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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
Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.
The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants.
There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.
Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
The analysis of sulfur in coal has been brought to the attention of the general public in recent years primarily as it concerns the pollution problem with coal-fired electric generation. Although our application is different, some of the results would be equally applicable to that circumstance. The Cement Division of Florida Mining and Materials Corporation produces annually about 500,000 tons of both Portland and Pozzolanic cements, using a coal-fired rotary kiln. The sulfur content of coal used in the manufacture of clinker ranges from traces to as much as 6%. Sulfur content in a dry process plant such as ours (this is the modern energy-efficient type of cement plant) is very critical, and in our case must be limited to 1.2% max.
Instrument specifications as published by manufacturers generally include values for stability of various parameters or components. For an X-ray fluorescence system, a typical example might be the generator high voltage stability (perhaps 0.01%). Parameters of this sort are of course of some use in comparing systems, and they may be (and often are) of great importance to the manufacturer as a criterion of manufacturing quality. It is difficult for the user to know how any single one, or combination of these factors really affect the total system performance as it may relate to his application.
Motivated by subsurface carbon sequestration, an experimental investigation of dissolution-driven Rayleigh–Darcy convection using two miscible fluids in a Hele-Shaw cell is conducted. A thin horizontal layer of circular impermeable discs is inserted to create an environment with heterogeneous and anisotropic permeability. The Sherwood number that measures the convective mass transfer rate between two fluids at the interface is linked to different parameters of the disc layer, including the disc size, spacing, layer permeability and its relative height with respect to the fluid interface. It is surprising that the convective mass transfer rate in our configuration is dominated by the disc spacing, but almost independent of either the disc size or the mean permeability of the layer. To explain this dependence, the convective mass transfer rate is decomposed into the number, velocity and density contrast of fingers travelling through the disc layer. Both the number and density contrast of fingers show dependences on the disc layer permeability, even though the product of them, the mass transfer rate, does not. In addition, the density contrast also shows a non-monotonic dependence on the disc spacing. The transition point is at a spacing that is close to the finger width. Based on this observation, a simple model based on mixing and scale competition is proposed, and it shows an excellent agreement with the experimental results.
High-energy electron radiography (HEER) has been proposed for time-resolved imaging of materials, high-energy density matter, and for inertial confinement fusion. The areal-density resolution, determined by the image intensity information is critical for these types of diagnostics. Preliminary experimental studies for different materials with the same thickness and the same areal-density target have been imaged and analyzed. Although there are some discrepancies between experimental and theory analysis, the results show that the density distribution can indeed be attained from HEER. The reason for the discrepancies has been investigated and indicates the importance of the uniformity in the transverse distribution beam illuminating the target. Furthermore, the method for generating a uniform transverse distribution beam using octupole magnets was studied and verified by simulations. The simulations also confirm that the octupole field does not affect the angle-position correlation in the center part beam, a critical requirement for the imaging lens. A more practical method for HEER using collimators and octupoles for generating more uniform beams is also described. Detailed experimental results and simulation studies are presented in this paper.
Cereal grains treated with organic acids were proved to increase ruminal resistant starch and can relieve the risk of ruminal acidosis. However, previous study mainly focussed on acid-treated barley, the effects of organic acid-treated corn is still unknown. The objectives of this study were to evaluate whether feeding ground corn steeped in citric acid (CA) would affect ruminal pH and fermentation patterns, milk production and innate immunity responses in dairy goats. Eight ruminally cannulated Saanen dairy goats were used in a crossover designed experiment. Each experimental period was 21 day long including 14 days for adaption to new diet and 7 days for sampling and data collection. The goats were fed high-grain diet contained 30% hay and 70% corn-based concentrate. The corn was steeped either in water (control) or in 0.5% (wt/vol) CA solution for 48 h. Goats fed CA diet showed improved ruminal pH status with greater mean and minimum ruminal pH, and shorter (P<0.05) duration of ruminal pH<5.6 and less area of ruminal pH<5.6, 5.8 and 6.0. Concentration of total volatile fatty acid and molar proportion of propionate were less but the molar proportion of acetate was greater (P<0.05) in goats fed the CA diet than the control diet. Concentration of ruminal lipopolysaccharide (LPS) was lower (P<0.05) and that of lactic acid also tended (P<0.10) to be lower in goats fed CA than the control. Although dry matter intake, actual milk yield, yield and content of milk protein and lactose were not affected, the milk fat content and 4% fat-corrected milk tended (P<0.10) to be greater in goats fed CA diet. For the inflammatory responses, peripheral LPS did not differ, whereas the concentration of LPS binding protein and serum amyloid A tended (P<0.10) to be less in goats fed CA diet. Similarly, goats fed CA diet had less (P<0.05) concentration of haptoglobin and tumour necrosis factor. These results indicated that feeding ground corn treated with CA effectively improved ruminal pH status, thus alleviated the risk of ruminal acidosis, reduced inflammatory response, and tend to improve milk yield and milk fat test.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
Here a compact three orthogonal planes high-energy electron radiography system was proposed. One of the critical technologies, the ultra-fast beam bunches split from the bunch train are studied. The separated bunches could be transported to the three orthogonal planes of the target for dynamic radiography diagnostics. The key elements of the ultra-fast bunches split system are transverse deflecting cavity (TDC) and the twin septum magnet (TSM). The principle of TDC and TSM are briefly introduced. An example of the beam bunches split system for test experiment (40 MeV electron beam) with TDC and TSM is designed and studied by particle-tracking simulation and it confirms this method is valid and feasible. Especially with TSM, a compact three orthogonal planes radiography system can be realized. The evolution of the beam parameters along the beam line from simulation are investigated. The detailed design of the beam split system and beam dynamics simulation study are presented in this paper.
We report the discovery in the Greenland ice sheet of a discrete layer of free nanodiamonds (NDs) in very high abundances, implying most likely either an unprecedented influx of extraterrestrial (ET) material or a cosmic impact event that occurred after the last glacial episode. From that layer, we extracted n-diamonds and hexagonal diamonds (lonsdaleite), an accepted ET impact indicator, at abundances of up to about 5×106 times background levels in adjacent younger and older ice. The NDs in the concentrated layer are rounded, suggesting they most likely formed during a cosmic impact through some process similar to carbon-vapor deposition or high-explosive detonation. This morphology has not been reported previously in cosmic material, but has been observed in terrestrial impact material. This is the first highly enriched, discrete layer of NDs observed in glacial ice anywhere, and its presence indicates that ice caps are important archives of ET events of varying magnitudes. Using a preliminary ice chronology based on oxygen isotopes and dust stratigraphy, the ND-rich layer appears to be coeval with ND abundance peaks reported at numerous North American sites in a sedimentary layer, the Younger Dryas boundary layer (YDB), dating to 12.9 ± 0.1 ka. However, more investigation is needed to confirm this association.
An experimental investigation into laser ablation of secondary explosives, cyclotetramethylene tetranitramine (HMX), has been carried out by using a solid-state laser at the wavelength of 1064 nm. The ion particles of decomposition were detected by using a time-of-flight mass spectrometer. Possible attributions of both negative ions and positive ions were obtained. Some obvious peaks were found at m/z = 18, 28, 46, 60, and 106, corresponding to H2O, CO/N2/H2CN, NO2, CH2NO2/N2O2, and N(NO2)2/CH2(NO2)2, respectively. According to the distribution of the particles, three possible pathways were proposed to explain the process of particles. The results may shed some light on the possible decomposition mechanism of HMX under laser initiation.
A stalagmite with high 238U content from Yangkou Cave, China, revealed the evolution of the Asian summer monsoon (ASM) between 49.1 and 59.5 ka, and the δ18O values recorded Dansgaard/Oeschger (D/O) events 13–17. The Yangkou record shows a relatively gradual transition into the D/O 14 and 16 events. The discrepancy between the abrupt and gradual transitions of D/O 14 in the records from northern and southern China, respectively, suggests different responses of the ASM to climate changes in the high northern latitudes. The higher resolution δ18O record and more precise 230Th dating indicate that the timing of D/O 14 and 17 in the Hulu records at 53 and 58 ka should be shifted to 54.3 and 59 ka, respectively. The gradual strengthening of the ASM at the onsets of D/O 16 and 14 in our record is different from the abrupt temperature rise in the northern high latitudes. Some other factors must contribute to this relatively gradual ASM change in southern China, but the actual reason is still unknown.
Elevated birth weight is linked to glucose intolerance and obesity health-related complications later in life. No studies have examined if infant birth weight is associated with gene expression markers of obesity and inflammation in a tissue that comes directly from the infant following birth. We evaluated the association between birth weight and gene expression on fetal programming of obesity. Foreskin samples were collected following circumcision, and gene expression analyzed comparing the 15% greatest birth weight infants (n=7) v. the remainder of the cohort (n=40). Multivariate linear regression models were fit to relate expression levels on differentially expressed genes to birth weight group with adjustment for variables selected from a list of maternal and infant characteristics. Glucose transporter type 4 (GLUT4), insulin receptor substrate 2 (IRS2), leptin receptor (LEPR), lipoprotein lipase (LPL), low-density lipoprotein receptor-related protein 1 (LRP1), matrix metalloproteinase 2 (MMP2), plasminogen activator inhibitor-1 (PAI-1) and transcription factor 7-like 2 (TCF7L2) were significantly upregulated and histone deacetylase 1 (HDAC1) and thioredoxin (TXN) downregulated in the larger birth weight neonates v. controls. Multivariate modeling revealed that the estimated adjusted birth weight group difference exceeded one standard deviation of the expression level for eight of the 10 genes. Between 25 and 50% of variation in expression level was explained by multivariate modeling for eight of the 10 genes. Gene expression related to glycemic control, appetite/energy balance, obesity and inflammation were altered in tissue from babies with elevated birth weight, and these genes may provide important information regarding fetal programming in macrosomic babies.
Deep-sea corals are a promising new archive of paleoclimate. Coupled radiocarbon and U-series dates allow 14C to be used as a tracer of ocean circulation rate in the same manner as it is used in the modern ocean. Diagenetic alteration of coral skeletons on the seafloor requires a thorough cleaning of contaminating phases of carbon. In addition, 10% of the coral must be chemically leached prior to dissolution to remove adsorbed modern CO2. A survey of modern samples from the full δ14C gradient in the deep ocean demonstrates that the coralline CaCO3 records the radiocarbon value of the dissolved inorganic carbon.
Ground-state OH masers identified in the Southern Parkes Large-Area Survey in Hydroxyl were observed with the Australia Telescope Compact Array to obtain positions with high accuracy (~1 arcsec). We classified these OH masers into evolved star OH maser sites, star formation OH maser sites, supernova remnant OH maser sites, planetary nebula OH maser sites and unknown maser sites using their accurate positions. Evolved star and star formation OH maser sites in the Galactic Centre region (between Galactic longitudes of −5° to +5° and Galactic latitudes of −2° and +2°) were studied in detail to understand their distributions.
This paper presents the design and optimisation of an aerofoil with active continuous trailing-edge flap (CTEF) investigated as a potential rotorcraft active control device. Several structural cross-section models are developed: high-fidelity NASA STRucture ANalysis (NASTRAN) and University of Michigan/Variational Asymptotic Beam Section Code (UM/VABS) models and a reduced-order analysis model. The validation of the reduced-order model is established by comparing its predictions of CTEF deformations with those of NASTRAN and UM/VABS analyses, which both show good agreement. The 2D aerodynamic characteristics of the CTEF aerofoil are evaluated using XFOIL and Computational Fluid Dynamics (CFD) analyses: FUN3D and Overset Transonic Unsteady Rotor Navier-Stokes (OVERTURNS). XFOIL, coupled with the reduced-order structure model, is adopted for optimisation study. The accuracy of XFOIL in predicting the aerodynamic pressure of the CTEF aerofoil is verified using CFD simulations, which shows sufficient fidelity. The predicted variations of aerodynamic coefficients with a CTEF angle are compared among the aerodynamic analyses. The optimisation process is developed and applied to two bimorph bender configurations: a Macro-Fibre Composite (MFC) solid bender and an MFC stack bender. The solid bender is used to confirm the functioning of the optimisation procedure and to use its optimal layout as a reference to the stack design, the primary design object. A linear tapered shape is found to be the optimum for a MFC solid bender, which generates an average of 63% more CTEF angles than those of an optimal rectangular bender. An optimised MFC stack bender is shown to resemble the shape of the solid bender. A four-ply bimorph is considered the best choice among the stack layouts because of its large output of CTEF angles and relatively less plies required. The CTEF angle produced by the four-ply optimal layout ranges from 7.6° to 5.3° with speeds from 0 to 200m/s at an angle of attack (AoA) of 6°. The reduction in the CTEF angle with AoA is less steep than that with speed, ranging from 6.5° to 5.8° with AoA from 0 to 8° at speed of 166m/s. An average of 14% increase in CTEF angles is achieved through optimisation for the four-ply bimorph.
Past research purporting to study employee resilience suffers from a lack of conceptual clarity about both the resilience construct and the methodological designs that examine resilience without ensuring the occurrence of significant adversity. The overall goal of this article is to address our contemporary understanding of employee resilience and identify pathways for the future advancement of resilience research in the workplace. We first address conceptual definitions of resilience both inside and outside of industrial and organizational psychology and make the case that researchers have generally failed to document the experience of significant adversity when studying resilience in working populations. Next, we discuss methods used to examine resilience, with an emphasis on distinguishing the capacity for resilience and the demonstration of resilience. Representative research is then reviewed by examining self-reports of resilience or resilience-related traits along with research on resilient and nonresilient trajectories following significant adversity. We then briefly address the issues involved in selecting resilient employees and building resilience in employees. The article concludes with recommendations for future research studying resilience in the workplace, including documenting significant adversity among employees, assessing multiple outcomes, using longitudinal designs with theoretically supported time lags, broadening the study of resilience to people in occupations outside the military who may face significant adversity, and addressing the potential dark side of an emphasis on resilience.