fibrosis (CF) lung disease. Forty children with CF aged 2 to 5 years and 37 age-matched healthy control subjects performed multiple-breath inert gas washout, plethysmography, and spirometry. Thirty children in each group successfully completed all measures, with success on first visit being between 68 and 86% for all three measures. Children with CF had significantly higher lung clearance index (mean [95% CI] difference for CF control 2.7 [1.9, 3.6], p < 0.001) and specific airway resistance (1.65 z-scores [0.96, 2.33], p < 0.001), and significantly lower forced expired volume in 0.5 seconds (-0.49 z-scores [-0.95, -0.03], p < 0.05). Abnormal lung function results were identified in 22 (73%) of 30 children with CF by multiple-breath washout, compared with 14 (47%) of 30 by plethysmography, and 4 (13%) of 30 by spirometry. Children with CF who were infected with Pseudomonas aeruginosa had significantly higher lung clearance index, but no significant difference in other lung function measures, when compared with noninfected children. Most preschool children can perform multiple-breath washout, plethysmography, and spirometry at first attempt. Multiple-breath washout detects abnormal lung function in children with CF more readily than plethysmography or spirometry.
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| 19. |
- Hillier, Ladeana W, et al.
(author)
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Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution
- 2004
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In: Nature. - 0028-0836 .- 1476-4687. ; 432:7018, s. 695-716
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Journal article (peer-reviewed)abstract
- We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.
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| 20. |
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| 21. |
- Sullivan, Nicola J., et al.
(author)
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Developing a mealybug pheromone monitoring tool to enhance IPM practices in New Zealand vineyards
- 2023
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In: Journal of Pest Science. - : Springer. - 1612-4758 .- 1612-4766. ; 96, s. 29-39
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Journal article (peer-reviewed)abstract
- Mealybugs are phloem-feeding insects found on many crops worldwide. In New Zealand vineyards, they transmit the economically important Grapevine leafroll-associated virus 3 (GLRaV-3). For some mealybug species, synthetic sex pheromones have been commercialised, and are used as monitoring tools. The mealybugs Pseudococcus longispinus and Pseudococcus calceolariae are major pests in many New Zealand vineyards. We present work on the development of a combined P. longispinus and P. calceolariae pheromone lure. The optimal dose for monitoring P. longispinus was found to be 10 mu g of the (S)-(+)-enantiomer, either alone or in the racemic mixture. Addition of the corresponding alcohol did not improve trap catch of P. longispinus. Both the P. longispinus and the P. calceolariae pheromone lures remained active in the field for 90 days. Combining the 2 species' pheromones had no negative effects on male mealybug trap catch for either species. We conclude that the pheromone ester alone is the best lure for the male P. longispinus. Combining the two mealybug species' pheromones into a single lure provides the New Zealand viticultural industry with an efficient monitoring tool. Late-vintage deployment of baited lures will provide information on mealybug abundance and local distribution that will inform the scope of future insecticide programmes, to target areas based on need rather than an area-wide application by default.
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| 22. |
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| 23. |
- Zody, Michael C., et al.
(author)
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Evolutionary toggling of the MAPT 17q21.31 inversion region
- 2008
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:9, s. 1076-83
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Journal article (peer-reviewed)abstract
- Using comparative sequencing approaches, we investigated the evolutionary history of the European-enriched 17q21.31 MAPT inversion polymorphism. We present a detailed, BAC-based sequence assembly of the inverted human H2 haplotype and compare it to the sequence structure and genetic variation of the corresponding 1.5-Mb region for the noninverted H1 human haplotype and that of chimpanzee and orangutan. We found that inversion of the MAPT region is similarly polymorphic in other great ape species, and we present evidence that the inversions occurred independently in chimpanzees and humans. In humans, the inversion breakpoints correspond to core duplications with the LRRC37 gene family. Our analysis favors the H2 configuration and sequence haplotype as the likely great ape and human ancestral state, with inversion recurrences during primate evolution. We show that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its tendency to undergo microdeletion associated with mental retardation in European populations.
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| 36. |
- Chen, Z. X., et al.
(author)
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RNA helicase a is a downstream mediator of KIF1Bβ tumor-suppressor function in neuroblastoma
- 2014
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In: Cancer Discovery. - 2159-8274 .- 2159-8290. ; 4:4, s. 434-451
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Journal article (peer-reviewed)abstract
- Inherited KIF1B loss-of-function mutations in neuroblastomas and pheochromocytomas implicate the kinesin KIF1B as a 1p36.2 tumor suppressor. However, the mechanism of tumor suppression is unknown. We found that KIF1B isoform β (KIF1Bβ) interacts with RNA helicase A (DHX9), causing nuclear accumulation of DHX9, followed by subsequent induction of the proapoptotic XIAP-associated factor 1 (XAF1) and, consequently, apoptosis. Pheochromocytoma and neuroblastoma arise from neural crest progenitors that compete for growth factors such as nerve growth factor (NGF) during development. KIF1Bβ is required for developmental apoptosis induced by competition for NGF. We show that DHX9 is induced by and required for apoptosis stimulated by NGF deprivation. Moreover, neuroblastomas with chromosomal deletion of 1p36 exhibit loss of KIF1Bβ expression and impaired DHX9 nuclear localization, implicating the loss of DHX9 nuclear activity in neuroblastoma pathogenesis. SIGNIFICANCE: KIF1Bβ has neuroblastoma tumor-suppressor properties and promotes and requires nuclear-localized DHX9 for its apoptotic function by activating XAF1 expression. Loss of KIF1Bβ alters subcellular localization of DHX9 and diminishes NGF dependence of sympathetic neurons, leading to reduced culling of neural progenitors, and, therefore, might predispose to tumor formation.
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| 37. |
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| 38. |
- Dhanani, Jayesh A, et al.
(author)
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A research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models
- 2018
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In: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 6:1
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Journal article (peer-reviewed)abstract
- Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic.
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| 39. |
- Dhanani, Jayesh A., et al.
(author)
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Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model
- 2019
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In: Anesthesiology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0003-3022 .- 1528-1175. ; 131:2, s. 344-355
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Journal article (peer-reviewed)abstract
- Editors PerspectiveWhat We Already Know about This Topic For most bacterial pneumonia, the lung interstitium is considered to be the site of infection, and adequate antibiotic concentrations are important for drug effect Despite systemic antibiotic therapy, therapeutic failure is common, perhaps due to poor lung penetration, and resulting low interstitial space fluid antibiotic concentrations Increasing systemic antibiotic doses in order to increase interstitial space fluid antibiotic concentrations could lead to toxicities such as nephrotoxicity What This Article Tells Us That Is New In a mechanically ventilated healthy large animal model, nebulized tobramycin produced higher peak lung interstitial space fluid concentrations, as well as higher initial epithelial lining fluid concentrations, with lower plasma concentrations than were observed after intravenous administration due to more extensive lung penetration Background: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Methods: Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. Results: The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P amp;lt; 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P amp;lt; 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P amp;lt; 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P amp;lt; 0.001). Conclusions: Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.
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| 40. |
- Dhanani, Jayesh A, et al.
(author)
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Recovery rates of combination antibiotic therapy using in vitro microdialysis simulating in vivo conditions
- 2018
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In: Journal of pharmaceutical analysis. - : Elsevier BV. - 2214-0883 .- 2095-1779. ; 8:6, s. 407-412
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Journal article (peer-reviewed)abstract
- Microdialysis is a technique used to measure the unbound antibiotic concentration in the interstitial spaces, the target site of action. In vitro recovery studies are essential to calibrating the microdialysis system for in vivo studies. The effect of a combination of antibiotics on recovery into microdialysate requires investigation. In vitro microdialysis recovery studies were conducted on a combination of vancomycin and tobramycin, in a simulated in vivo model. Comparison was made between recoveries for three different concentrations and three different perfusate flow rates. The overall relative recovery for vancomycin was lower than that of tobramycin. For tobramycin, a concentration of 20µg/mL and flow rate of 1.0µL/min had the best recovery. A concentration of 5.0µg/mL and flow rate of 1.0µL/min yielded maximal recovery for vancomycin. Large molecular size and higher protein binding resulted in lower relative recoveries for vancomycin. Perfusate flow rates and drug concentrations affected the relative recovery when a combination of vancomycin and tobramycin was tested. Low perfusate flow rates were associated with higher recovery rates. For combination antibiotic measurement which includes agents that are highly protein bound, in vitro studies performed prior to in vivo studies may ensure the reliable measurement of unbound concentrations.
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| 41. |
- Fredenberg, Erik, et al.
(author)
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Measurement of breast-tissue x-ray attenuation by spectral mammography : solid lesions
- 2016
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In: Physics in Medicine and Biology. - : Institute of Physics Publishing (IOPP). - 0031-9155 .- 1361-6560. ; 61:7, s. 2595-2612
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Journal article (peer-reviewed)abstract
- Knowledge of x-ray attenuation is essential for developing and evaluating x-ray imaging technologies. For instance, techniques to distinguish between cysts and solid tumours at mammography screening would be highly desirable to reduce recalls, but the development requires knowledge of the x-ray attenuation for cysts and tumours. We have previously measured the attenuation of cyst fluid using photon-counting spectral mammography. Data on x-ray attenuation for solid breast lesions are available in the literature, but cover a relatively wide range, likely caused by natural spread between samples, random measurement errors, and different experimental conditions. In this study, we have adapted a previously developed spectral method to measure the linear attenuation of solid breast lesions. A total of 56 malignant and 5 benign lesions were included in the study. The samples were placed in a holder that allowed for thickness measurement. Spectral (energy-resolved) images of the samples were acquired and the image signal was mapped to equivalent thicknesses of two known reference materials, which can be used to derive the x-ray attenuation as a function of energy. The spread in equivalent material thicknesses was relatively large between samples, which is likely to be caused mainly by natural variation and only to a minor extent by random measurement errors and sample inhomogeneity. No significant difference in attenuation was found between benign and malignant solid lesions. The separation between cyst-fluid and tumour attenuation was, however, significant, which suggests it may be possible to distinguish cystic from solid breast lesions, and the results lay the groundwork for a clinical trial. In addition, the study adds a relatively large sample set to the published data and may contribute to a reduction in the overall uncertainty in the literature.
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| 42. |
- Fredenberg, Erik, et al.
(author)
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X-ray attenuation of adipose breast tissue : In-vitro and in-vivo measurements using spectral imaging
- 2015
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In: MEDICAL IMAGING 2015: PHYSICS OF MEDICAL IMAGING. - : SPIE. - 9781628415025
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Conference paper (peer-reviewed)abstract
- The development of new x-ray imaging techniques often requires prior knowledge of tissue attenuation, but the sources of such information are sparse. We have measured the attenuation of adipose breast tissue using spectral imaging, in vitro and in vivo. For the in-vitro measurement, fixed samples of adipose breast tissue were imaged on a spectral mammography system, and the energy-dependent x-ray attenuation was measured in terms of equivalent thicknesses of aluminum and poly-methyl methacrylate (PMMA). For the in-vivo measurement, a similar procedure was applied on a number of spectral screening mammograms. The results of the two measurements agreed well and were consistent with published attenuation data and with measurements on tissue-equivalent material.
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| 43. |
- Greenslade, Jaimi H., et al.
(author)
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Development of a revised Jalowiec Coping Scale for use by emergency clinicians: a cross-sectional scale development study
- 2019
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In: BMJ Open. - : BMJ PUBLISHING GROUP. - 2044-6055. ; 9:12
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Journal article (peer-reviewed)abstract
- Objectives The aim of this study was to develop and validate a scale to measure the coping strategies used by emergency staff in response to workplace stress. To achieve this aim, we developed a refined Jalowiec Coping Scale (JCS), termed the Jalowiec Coping Scale-Emergency Department (JCS-ED) and validated this scale on a sample of emergency clinicians. Design A cross-sectional survey incorporating the JCS, the working environment scale-10 and a measure of workplace stressors was administered between July 2016 and June 2017. The JCS-ED was developed in three stages: 1) item reduction through content matter experts, 2) exploratory factor analysis for further item reduction and to identify the factor structure of the revised scale and 3) confirmatory factor analyses to confirm the factors identified within the exploratory factor analysis. Setting Six Emergency Departments (EDs) in Australia and four in Sweden. There were three tertiary hospitals, five large urban hospitals and two small urban hospitals. Participants Participants were eligible for inclusion if they worked full-time or part-time as medical or nursing staff in the study EDs. The median age of participants was 35 years (IQR: 28-45 years) and they had been working in the ED for a median of 5 years (IQR: 2-10 years). 79% were females and 76% were nurses. Results A total of 875 ED staff completed the survey (response rate 51%). The content matter experts reduced the 60-item scale to 32 items. Exploratory factor analyses then further reduced the scale to 18 items assessing three categories of coping: problem-focussed coping, positive emotion-focussed coping and negative emotion-focussed coping. Confirmatory factor analysis supported this three-factor structure. Negative coping strategies were associated with poor perceptions of the work environment and higher ratings of stress. Conclusions The JCS-ED assesses maladaptive coping strategies along with problem-focussed and emotion-focussed coping styles. It is a short instrument that is likely to be useful in measuring the types of coping strategies employed by staff.
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| 44. |
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| 45. |
- Kong, Fabian Y. S., et al.
(author)
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Optimisation of treatments for oral Neisseria gonorrhoeae infection : Pharmacokinetics Study (STI-PK project) - study protocol for non-randomised clinical trial
- 2022
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In: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:11
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Neisseria gonorrhoeae infections are common and incidence increasing. Oropharyngeal infections are associated with greater treatment failure compared with other sites and drive transmission to anogenital sites through saliva. Gonococcal resistance is increasing and new treatments are scarce, therefore, clinicians must optimise currently available and emerging treatments in order to have efficacious therapeutic options. This requires pharmacokinetic data from the oral cavity/oropharynx, however, availability of such information is currently limited.METHODS AND ANALYSIS: Healthy male volunteers (participants) recruited into the study will receive single doses of either ceftriaxone 1 g, cefixime 400 mg or ceftriaxone 500 mg plus 2 g azithromycin. Participants will provide samples at 6-8 time points (treatment regimen dependent) from four oral sites, two oral fluids, one anorectal swab and blood. Participants will complete online questionnaires about their medical history, sexual practices and any side effects experienced up to days 5-7. Saliva/oral mucosal pH and oral microbiome analysis will be undertaken. Bioanalysis will be conducted by liquid chromatography-mass spectrometry. Drug concentrations over time will be used to develop mathematical models for optimisation of drug dosing regimens and to estimate pharmacodynamic targets of efficacy.ETHICS AND DISSEMINATION: This study was approved by Royal Melbourne Hospital Human Research Ethics Committee (60370/MH-2021). The study results will be submitted for publication in peer-reviewed journals and reported at conferences. Summary results will be sent to participants requesting them. All data relevant to the study will be included in the article or uploaded as supplementary information.TRIAL REGISTRATION NUMBER: ACTRN12621000339853.
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| 46. |
- Litjens, Carlijn H. C., et al.
(author)
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Protein binding of rifampicin is not saturated when using high-dose rifampicin
- 2019
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In: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990
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Journal article (peer-reviewed)abstract
- Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
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| 47. |
- Lum, S., et al.
(author)
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Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests
- 2007
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In: Thorax. - : BMJ. - 0040-6376. ; 62:4, s. 341-7
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Journal article (peer-reviewed)abstract
- BACKGROUND: Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from the multiple-breath inert gas washout (MBW) technique, has been shown to detect abnormal lung function more readily than spirometry in preschool children with cystic fibrosis, but whether this holds true during infancy is unknown. OBJECTIVES: To compare the extent to which parameters derived from the MBW and the raised lung volume rapid thoraco-abdominal compression (RVRTC) techniques identify diminished airway function in infants with cystic fibrosis when compared with healthy controls. METHODS: Measurements were performed during quiet sleep, with the tidal breathing MBW technique being performed before the forced expiratory manoeuvres. RESULTS: Measurements were obtained in 39 infants with cystic fibrosis (mean (SD) age 41.4 (22.0) weeks) and 21 controls (37.0 (15.1) weeks). Infants with cystic fibrosis had a significantly higher respiratory rate (38 (10) vs 32 (5) bpm) and LCI (8.4 (1.5) vs 7.2 (0.3)), and significantly lower values for all forced expiratory flow-volume parameters compared with controls. Girls with cystic fibrosis had significantly lower forced expiratory volume (FEV(0.5) and FEF(25-75 )) than boys (mean (95% CI girls-boys): -1.2 (-2.1 to -0.3) for FEV(0.5) Z score; FEF(25-75): -1.2 (-2.2 to -0.15)). When using both the MBW and RVRTC techniques, abnormalities were detected in 72% of the infants with cystic fibrosis, with abnormalities detected in 41% using both techniques and a further 15% by each of the two tests performed. CONCLUSIONS: These findings support the view that inflammatory and/or structural changes in the airways of children with cystic fibrosis start early in life, and have important implications regarding early detection and interventions. Monitoring of early lung disease and functional status in infants and young children with cystic fibrosis may be enhanced by using both MBW and the RVRTC.
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| 48. |
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| 49. |
- Olmeda, David, et al.
(author)
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Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine
- 2017
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In: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 546:7660, s. 676-680
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Journal article (peer-reviewed)abstract
- Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis(1-3). However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma(4,5). Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress(6,7). Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma(8-14). Still, the identities and prognostic value of lymphangiogenic mediators remain unclear(2,14). Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches(15). Injectable lymphatic tracers have been developed(7), but their limited diffusion precludes whole-body imaging at visceral sites(16). Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' 17 because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer(17,18). Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis.
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| 50. |
- Paetzold, Martin, et al.
(author)
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Rosetta Radio Science Investigations (RSI)
- 2007
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In: Space Science Reviews. - : Springer Science and Business Media LLC. - 0038-6308 .- 1572-9672. ; 128:1-4, s. 599-627
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Research review (peer-reviewed)abstract
- The Rosetta spacecraft has been successfully launched on 2nd March 2004 to its new target comet 67 P/Churyurnov-Gerasimenko. The science objectives of the Rosetta Radio Science Investigations (RSI) experiment address fundamental aspects of cometary physics such as the mass and bulk density of the nucleus, its gravity field, its interplanetary orbit perturbed by nongravitational forces, its size and shape, its internal structure, the composition and roughness of the nucleus surface, the abundance of large dust grains, the plasma content in the coma and the combined dust and gas mass flux. The masses of two asteroids, Steins and Lutetia, shall be determined during flybys in 2008 and 2010. respectively. Secondary objectives are the radio sounding of the solar corona during the superior conjunctions of the spacecraft with the Sun during the cruise phase. The radio carrier links of the spacecraft Telemetry, Tracking and Command (TT&C) subsystem between the orbiter and the Earth will be used for these investigations. An Ultrastable oscillator (USO) connected to both transponders of the radio subsystem serves as a stable frequency reference source for both radio downlinks at X-band (8.4 GHz) and S-band (2.3 GHz) in the one-way mode. The Simultaneous and coherent dual-frequency downlinks via the High Gain Antenna (HGA) permit separation of contributions from the classical Doppler shift and the dispersive media effects caused by the motion of the spacecraft with respect to the Earth and the propagation of the signals through the dispersive media, respectively.
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