The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes.

AIMS: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies. METHODS: We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). RESULTS: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second-generation subtypes II/III/IV. Subtype II strongly associated with large-cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very-high-risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4 ) and subtype IV tumours were standard risk (80% OS) using upfront CSI-based therapies; randomized-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. Seventy-five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non-DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH . iMBSHH harboured two distinct subtypes (iMBSHH-I/II ). Within the discriminated favourable-risk iMBSHH DN/MBEN patient group, iMBSHH-II had significantly better progression-free survival than iMBSHH-I , offering opportunities for risk-adapted stratification of upfront therapies. Both iMBSHH-I and iMBSHH-II showed notable rescue rates (56% combined post-relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. CONCLUSIONS: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.

3D Echocardiography Provides Highly Accurate 3D Printed Models in Congenital Heart Disease.

Cardiac 3D printing is mainly performed from magnetic resonance imaging (MRI) and computed tomography (CT) 3D datasets, though anatomic detail of atrioventricular (AV) valves may be limited. 3D echo provides excellent visualization of AV valves. Thus, we tested the feasibility and accuracy of 3D printing from 3D echo in this pilot series of subjects with congenital heart disease (CHD), with a focus on valve anatomy. Five subjects with CHD were identified. 3D echo data were converted to 3D printable files and printed in collaboration with 3D Systems Healthcare (Golden, Colorado). A novel technique for valve modeling was utilized using commercially available software. Two readers (KM, SA) independently measured valve structures from 3D models and compared to source echo images. 3D printing was feasible for all cases. Table 1 shows measurements comparing 2D echo to 3D models. Bland Altman analysis showed close agreement and no significant bias between 2D and digital 3D models (mean difference 0.0, 95% CI 1.1 to - 1.1) or 2D vs printed 3D models, though with wider limits of agreement (mean difference - 0.3, 95% CI 1.9 to - 2.6). Accuracy of 3D models compared to 2D was within < 0.5 mm. This pilot study shows 3D echo datasets can be used to reliably print AV and semilunar valve structures in CHD. The 3D models are highly accurate compared to the source echo images. This is a novel and value-added technique that adds incremental information on cardiac anatomy over current methods.

Erratum: Evidence for a Phase Transition in Silicate Melt at Extreme Pressure and Temperature Conditions [Phys. Rev. Lett. 108, 065701 (2012)].

This corrects the article DOI: 10.1103/PhysRevLett.108.065701.

Pathobiological investigation of naturally infected canine rabies cases from Sri Lanka.

BACKGROUND: The recommended screening of rabies in 'suspect' animal cases involves testing fresh brain tissue. The preservation of fresh tissue however can be difficult under field conditions and formalin fixation provides a simple alternative that may allow a confirmatory diagnosis. The occurrence and location of histopathological changes and immunohistochemical (IHC) labelling for rabies in formalin fixed paraffin embedded (FFPE) canine brain is described in samples from 57 rabies suspect cases from Sri-Lanka. The presence of Negri bodies and immunohistochemical detection of rabies virus antigen were evaluated in the cortex, hippocampus, cerebellum and brainstem. The effect of autolysis and artefactual degeneration of the tissue was also assessed. RESULTS: Rabies was confirmed in 53 of 57 (93%) cases by IHC. IHC labelling was statistically more abundant in the brainstem. Negri bodies were observed in 32 of 53 (60.4%) of the positive cases. Although tissue degradation had no effect on IHC diagnosis, it was associated with an inability to detect Negri bodies. In 13 cases, a confirmatory Polymerase chain reaction (PCR) testing for rabies virus RNA was undertaken by extracting RNA from fresh frozen tissue, and also attempted using FFPE samples. PCR detection using fresh frozen samples was in agreement with the IHC results. The PCR method from FFPE tissues was suitable for control material but unsuccessful in our field cases. CONCLUSIONS: Histopathological examination of the brain is essential to define the differential diagnoses of behaviour modifying conditions in rabies virus negative cases, but it is unreliable as the sole method for rabies diagnosis, particularly where artefactual change has occurred. Formalin fixation and paraffin embedding does not prevent detection of rabies virus via IHC labelling even where artefactual degeneration has occurred. This could represent a pragmatic secondary assay for rabies diagnosis in the field because formalin fixation can prevent sample degeneration. The brain stem was shown to be the site with most viral immunoreactivity; supporting recommended sampling protocols in favour of improved necropsy safety in the field. PCR testing of formalin fixed tissue may be successful in certain circumstances as an alternative test.

Changes in aquaporin-4 and Kir4.1 expression in rats with inherited retinal dystrophy.

Muller glial cells (MGC) are essential for normal functioning of retina. They are especially involved in potassium (K+) and water homeostasis, via inwardly rectifying K+ (Kir 4.1) and aquaporin-4 (AQP4) channels respectively. Because MGC appear morphologically and functionally altered in most retinal pathologies, we studied the expression of AQP 4 and Kir 4.1 during the time course of progressive retinal degeneration in Royal College of Surgeons (RCS) rats, an animal model for the hereditary human retinal degenerative disease Retinitis pigmentosa. Simultaneous detection of AQP4 and Kir 4.1 was performed by quantitative real-time polymerase chain reaction (QRT-PCR), Western blot and immunohistochemistry at birth and during progression of the pathology. Although small quantities of AQP4 and Kir 4.1 mRNA were detected at birth (postnatal day (PNd) 0) in both control and dystrophic rat retinas, proteins could not be detected at this age. Detectable proteins appeared in the second week of postnatal life. From PNd15 onwards, the time course in the expression of both AQP4 and Kir 4.1 mRNAs and protein was similar in dystrophic and control rats, with a progressive increase peaking at PNd60 and a subsequent decrease by one year. AQP4 protein and mRNA content were significantly lowered in dystrophic compared to control rats. Kir 4.1 protein levels were also lower in dystrophic retinas, while mRNA concentrations were unchanged and/or slightly higher in dystrophic rats. The discrepancies between Kir4.1 mRNA and protein suggest perturbation in protein translation due to the pathology. AQP4 and Kir 4.1/vimentin co-immunolabeling showed that: 1) apical radial processes of some MGC invaded the subretinal zone, and 2) MGC morphology was distorted in advanced pathology. MGC became hypertrophic both during the pathology and also with age in control rats. In conclusion, our results confirm that this inherited photoreceptor degeneration also leads to progressive alterations in physiological and morphological parameters of MGC which may aggravate retinal impairment.

Assessment of a numerical model to reproduce event-scale erosion and deposition distributions in a braided river.

Numerical morphological modeling of braided rivers, using a physics-based approach, is increasingly used as a technique to explore controls on river pattern and, from an applied perspective, to simulate the impact of channel modifications. This paper assesses a depth-averaged nonuniform sediment model (Delft3D) to predict the morphodynamics of a 2.5 km long reach of the braided Rees River, New Zealand, during a single high-flow event. Evaluation of model performance primarily focused upon using high-resolution Digital Elevation Models (DEMs) of Difference, derived from a fusion of terrestrial laser scanning and optical empirical bathymetric mapping, to compare observed and predicted patterns of erosion and deposition and reach-scale sediment budgets. For the calibrated model, this was supplemented with planform metrics (e.g., braiding intensity). Extensive sensitivity analysis of model functions and parameters was executed, including consideration of numerical scheme for bed load component calculations, hydraulics, bed composition, bed load transport and bed slope effects, bank erosion, and frequency of calculations. Total predicted volumes of erosion and deposition corresponded well to those observed. The difference between predicted and observed volumes of erosion was less than the factor of two that characterizes the accuracy of the Gaeuman et al. bed load transport formula. Grain size distributions were best represented using two φ intervals. For unsteady flows, results were sensitive to the morphological time scale factor. The approach of comparing observed and predicted morphological sediment budgets shows the value of using natural experiment data sets for model testing. Sensitivity results are transferable to guide Delft3D applications to other rivers.

Distress in patients with bleeding disorders: a single institutional cross-sectional study.

INTRODUCTION: Distress may affect a patient's ability to cope with and manage disease. AIM: To report distress prevalence in adult patients with bleeding disorders and determine whether specific clinical and health characteristics, including disease severity and employment status, are associated with distress. METHODS: Patients who visited a Haemophilia Treatment Centre (HTC) between January 1st, 2012 through February 28th, 2014 and who completed a distress screen, pain screen and questionnaire were evaluated cross sectionally. Distress was measured by the National Comprehensive Cancer Network Distress Management Tool, which allowed patients to rate recent distress on a 0-10 point scale. A rating of five or more was categorized as high distress. Pain was measured by the Brief Pain Inventory Short Form, which asked patients to rate pain types on 0-10 point scales. Patients reported employment and other demographic and behavioural information on the questionnaire. Primary diagnosis, age, HIV and HCV status were abstracted from medical records. Adjusted logistic regression was used to identify distress associations. RESULTS: High distress prevalence among 152 patients with bleeding disorders was 31.6%. Unemployment, disability, greater depressive symptoms and higher pain were associated with high distress in multivariable models. Bleeding disorder diagnosis, race/ethnicity, HIV/HCV status and on-demand treatment regimen were not associated with high distress. CONCLUSION: Distress among patients with congenital bleeding disorders followed at a comprehensive HTC was high and similar to that reported among patients with cancer. Future research should determine whether distress impacts clinical outcomes in patients with bleeding disorders as demonstrated in other chronic disorders.

Solid iron compressed up to 560 GPa.

Dynamic compression by multiple shocks is used to compress iron up to 560 GPa (5.6 Mbar), the highest solid-state pressure yet attained for iron in the laboratory. Extended x-ray absorption fine structure (EXAFS) spectroscopy offers simultaneous density, temperature, and local-structure measurements for the compressed iron. The data show that the close-packed structure of iron is stable up to 560 GPa, the temperature at peak compression is significantly higher than expected from pure compressive work, and the dynamic strength of iron is many times greater than the static strength based on lower pressure data. The results provide the first constraint on the melting line of iron above 400 GPa.

Performance of high-convergence, layered DT implosions with extended-duration pulses at the National Ignition Facility.

Radiation-driven, low-adiabat, cryogenic DT layered plastic capsule implosions were carried out on the National Ignition Facility (NIF) to study the sensitivity of performance to peak power and drive duration. An implosion with extended drive and at reduced peak power of 350 TW achieved the highest compression with fuel areal density of ~1.3±0.1 g/cm2, representing a significant step from previously measured ~1.0 g/cm2 toward a goal of 1.5 g/cm2. Future experiments will focus on understanding and mitigating hydrodynamic instabilities and mix, and improving symmetry required to reach the threshold for thermonuclear ignition on NIF.

Onset of hydrodynamic mix in high-velocity, highly compressed inertial confinement fusion implosions.

Deuterium-tritium inertial confinement fusion implosion experiments on the National Ignition Facility have demonstrated yields ranging from 0.8 to 7×10(14), and record fuel areal densities of 0.7 to 1.3 g/cm2. These implosions use hohlraums irradiated with shaped laser pulses of 1.5-1.9 MJ energy. The laser peak power and duration at peak power were varied, as were the capsule ablator dopant concentrations and shell thicknesses. We quantify the level of hydrodynamic instability mix of the ablator into the hot spot from the measured elevated absolute x-ray emission of the hot spot. We observe that DT neutron yield and ion temperature decrease abruptly as the hot spot mix mass increases above several hundred ng. The comparison with radiation-hydrodynamic modeling indicates that low mode asymmetries and increased ablator surface perturbations may be responsible for the current performance.

Hot-spot mix in ignition-scale inertial confinement fusion targets.

Mixing of plastic ablator material, doped with Cu and Ge dopants, deep into the hot spot of ignition-scale inertial confinement fusion implosions by hydrodynamic instabilities is diagnosed with x-ray spectroscopy on the National Ignition Facility. The amount of hot-spot mix mass is determined from the absolute brightness of the emergent Cu and Ge K-shell emission. The Cu and Ge dopants placed at different radial locations in the plastic ablator show the ablation-front hydrodynamic instability is primarily responsible for hot-spot mix. Low neutron yields and hot-spot mix mass between 34(-13,+50) ng and 4000(-2970,+17 160) ng are observed.

Dam design can impede adaptive management of environmental flows: a case study from the Opuha Dam, New Zealand.

The Opuha Dam was designed for water storage, hydropower, and to augment summer low flows. Following its commissioning in 1999, algal blooms (dominated first by Phormidium and later Didymosphenia geminata) downstream of the dam were attributed to the reduced frequency and magnitude of high-flow events. In this study, we used a 20-year monitoring dataset to quantify changes associated with the dam. We also studied the effectiveness of flushing flows to remove periphyton from the river bed. Following the completion of the dam, daily maximum flows downstream have exceeded 100 m(3) s(-1) only three times; two of these floods exceeded the pre-dam mean annual flood of 203 m(3) s(-1) (compared to 19 times >100 m(3) s(-1) and 6 times >203 m(3) s(-1) in the 8 years of record before the dam). Other changes downstream included increases in water temperature, bed armoring, frequency of algal blooms, and changes to the aquatic invertebrate community. Seven experimental flushing flows resulted in limited periphyton reductions. Flood wave attenuation, bed armoring, and a shortage of surface sand and gravel, likely limited the effectiveness of these moderate floods. Floods similar to pre-dam levels may be effective for control of periphyton downstream; however, flushing flows of that magnitude are not possible with the existing dam infrastructure. These results highlight the need for dams to be planned and built with the capacity to provide the natural range of flows for adaptive management, particularly high flows.

Developments in rabies vaccines.

The development of vaccines that prevent rabies has a long and distinguished history, with the earliest preceding modern understanding of viruses and the mechanisms of immune protection against disease. The correct application of inactivated tissue culture-derived vaccines is highly effective at preventing the development of rabies, and very few failures are recorded. Furthermore, oral and parenteral vaccination is possible for wildlife, companion animals and livestock, again using inactivated tissue culture-derived virus. However, rabies remains endemic in many regions of the world and causes thousands of human deaths annually. There also remain no means of prophylaxis for rabies once the virus enters the central nervous system (CNS). One reason for this is the poor immune response within the CNS to infection with rabies virus (RABV). New approaches to vaccination using modified rabies viruses that express components of the innate immune system are being applied to this problem. Preliminary reports suggest that direct inoculation of such viruses could trigger an effective anti-viral response and prevent a fatal outcome from RABV infection.

Evidence for a phase transition in silicate melt at extreme pressure and temperature conditions.

Laser-driven shock compression experiments reveal the presence of a phase transition in MgSiO(3) over the pressure-temperature range 300-400 GPa and 10 000-16 000 K, with a positive Clapeyron slope and a volume change of ∼6.3 (±2.0) percent. The observations are most readily interpreted as an abrupt liquid-liquid transition in a silicate composition representative of terrestrial planetary mantles, implying potentially significant consequences for the thermal-chemical evolution of extrasolar planetary interiors. In addition, the present results extend the Hugoniot equation of state of MgSiO(3) single crystal and glass to 950 GPa.

Precision shock tuning on the national ignition facility.

Ignition implosions on the National Ignition Facility [J. D. Lindl et al., Phys. Plasmas 11, 339 (2004)] are underway with the goal of compressing deuterium-tritium fuel to a sufficiently high areal density (ρR) to sustain a self-propagating burn wave required for fusion power gain greater than unity. These implosions are driven with a very carefully tailored sequence of four shock waves that must be timed to very high precision to keep the fuel entropy and adiabat low and ρR high. The first series of precision tuning experiments on the National Ignition Facility, which use optical diagnostics to directly measure the strength and timing of all four shocks inside a hohlraum-driven, cryogenic liquid-deuterium-filled capsule interior have now been performed. The results of these experiments are presented demonstrating a significant decrease in adiabat over previously untuned implosions. The impact of the improved shock timing is confirmed in related deuterium-tritium layered capsule implosions, which show the highest fuel compression (ρR~1.0 g/cm(2)) measured to date, exceeding the previous record [V. Goncharov et al., Phys. Rev. Lett. 104, 165001 (2010)] by more than a factor of 3. The experiments also clearly reveal an issue with the 4th shock velocity, which is observed to be 20% slower than predictions from numerical simulation.

Assembly of high-areal-density deuterium-tritium fuel from indirectly driven cryogenic implosions.

The National Ignition Facility has been used to compress deuterium-tritium to an average areal density of ~1.0±0.1 g cm(-2), which is 67% of the ignition requirement. These conditions were obtained using 192 laser beams with total energy of 1-1.6 MJ and peak power up to 420 TW to create a hohlraum drive with a shaped power profile, peaking at a soft x-ray radiation temperature of 275-300 eV. This pulse delivered a series of shocks that compressed a capsule containing cryogenic deuterium-tritium to a radius of 25-35 µm. Neutron images of the implosion were used to estimate a fuel density of 500-800 g cm(-3).

Pathology associated with a human case of rabies in the United Kingdom caused by European bat lyssavirus type-2.

Human infection with the rabies-related virus European bat lyssavirus type-2 (EBLV-2) has only been reported on two occasions. Here we report the pathology observed within spinal cord and visceral tissues associated with EBLV-2 infection for the first time. Neuronal labelling with an anti-rabies nucleocapsid monoclonal antibody was observed and appeared indistinguishable from the labelling reported from human infection with rabies virus.

Velocity and timing of multiple spherically converging shock waves in liquid deuterium.

The fuel entropy and required drive energy for an inertial confinement fusion implosion are set by a sequence of shocks that must be precisely timed to achieve ignition. This Letter reports measurements of multiple spherical shock waves in liquid deuterium that facilitate timing inertial confinement fusion shocks to the required precision. These experiments produced the highest shock velocity observed in liquid deuterium (U(s) = 135 km/s at ∼2500 GPa) and also the first observation of convergence effects on the shock velocity. Simulations model the shock-timing results well when a nonlocal transport model is used in the coronal plasma.

Insulator-to-conducting transition in dense fluid helium.

By combining diamond-anvil-cell and laser-driven shock wave techniques, we produced dense He samples up to 1.5 g/cm(3) at temperatures reaching 60 kK. Optical measurements of reflectivity and temperature show that electronic conduction in He at these conditions is temperature-activated (semiconducting). A fit to the data suggests that the mobility gap closes with increasing density, and that hot dense He becomes metallic above approximately 1.9 g/cm(3). These data provide a benchmark to test models that describe He ionization at conditions found in astrophysical objects, such as cold white dwarf atmospheres.