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We describe the case of an 11-month-old girl with a rare cerebellar glioblastoma driven by a NACC2-NTRK2 (Nucleus Accumbens Associated Protein 2-Neurotrophic Receptor Tyrosine Kinase 2) fusion. Initial workup of our case demonstrated homozygous CDKN2A deletion, but immunohistochemistry for other driver mutations, including IDH1 R132H, BRAF V600E, and H3F3A K27M were negative, and ATRX was retained. Tissue was subsequently submitted for personalized oncogenomic analysis, including whole genome and whole transcriptome sequencing, which demonstrated an activating NTRK2 fusion, as well as high PD-L1 expression, which was subsequently confirmed by immunohistochemistry. Furthermore, H3 and IDH demonstrated wildtype status. These findings suggested the possibility of treatment with either NTRK- or immune checkpoint- inhibitors through active clinical trials. Ultimately, the family pursued standard treatment that involved Head Start III chemotherapy and proton radiotherapy. Notably, at most recent follow upapproximately two years from initial diagnosis, the patient is in disease remission and thriving, suggesting favorable biology despite histologic malignancy. This case illustrates the value of personalized oncogenomics, as the molecular profiling revealed two actionable changes that would not have been apparent through routine diagnostics. NTRK fusions are known oncogenic drivers in a range of cancer types, but this is the first report of a NACC2-NTRK2 fusion in a glioblastoma.
This presentation will enable the learner to:
1.Explore the current molecular landscape of pediatric high grade gliomas
2.Recognize the value of personalized oncogenomic analysis, particularly in rare and/or aggressive tumors
3.Discuss the current status of NTRK inhibitor clinical trials
Geomicrobiological investigations benefit from knowledge of geochemical and biological systems at different scales, including information about both the abiotic and the biotic components. Gathering this information requires analysis and characterization of both abiotic and biotic components of the target system. The techniques presented in this chapter were selected to cover a variety of needs in geomicrobiological studies, including general sample collection and storage, organic and inorganic compound quantification, and best practices for cultivation, observation, and analysis of microorganisms and microbial communities. In this chapter, introductions and discussions for common techniques provide the reader with a basic understanding of the technique itself, which samples can be analyzed using the technique, and how to prepare samples for analysis. Detailed methods are provided for select techniques, and citations to standard methods are provided for techniques whenever available. For techniques that are rapidly evolving, recent developments and applications are discussed.
The National Institute for Health and Care Excellence (NICE) invited the manufacturer of olaratumab (Lartruvo®), Eli Lilly & Company Limited, to submit evidence for the clinical and cost effectiveness of this drug, in combination with doxorubicin, for advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy, as part of the Institute's Single Technology Appraisal. The Peninsula Technology Assessment Group critically reviewed the submitted evidence.
Clinical effectiveness was derived from an open-label, randomized controlled trial, JGDG. The economic analysis was based on a partitioned survival model with a time horizon of 25 years. The perspective was of the UK National Health Service (NHS) and Personal Social Services. Costs and benefits were discounted at 3.5 percent per year. The company's evidence was submitted in anticipation that olaratumab would be considered as an alternative to doxorubicin, which has been used as a first-line treatment for advanced STS. To improve the cost effectiveness of olaratumab, the company offered a discount through a Commercial Access Agreement with the NHS England.
In the company's submission, the mean base-case and probabilistic incremental cost-effectiveness ratios (ICERs) for olaratumab plus doxorubicin versus doxorubicin alone were GBP 46,076 (USD 61,403) and GBP 47,127 (USD 62,804) per quality-adjusted life-year (QALY) gained, respectively; the probability of this treatment being cost effective at the willingness-to-pay threshold of GBP 50,000 (USD 66,632) per QALY gained, applicable to end-of-life treatments, was 0.54. The respective estimates in our analysis were approximately GBP 60,000 (USD 79,959) per QALY gained, and the probability of cost-effectiveness was 0.21. The increase in the ICERs was primarily due to differences in extrapolation of overall survival, and drug administration costs.
Based on the available evidence, olaratumab in combination with doxorubicin improves the survival of patients with advanced STS. However, this treatment is unlikely to be cost-effective. Olaratumab is now recommended for use within the Cancer Drugs Fund.
The Kapalagulu intrusion displays the following sequence of cumulus phase layering in a stratigraphic sequence of 1400 m: Basal Zone (BZ) olivine ± chromite → Intermediate Zone (IZ) olivine + plag + opx →, olivine + plag + opx + cpx → Main Zone (MZ) plag + opx + cpx → plag + cpx + Fe/Ti oxide + apatite. The corresponding cryptic variation is olivine Fo83 − 77 (limited to BZ and IZ), orthopyroxene En82 − 56, clinopyroxene Ca46Mg45Fe9 to Ca43Mg37Fe21 and plagioclase An88 − 80. Reversals of the cryptic variation occur at the base of MZ (minor reversal) and in the middle of MZ (major reversal), and are attributed to the influx of relatively primitive magma. The major reversal indicates that progressive mixing of fresh and residual magmas occurred. Because of the major reversal, inverted pigeonite appears twice in the layered sequence, but at different compositions (En65 and En56). Unlike the cumulus olivine and pyroxene, cumulus plagioclase exhibits a wide range of composition (5−10% An) in individual rocks and even in single crystals.
To describe a case of concurrent cricopharyngeal achalasia with laryngomalacia as a cause of failure to thrive, and to review the literature and management options of cricopharyngeal achalasia in the paediatric population.
A chart review was performed on a four-month-old male, referred for failure to thrive, and diagnosed with cricopharyngeal achalasia and laryngomalacia. A PubMed and Embase search for ‘cricopharyngeal achalasia’ and ‘laryngomalacia’ was conducted. A review of reported paediatric cricopharyngeal achalasia patients, with emphasis on management options, was undertaken.
A flexible laryngoscopic examination confirmed the laryngomalacia diagnosis, and videofluoroscopic evaluation of swallowing demonstrated cricopharyngeal achalasia via a cricopharyngeal bar. Supraglottoplasty was performed, with botulinum toxin injection into the cricopharyngeus muscle, with resultant improvement in oral intake and resolution of failure to thrive. The literature review revealed no reported case of the combined pathologies as a cause of failure to thrive.
Functional endoscopic evaluation of swallowing and videofluoroscopic evaluation of swallowing are complimentary in the evaluation of paediatric patients with failure to thrive and suspected oropharyngeal dysphagia. Both supraglottoplasty and botulinum toxin injection are effective for definitive management in cases of combined pathology, and can be safely performed in a single surgical setting.
SVcPACNS is a rare inflammatory/immune disorder that typically affects the small blood vessels of the brain. SVcPACNS differs from most adult forms of PACNS by being predominantly lymphocytic, non-granulomatous and non-necrotizing. Previously healthy children are typically affected by range of signs and symptoms, including: seizures, headache, cognitive decline, behavior/personality change, focal neurological deficits and potentially a decreased level of consciousness. Treatment protocols featuring induction (steroids and cyclophosphamide) and subsequent maintenance phases (e.g., mycophenolate mofetil) have been demonstrated to yield favorable outcomes. Since SVcPACNS is characteristically angiography negative, the diagnostic gold standard is brain biopsy. Interpretation of these biopsies is often challenging given the histologic overlap between SVcPACNS and encephalitis. Distinguishing the foregoing is critical since the treatment of these entities is significantly different.
Herein, a rare autopsy case of SVcPACNS in a 4 year old male is presented. This case provides a unique opportunity to review the Alrawi criteria for the histologic diagnosis of PACNS and establish/refine criteria specific to SVcPACNS. Generally, such criteria should feature: 1) an intramural and lymphocyte predominant infiltrate devoid of multinucleated giant cells; 2) structural vessel alterations lacking fibrinoid necrosis; 3) perivascular pathology supportive of an angiocentric process; 4) the absence of encephalitis; and, 5) the absence of a concurrent systemic or rheumatic illness that could account for the CNS findings.
By contrast to infantile spinal muscular atrophy, which usually links to deletions in the SMN genes, fetal onset motor neuron disease is poorly reported. We collected a series of twelve cases of fetal arthrogryposis (16-31 weeks gestational age) with fetal motor neuron disease and excluded infectious diseases, lysosomal storage disease and neuroaxonal dystrophy. Of these twelve, 3 were thought to be ischemic in nature with microvascular alterations and systemic or central nervous system ischemic injury. The remaining 9 all displayed marked reduction in anterior horn motor neurons. Of these 9, four demonstrated mineralised neurons, four demonstrated either neuronal loss or cavitation in the globus pallidus, and in two, degenerating neurons were detectable in the brainstem or globus pallidus. Specific sequencing of SMN1 was performed in 6 of 9 and was reported as normal. Whole exome sequencing was performed in 4 without definitive diagnosis. We conclude that fetal motor neuron disease can be distinguished from ischemic injury, is morphologically heterogeneous, may affect the globus pallidus and is rarely linked to SMN1 mutations.
High quality active layers for hybrid organic-inorganic perovskite solar cells are essential for achieving maximum device performance. However, perovskite active layers in solar cells are frequently prepared with unoptimized processes that lead to layers of inferior quality. This is often the case when research focuses on other aspects of the solar cell device, such as device design and architecture, carrier transport layers, electrodes, interlayers, etc. In this study, a single-step spin-coating method was used to prepare semi-crystalline PbI2(DMSO) complex films via evaporation-induced self-assembly. These optimized intermediate films were then used to form homogeneous methylammonium lead iodide (MAPbI3) perovskite films of optimum thickness (ca. 400 nm) with uniform surface coverage, good crystallinity, high purity, and grain sizes up to one micron, by employing a sequential deposition process involving intramolecular exchange between the PbI2(DMSO) complex film and a methylammonium iodide (MAI) layer deposited on top of it. We found that for certain ranges of MAI concentration, the formation of optimal-quality perovskite active layers was independent of MAI concentration, so long as MAI deposition occurred at specific corresponding spin speeds. Planar p-i-n perovskite solar cells comprising the optimized active layers were fabricated, and they exhibited negligible hysteresis and a maximum power conversion efficiency (PCE) of 16.72%, without any additional compositional and interfacial engineering. The latter can be used in the future to further enhance the PCE. These findings demonstrate the importance of an optimized perovskite active layer for reproducibly fabricating high-efficiency planar p-i-n photovoltaic devices. Additionally, the simplicity of the PbI2(DMSO) complex film preparation and the versatility of the MAI deposition with this fabrication method further enhances the potential of this material for large-scale processing.
Northern bobwhite (Colinus virginianus) and scaled quail (Callipepla squamata) have experienced chronic declines within the Rolling Plains ecoregion of Texas. Parasitic infection, which has long been dismissed as a problem in quail, has not been studied thoroughly until recently. A total of 219 northern bobwhite and 101 scaled quail from Mitchell County, Texas were captured and donated from 2014 to 2015, and examined for eyeworm (Oxyspirura petrowi) and caecal worm (Aulonocephalus pennula) infections. In 2014, bobwhites averaged 19.6 ± 1.8 eyeworms and 98.6 ± 8.2 caecal worms, and 23.5 ± 2.1 eyeworms and 129.9 ± 10.7 caecal worms in 2015. Scaled quail averaged 4.8 ± 1.0 eyeworms and 50 ± 6.8 caecal worms in 2014, and 5.7 ± 1.3 eyeworms and 38.1 ± 7.1 caecal worms in 2015. This study expands the knowledge of parasitic infection in quail inhabiting the Rolling Plains of Texas. A significant difference was documented in O. petrowi infection between species but there was no significant difference in A. pennula between quail species. No significant difference was detected in parasite infection between the sexes of both northern bobwhite and scaled quail. This study also documented the highest reported O. petrowi infection in both species of quail. Additional research is needed on the life history and infection dynamics of O. petrowi and A. pennula infections to determine if there are individual- and/or population-level implications due to parasitic infection.
Northern bobwhite (Colinus virginianus) and Scaled quail (Callipepla squamata) have been declining steadily throughout much of their historical range over the past few decades. Even the Rolling Plains of Texas, historically rich with wild quail and one of the last remaining quail strongholds, has been suffering a population decline, most notably since 2010. Gambel's quail (Callipepla gambelii) have also been experiencing their own decline throughout their respective range, but not as significant as that of other species of quail. Eyeworms (Oxyspirura petrowi) in quail have been recognized for years but not thoroughly studied until recently. New research reveals that O. petrowi infection can cause inflammation, oedema, and cellular damage to the eye of the quail host. The objective of this research was to better understand the prevalence of the eyeworm infection in different quail species, expand on known distribution, and determine if there is a relationship between location and species infected with eyeworms. Northern bobwhite, Scaled quail and Gambel's quail were hunter-donated from one county within Texas, New Mexico and Arizona, and examined for the prevalence, mean abundance and mean intensity of eyeworm infection from November 2013 to February 2014. Quail from every location were found to have individuals with a varying degree of eyeworm infection. This is the first study to document eyeworm infection in Gambel's quail and in quail in New Mexico and Arizona, and reports the highest eyeworm infection found in Northern bobwhite and Scaled quail.
Oxyspirura petrowi is a heteroxenous parasitic nematode that has been reported in high prevalences from birds in the Order Galliformes experiencing population declines in the USA. There is a paucity of information regarding the natural history O. petrowi, including the life cycle and effects of infection on wild bird populations. In order to study the life cycle of this parasite, we collected plains lubber grasshoppers (Brachystola magna) from a field location in Mitchell County, Texas. We found third-stage larvae (L3) in 37.9% (66/174) B. magna. We determined that they were O. petrowi through morphological comparison of L3 from experimentally infected Acheta domesticus and by sequence analysis. Then, we showed that B. magna are a potential intermediate hosts for O. petrowi infections in northern bobwhites (Colinus virginianus) in a laboratory setting by experimental infection. We first detected shedding of eggs in feces using a fecal float technique 52 days post infection. In addition, we recovered 87 O. petrowi from experimentally infected northern bobwhites. Although we detected shedding in feces, recovery of eggs was low (>5 eggs/g). Future work is needed to understand shedding routes and shedding patterns of northern bobwhites infected with O. petrowi.
Oscillations of magma in volcanic conduits are thought to be the source of certain seismic and infrasonic signals observed near active volcanoes. However, the multiphase and stratified nature of magma within the conduit complicates the calculation of resonant modes that is required to interpret observations. Here we present a linearized mathematical framework to describe small-amplitude oscillations and waves in a stably stratified column of two-phase magma (liquid melt and gas bubbles) with a traction-free upper surface (a lava lake). We explore the role of time-dependent mass exchange between the phases, depth-varying fluid properties and gravity on the modes of oscillation of inviscid magma within an axisymmetric, vertical conduit. Non-equilibrium phase exchange, which we refer to as bubble growth and resorption (BGR), is parameterized by introduction of a kinetic time scale quantifying mass exchange between the liquid and gas phases that evolves the mixture towards a state of thermodynamic equilibrium. Using a provably stable finite difference method, we solve the eigenvalue problem for the resonance frequencies, decay rates, and spatial structure of the conduit eigenmodes. The numerical method is then extended to time-domain simulations of waves excited by internal volumetric sources in the conduit or forces applied to the surface of the lava lake. We connect time-dependent wave propagation simulations to the modal analysis by identifying the primary modes that are excited by representative excitation processes. Waves propagating through bubbly magma are dispersive, and their behaviour is determined by three dimensionless parameters. One quantifies the importance of buoyancy and gravitational restoring forces relative to compressibility, the second quantifies differences between fluid properties (e.g. mixture compressibility) under equilibrium and non-equilibrium conditions, and the third compares the wave period to the BGR time scale. Pronounced depth variations in background fluid properties, such as the transition from liquid melt with dissolved volatiles at the high pressures at depth to bubbly magma above the gas exsolution depth, segment the conduit into distinct regions. The longest-period modes, which are expressed with the largest amplitudes for typical excitation processes, are most sensitive to the length of the bubbly region and properties of the bubbly magma within it. While the boundary condition at the bottom of the conduit determines whether the fundamental mode is affected by the total conduit length, modes localized above the exsolution depth are remarkably insensitive to the overall conduit length. Our analysis suggests that parameters affecting eruption style, such as total volatile content and kinetic time scales of BGR, along with excitation source characteristics, are imprinted on long-period seismic and infrasonic signals at active volcanoes.
At the first meeting of the newly formed Commission on Spectrophotometry, at Paris in 1935, a thorough discussion, aided by several reports, took place on the principles of this branch of astrophysics. So it will be sufficient now to treat only such special points of theory and practice as have won interest by researches of the last few years.
The following work embodying researches coming within the scope of this commission has been published since the last meeting of the Union: La Planète Mercure et la Rotation des Satellites, by E. M. Antoniadi; Gauthier-Villars, Paris.
In addition to references to the work of other astronomers the author gives a summary of his own observations with the 0.83 m. refractor at Meudon and his conclusions.
The following Memoirs or papers not specifically referred to in the body of the Report have also been published since the last meeting of the Union: Cometa Halley. Vol. xxv of Resultados del Observatorio Nacional Argentino. This is a monograph on the Comet at its 1910 return. By C. D. Perrine. Les Comètes en 1930,1931 et 1932. By F. Baldet. (L’ Astronomie 46,497 et 48,175.) I Fondamenti Psicologici dell’ Indagine Visuale. By M. Maggini. (Memorie dellaSoc. Astron. Italiana, Vol. VIII, 2.) Théorie Photométrique des Eclipses de Lune. By F. M. Link. (Bulletin Astronomique,
8 fase. 11.) Relative Lunar Heights and Topography by means of the Motion Picture Negative.
A modern coudé spectrograph for observing the spectra of stars and planets with maximum efficiency is a complex and versatile instrument, which represents an investment about equal to that for a 40-inch telescope. The trend toward special telescopes for special kinds of work began in the 1930s with Schmidt telescopes for wide angle photography, and has been followed by the use of specialized telescopes for photoelectric photometry, and more recently by telescopes for polarization measurements. Two telescopes designed for exclusive use with coudé spectrographs already exist—the 48-inch at Victoria and the 60-inch at Haute Provence. More are needed, particularly in the southern hemisphere.