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The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis as well as transcriptome data across 763 primary tumors. Characterization of CD271+ and CD271- cells by RNA sequencing revealed that these two subpopulations are molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling is upregulated in the CD271+ population and inhibiting this pathway reduced CD271 levels, stem/progenitor cell proliferation and cell survival as well as cell migration in vitro. Importantly, the MEK inhibitor selumetinib extends survival and reduces CD271 levels in vivo. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH MB tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH MB cells.
The morphology of englacial drainage networks and their temporal evolution are poorly characterised, particularly within cold ice masses. At present, direct observations of englacial channels are restricted in both spatial and temporal resolution. Through novel use of a terrestrial laser scanning (TLS) system, the interior geometry of an englacial channel in Austre Brøggerbreen, Svalbard, was reconstructed and mapped. Twenty-eight laser scan surveys were conducted in March 2016, capturing the glacier surface around a moulin entrance and the uppermost 122 m reach of the adjoining conduit. The resulting point clouds provide detailed 3-D visualisation of the channel with point accuracy of 6.54 mm, despite low (<60%) overall laser returns as a result of the physical and optical properties of the clean ice, snow, hoar frost and sediment surfaces forming the conduit interior. These point clouds are used to map the conduit morphology, enabling extraction of millimetre-to-centimetre scale geometric measurements. The conduit meanders at a depth of 48 m, with a sinuosity of 2.7, exhibiting teardrop shaped cross-section morphology. This improvement upon traditional surveying techniques demonstrates the potential of TLS as an investigative tool to elucidate the nature of glacier hydrological networks, through reconstruction of channel geometry and wall composition.
Holstein-Friesian cattle are the predominant breed of dairy cattle in Northern Ireland. Breeding programmes for the Holstein Friesian have focused on improved milk production with little emphasis on functional traits such as fertility or disease resistance. In contrast Norwegian dairy cattle have been bred via a multi-trait selection procedure and there is evidence that problems associated with disease and fertility have tended to decrease in recent years. It is important, however, to investigate possible differences in efficiency of food use and partitioning of nutrients between the two breeds which may offset the potential advantages of improvements in secondary characteristics. Consequently, the objectives of this experiment were firstly to investigate the effects of breed type on the efficiency of utilization and partitioning of nutrients for milk production and secondly to investigate if there are differences in the energy requirement for maintenance and the efficiency of utilization of ME for lactation (kl) between the two breeds.
A number of equations for predicting methane energy output (CH4-E) in ruminants have been published since 1930. However the data used to develop these equations were collected from diets containing mainly dried or high dry matter (DM) forages, rather than low DM heavily fermented grass silages. Since 1992 a number of calorimetric studies have been carried out with growing and lactating cattle offered grass-silage based diets at the Agricultural Research Institute of Northern Ireland. The objective of the present study was to use these data to develop new relationships between CH4-E output and animal and dietary factors.
One of the cornerstones in the development of a new feed rationing system for dairy cows must involve a reappraisal of both the concepts and ‘numbers’ adopted in defining the energy requirements for dairy cows. This is particularly important in the present scenario where increasingly high levels of animal output are being achieved from very different animal genotypes to those used in UK dairying 20 - 30 years ago. One of the tasks within the Feed Into Milk (FIM) project was to develop a new system to predict the energy requirements of todays dairy cow. The objective of the present study was to collate all available energy metabolism data with dairy cows in the UK and to develop relationships for describing metabolisable energy (ME) requirement for maintenance (MEm) and efficiency of ME use for lactation (kl) using both existing and new methodologies.
The Feed into Milk (FIM) project in the United Kingdom has developed a Mitscherlich equation from calorimetric data for energy rationing of dairy cattle (Agnew et al., 2004). The objective of the present study was to evaluate this equation using independent data sets obtained in both calorimetric and production studies.
The current energy (E) feeding standards (AFRC, 1993) have the objective of providing accurate feeding of dairy cows when there is either zero tissue E retention or a given tissue E change. Such approaches are of limited practical value in the real world in which we must be able to predict optimum feeding levels and strategies for animals of differing milk yield potential producing in a range of physical and economic environments. In the latter context the key economic factor is how the animal responds to additional increments of feed. This is primarily driven by how the animal partitions that additional E between milk output and body tissue gain. The objective of this experiment was to use calorimetric techniques to explore the impact of level of metabolisable E (ME) intake (MEI) on milk E output (E1) and tissue E gain (Eg) and hence partitioning of increments of MEI between milk and tissues.
San Pietro and Rittenberg (1953) reported that urea appeared to meet all the requirements of a satisfactory tracer. Urea is non toxic, not foreign to the body and it shows an even and rapid distribution throughout the total body water without any physiological effect. For these reasons in addition to its easy and accurate measurement, urea is an ideal candidate tracer to estimate empty body water in vivo. Total body water volume (urea space) can be estimated by dividing the total amount of urea infused by the increase in plasma urea concentration from prior to infusion until 12 or 30 minutes after mean infusion time. Kock and Preston (1973) reported significant relationships between urea space measurements and percentage of empty body fat and water in cattle. However, Andrew et al. (1995) using 21 Holstein cows showed that prediction of empty body water using the urea space technique only explained 31 % of the variation. The objective of this experiment was to use the urea dilution technique to estimate the body composition of lactating dairy cows and produce relationships between urea space and body fat and protein content.
Background: Dysphagia is a common and devastating complication after acute stroke. Percutaneous endoscopic gastrostomy (PEG) tubes are often placed for persistent dysphagia. However, little is known regarding outcomes after PEG tube placement. Methods: We used a 10-year Ontario Stroke Registry to shed light on the clinical outcomes of patients with PEG tube insertion after ischemic stroke or intracranial hemorrhage compared to patients with only NG tubes, including rate of pneumonia, disability, and mortality. Results: Using propensity score matching, 1,793 patients were successfully matched and had similar baseline characteristics. Compared with NG, patients with PEG had a higher rate of pneumonia (32.6% vs. 20.6%; RR 1.59), higher disability at discharge (modified Rankin Scale Score 3-5; 74.0% vs. 65.4%; RR 1.13), and higher rate of long-term care placement (27.1% vs. 9.3%; RR 2.9). >From stroke onset, there was a lower rate of death in patients with PEG compared to NG at 30 days (15.3% vs. 34.3%; RR 0.45) but no difference at 2 years (52.8% vs. 53.5%; RR 0.99, p=0.71). *All significant p <0.0001. Conclusions: In conclusion, PEG tube placement after stroke may prolong survival in patients with poor outcomes. Our study provides a framework for discussions between physicians, patients, and families with regards to expected prognosis after PEG tube placement.
Background: In patients with acute stroke, nasogastric (NG) tubes are commonly inserted for feeding when dysphagia is identified, and percutaneous endoscopic gastrostomy (PEG) tubes are placed for severe or persistent dysphagia. However, little is known regarding predictors of PEG insertion. Methods: We used the Ontario stroke registry from 2003-2013 to identify baseline characteristics of all patients with NG or PEG tube insertion after stroke. We used multiple logistic regression with backwards selection to determine variables that were independent predictors of PEG tube insertion during admission. Results: 4002 patients with NG and 1903 patients with PEG were included in the analysis. Independent predictors of PEG were: Age (80+ vs. <60; odds ratio [OR] 1.70), past history of stroke (OR 1.17), higher stroke severity (severe vs. mild stroke; OR 1.37), stroke unit admission (OR 1.46), and dysphagia screening (OR 1.52). Factors associated with reduced odds of PEG insertion were: Prior history of peptic ulcer disease (OR 0.70), prior independence (OR 0.78), dementia (OR 0.76), palliative status (OR 0.49), and thrombolysis (OR 0.66). *All p<0.01 Conclusions: The strongest predictors of PEG were older age, higher stroke severity, stroke unit admission and dysphagia screening. Patients with dementia had reduced odds of PEG. Thrombolysis also reduced odds of PEG and may be protective.
Bakaninbreen, a 17 km long glacier terminating in fjord waters in central Spitsbergen (77°45′ N, 17°20′E), began to surge between the springs of 1985 and 1986. By summer 1994 the surge front had reached a position 3 km from the terminus and had almost ceased propagation. Structural investigations were undertaken to characterise the tectonic evolution of this thermally complex surge-type glacier, and the role played by thrusting and its effect on debris entrainment. Much of the glacier surface, particularly within and below the surge front, displayed transverse high-angle thrusts, defined by discrete fractures bounded by coarse clear ice. Some fractures were associated with a film of mud, whereas in others a discrete laver of diamicton, with interstitial ice several decimetres thick, was evident. Within the surge front, and genetically related to the thrusts, was a number of shear zones several metres wide. These were defined by fine-grained ice that was the product of the grinding up of crystals during shear (mylonitization). Three main sedimentary facies are associated with the thrusts: mud, gravelly mud and clast-rich muddy diamicton. The diamicton has the character of basal glacial debris: grain-size distribution ranging from clay to cobble size, clasts with a predominance in the sub-angular and sub-rounded classes, and striated and faceted clasts. Hot-water drilling through the glacier revealed several englacial layers above the surge front, and debris brought up on the drill stem suggests a basal origin. At least some of these englacial layers are probably the sub-surface continuations of the thrusts. The observed facies indicate that the glacier is moving over a soft, deformable bed and that thrusting is an important process in transferring debris to the surface, especially when the surge front is propagating down-glacier.
Introduction: Multiples barriers to appropriate analgesia are reported in the paediatric emergency department (PED), including limited accessibility to effective strategies. Our objective: was to evaluate the improvement in the accessibility of pain and anxiety management strategies in Canadian PEDs, after the creation of a national pediatric pain Quality Improvement Collaborative (QIC), through Pediatric Emergency Research Canada (PERC). Methods: In 2013, the TRAPPED 1 survey was administered to Canadian PEDs, in order to evaluate what resources were in place for pain and anxiety management. A pain QIC was then created to stimulate the implementation of new strategies, through information sharing between PEDs. In 2015, the TRAPPED 2 cross sectional survey was administered. Its focus was to evaluate the improvement in the accessibility of specific strategies reported by each centre, after participating in this QIC, and working to implement change within their own PEDs. Results: All 15/15 Canadian PEDs responded to the TRAPPED 1 survey in 2013 and 11 agreed to participate in the national pain QIC. In-person, phone meetings, follow up surveys and email communications were employed for information sharing. Strategies identified by the QIC to be newly introduced in individual centres were educational initiatives, distraction options, nurse-initiated protocols and intranasal (IN) medications. All 15 PEDs completed the TRAPPED 2 survey. Compared to 2013, an increased number of PEDs used face-based pain scales (14/15 vs 6/15) and behavioural scales (5/15 vs 1/15) for pain assessment in 2015. Use of reminder posters on pain management at triage increased from 4/15 to 6/15 PEDs. Availability of tablets for distraction increased from 4/15 to 10/15 PEDs. Nurse-initiated protocols for topical anesthetic and oral sucrose (for needle procedures) increased from 10/15 to 12/15 sites and from 12/15 to 14/15 sites respectively. Availability of IN medications increased; fentanyl from 9/15 to 14/15 sites and midazolam from 8/15 to 10/15 sites. Ten of the 11 PEDs involved in the QIC strategy reported the implementation of at least one of their own identified strategies. Conclusion: This study suggests that the use of a QIC may improve the introduction of new strategies to reduce pain and anxiety in EDs. QICs may also be helpful to other centres when introducing new strategies.
A multi-faceted, multi-institutional laboratory astrophysics program is carried out at the Livermore electron beam ion trap facility, which is a mature spectroscopic source with unsurpassed controls and capabilities, and an unparalleled assortment of spectroscopic equipment, including a full complement of grating and crystal spectrometers and a 6x6 micro-calorimeter array. Recent results range from the calibration of x-ray diagnostics, including the Fe XVII and Fe XXV emission lines, extensive lists of L-shell ions, the first laboratory simulation and fit of a cometary x-ray emission spectrum, and the discovery of new spectral diagnostics for measuring magnetic field strengths.
Impaired neuropsychological functioning is a feature of major depression. Previous studies have suggested that at least some aspects of neuropsychological functioning improve with successful treatment of major depression. The extent to which medications may affect the degree of normalization of these functions is unclear. The aim of the current study was to examine the course of neuropsychological functioning during treatment of major depression with cognitive–behaviour therapy (CBT) or schema therapy (ST).
A total of 69 out-patients with a primary diagnosis of major depression and 58 healthy controls completed mood ratings, neuropsychological measures, and measures of emotional processing at baseline and after 16 weeks. Participants were randomized after baseline assessment to a year-long course of CBT or ST. Patients reassessed at 16 weeks were medication-free throughout the study.
Significant neuropsychological impairment was evident at baseline in depressed participants compared with healthy controls. After 16 weeks of psychotherapy, mean depression rating scores fell more than 50%. However, no neuropsychological measures showed convincing evidence of significant improvement and emotional processing did not change.
Persisting impairment in neuropsychological functioning after the first 16 weeks of CBT or ST suggests a need to modify psychological treatments to include components targeting cognitive functioning.
Resonance lines of coronal ions of silicon are prominent in the spectral ranges 40–62 Å and 254–356 Å.
An unexpected feature of the soft X-ray spectrum is the weakness or absence of the resonance lines of iron in ionization stages XI through XV.
A second feature is the prominence of lines of the type (3d → 2p) relative to the resonance transitions (3p → 2s) in Li-like and Beryllium-like spectra. It is suggested that the upper levels (3d) are excited by quadrupole collisions from the ground 2s or 2s2 levels.
The intensity of the soft X-ray lines relative to the resonance lines in the 300 Å region seems to be more consistent with temperatures well above one million degrees than with temperatures as low as 700000°K, but the data are not adequate for a precise comparison. The relative intensity of the line emission from the various stages of silicon ionization may be interpreted as indicating that the ionization of silicon peaks in stages IX and X.
The abundances of C, Mg, S, and Al relative to silicon do not seem to be greatly different from the chromospheric abundances reported by Pottasch or with the photospheric abundances.
Attentional impairment is a core cognitive feature of major depressive disorder (MDD) and bipolar disorder (BD). However, little is known of the characteristics of response time (RT) distributions from attentional tasks. This is crucial to furthering our understanding of the profile and extent of cognitive intra-individual variability (IIV) in mood disorders.
A computerized sustained attention task was administered to 138 healthy controls and 158 patients with a mood disorder: 86 euthymic BD, 33 depressed BD and 39 medication-free MDD patients. Measures of IIV, including individual standard deviation (iSD) and coefficient of variation (CoV), were derived for each participant. Ex-Gaussian (and Vincentile) analyses were used to characterize the RT distributions into three components: mu and sigma (mean and standard deviation of the Gaussian portion of the distribution) and tau (the ‘slow tail’ of the distribution).
Compared with healthy controls, iSD was increased significantly in all patient samples. Due to minimal changes in average RT, CoV was only increased significantly in BD depressed patients. Ex-Gaussian modelling indicated a significant increase in tau in euthymic BD [Cohen's d = 0.39, 95% confidence interval (CI) 0.09–0.69, p = 0.011], and both sigma (d = 0.57, 95% CI 0.07–1.05, p = 0.025) and tau (d = 1.14, 95% CI 0.60–1.64, p < 0.0001) in depressed BD. The mu parameter did not differ from controls.
Increased cognitive variability may be a core feature of mood disorders. This is the first demonstration of differences in attentional RT distribution parameters between MDD and BD, and BD depression and euthymia. These data highlight the utility of applying measures of IIV to characterize neurocognitive variability and the great potential for future application.
The paper describes a process which allows a vertical circular cylinder subject to plane monochromatic surface gravity waves to appear invisible to the far-field observer. This is achieved by surrounding the cylinder with an annular region of variable bathymetry. Two approaches are taken to investigate this effect. First a mild-slope approximation is applied to the governing linearised three-dimensional water wave equations to formulate a depth-averaged two-dimensional wave equation with varying wavenumber over the variable bathmetry. This is then solved by formulating a domain integral equation, solved numerically by discretisation. For a given set of geometrical and wave parameters, the bathymetry is selected by a numerical optimisation process and it is shown that the scattering cross-section is reduced towards zero with increasing refinement of the bathymetry. A fully three-dimensional boundary-element method, based on the WAMIT solver (see www.wamit.com) but adapted here to allow for depressions in the bed, is used to assess the accuracy of the mild-slope results and then further numerically optimise the bathymetry towards a cloaking structure. Numerical results provide strong evidence that perfect cloaking is possible for the fully three-dimensional problem. One practical application of the results is that cloaking implies a reduced mean drift force on the cylinder.