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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
Objective: Focal cortical dysplasia (FCD) is a common cause of refractory, focal onset epilepsy in children. Interictal, scalp electroencephalograph (EEG) markers have been associated with these pathologies and epilepsy surgery may be an option for some patients. We aim to study how scalp EEG and magnetic resonance imaging (MRI) markers of FCD affect referral of these patients for surgical evaluation. Methods: A single-center, retrospective review of children with focal onset epilepsy. Patients were included if they were between 1 month and 18 years of age, had focal onset seizures, prolonged scalp EEG monitoring, and an MRI conducted after 2 years of age. Statistics were carried out using the chi-squared and student’s t-test, as well as a logistic regression model. Results: Sixty-eight patients were included in the study. Thirty-seven of these patients were referred to a comprehensive pediatric epilepsy program (CPEP) for surgical evaluation, and of these 22% showed FCD EEG markers, 32% FCD MRI markers, and 10% had both. These markers were also present in patients not referred to a CPEP. The MRI markers were significantly associated with CPEP referral, whereas EEG markers were not. Neither marker type was associated with epilepsy surgery. Conclusion: This study found that children with focal onset epilepsy were more likely to be referred for surgical evaluation if they were medically refractory, or were diagnosed with FCD or tumor on MRI. Scalp EEG markers of FCD were not associated with CPEP referral. The online tool CASES may be a useful physician guide for identifying appropriate children for epilepsy surgery referral.
India has the second largest number of people with type 2 diabetes (T2D) globally. Epidemiological evidence indicates that consumption of white rice is positively associated with T2D risk, while intake of brown rice is inversely associated. Thus, we explored the effect of substituting brown rice for white rice on T2D risk factors among adults in urban South India. A total of 166 overweight (BMI ≥ 23 kg/m2) adults aged 25–65 years were enrolled in a randomised cross-over trial in Chennai, India. Interventions were a parboiled brown rice or white rice regimen providing two ad libitum meals/d, 6 d/week for 3 months with a 2-week washout period. Primary outcomes were blood glucose, insulin, glycosylated Hb (HbA1c), insulin resistance (homeostasis model assessment of insulin resistance) and lipids. High-sensitivity C-reactive protein (hs-CRP) was a secondary outcome. We did not observe significant between-group differences for primary outcomes among all participants. However, a significant reduction in HbA1c was observed in the brown rice group among participants with the metabolic syndrome (−0·18 (se 0·08) %) relative to those without the metabolic syndrome (0·05 (se 0·05) %) (P-for-heterogeneity = 0·02). Improvements in HbA1c, total and LDL-cholesterol were observed in the brown rice group among participants with a BMI ≥ 25 kg/m2 compared with those with a BMI < 25 kg/m2 (P-for-heterogeneity < 0·05). We observed a smaller increase in hs-CRP in the brown (0·03 (sd 2·12) mg/l) compared with white rice group (0·63 (sd 2·35) mg/l) (P = 0·04). In conclusion, substituting brown rice for white rice showed a potential benefit on HbA1c among participants with the metabolic syndrome and an elevated BMI. A small benefit on inflammation was also observed.
Laser–solid interactions are highly suited as a potential source of high energy X-rays for nondestructive imaging. A bright, energetic X-ray pulse can be driven from a small source, making it ideal for high resolution X-ray radiography. By limiting the lateral dimensions of the target we are able to confine the region over which X-rays are produced, enabling imaging with enhanced resolution and contrast. Using constrained targets we demonstrate experimentally a
X-ray source, improving the image quality compared to unconstrained foil targets. Modelling demonstrates that a larger sheath field envelope around the perimeter of the constrained targets increases the proportion of electron current that recirculates through the target, driving a brighter source of X-rays.
X-ray microscopy is a field that has developed rapidly in recent years. Two different approaches have been used. Zone plates have been employed to produce focussed beams with sizes as low as 0.07 pm for x-ray energies below 1 keV. Images of biological materials and elemental maps for major and minor low Z have been produced using above and below absorption edge differences. At higher energies collimators and focussing mirrors have been used to make small diameter beams for excitation of characteristic K— or L-x rays of all elements in the periodic
The hypothalamic–pituitary–adrenal axis (HPAA) plays a critical role in the functioning of all other biological systems. Thus, studying how the environment may influence its ontogeny is paramount to understanding developmental origins of health and disease. The early post-conceptional (EPC) period could be particularly important for the HPAA as the effects of exposures on organisms’ first cells can be transmitted through all cell lineages. We evaluate putative relationships between EPC maternal cortisol levels, a marker of physiologic stress, and their children’s pre-pubertal HPAA activity (n=22 dyads). Maternal first-morning urinary (FMU) cortisol, collected every-other-day during the first 8 weeks post-conception, was associated with children’s FMU cortisol collected daily around the start of the school year, a non-experimental challenge, as well as salivary cortisol responses to an experimental challenge (all Ps<0.05), with some sex-related differences. We investigated whether epigenetic mechanisms statistically mediated these links and, therefore, could provide cues as to possible biological pathways involved. EPC cortisol was associated with >5% change in children’s buccal epithelial cells’ DNA methylation for 867 sites, while children’s HPAA activity was associated with five CpG sites. Yet, no CpG sites were related to both, EPC cortisol and children’s HPAA activity. Thus, these epigenetic modifications did not statistically mediate the observed physiological links. Larger, prospective peri-conceptional cohort studies including frequent bio-specimen collection from mothers and children will be required to replicate our analyses and, if our results are confirmed, identify biological mechanisms mediating the statistical links observed between maternal EPC cortisol and children’s HPAA activity.
Globally, the prevalence of tuberculosis (TB) disease is higher in males. This study examined the effect of sex and age on Mycobacterium tuberculosis (Mtb) infection. Demographic and exposure data were collected on household contacts of sputum smear-positive pulmonary TB patients in Brazil. Contacts with tuberculin skin test induration ⩾10 mm at baseline or 12 weeks were considered Mtb infected. The study enrolled 917 household contacts from 160 households; 508 (55.4%) were female, median age was 21.0 years (range 0.30–87.0) and 609 (66.4%) had Mtb infection. The proportion infected increased with age from 63.3% in girls <5 years to 75.4% in women ⩾40 years and from 44.9% in boys <5 years to 73.6% in men ⩾40 years. Multivariable modelling showed the odds of infection increased between age 5 and 14 years among female contacts (OR 1.5 per 5-year age increase; 95% CI 1.1–2.2; P = 0.02) and between ages 0–4 and 15–39 years among male contacts (OR 2.7, 95% CI 0.83–8.9 and 1.1, 95% CI 0.99–1.3 per 5-year age increase; P = 0.10, 0.07, respectively). The study suggests that the age at which Mtb infection increases most is different in females compared with males. Studies are needed to explore whether these findings are due to differences in host susceptibility, exposure outside the household or other factors.
To assess whether pre-operative assessment with a bone conduction hearing device on a softband is an accurate predictor of performance with one of two transcutaneous hearing implants.
Cohort study comparing pre-and post-operative speech audiometry using correlation analysis.
Pre-operative pure tone audiometry and aided half optimum speech recognition thresholds were compared with post-operative aided results for each ear that had undergone implantation. Data were collected prospectively.
Full data were available in 24 ears. In 19 out of 24 ears (79 per cent), the difference between pre- and post-operative speech scores was less than 10 dB, demonstrating a good clinical correlation. The Pearson correlation coefficient was calculated at 0.66 (95 per cent confidence interval = 0.357–0.842), indicating a strong statistical correlation.
Pre-operative softband testing shows good clinical correlation and strong statistical correlation with hearing implant performance. The findings suggest there is value in using the test to predict performance and guide patients’ expectations.
Giant electromagnetic pulses (EMP) generated during the interaction of high-power lasers with solid targets can seriously degrade electrical measurements and equipment. EMP emission is caused by the acceleration of hot electrons inside the target, which produce radiation across a wide band from DC to terahertz frequencies. Improved understanding and control of EMP is vital as we enter a new era of high repetition rate, high intensity lasers (e.g. the Extreme Light Infrastructure). We present recent data from the VULCAN laser facility that demonstrates how EMP can be readily and effectively reduced. Characterization of the EMP was achieved using B-dot and D-dot probes that took measurements for a range of different target and laser parameters. We demonstrate that target stalk geometry, material composition, geodesic path length and foil surface area can all play a significant role in the reduction of EMP. A combination of electromagnetic wave and 3D particle-in-cell simulations is used to inform our conclusions about the effects of stalk geometry on EMP, providing an opportunity for comparison with existing charge separation models.
Ventenata [Ventenata dubia (Leers) Coss.], an invasive winter annual grass, significantly reduces forage production in grassland systems and displaces species within both perennial- and annual-dominated grasslands within the Inland Northwest. The range of V. dubia is expanding into sagebrush steppe communities, an expansive habitat critical for forage production, wildlife, and recreation. Currently, there is limited knowledge of V. dubia’s distribution and abundance within sagebrush steppe communities. We performed field surveys at 15 locations in sagebrush steppe rangelands in southern Idaho and eastern Oregon to assess where V. dubia occurs, with the aim of providing insight about its niche in this new habitat. Specifically, we evaluated biotic and abiotic factors of the plant community as indicators of V. dubia presence. We also correlated species diversity measures with no, low (<12.5%), and high (>12.5%) V. dubia cover. Though widely distributed throughout the study region, V. dubia only appeared in 45% of the 225 plots, and foliar cover was typically less than 50%. It was primarily found in ephemerally wet microhabitats. Species richness and the Shannon diversity index were lowest in plots with high V. dubia cover. Nonmetric multidimensional scaling analysis revealed that V. dubia and medusahead [Taeniatherum caput-medusae (L.) Nevski] were closely associated. Furthermore, chi-square indicator analysis showed that T. caput-medusae was more prevalent, while mountain big sagebrush [Artemisia tridentata Nutt. spp. vaseyana (Rydb.) Beetle] was less prevalent, in plots containing V. dubia. Abiotic factors that explained variation in V. dubia abundance included rock cover, soil depth, and a north/south aspect. Higher V. dubia cover also correlated with higher clay content and lower phosphorus and potassium concentrations in the soil. We suggest that at this point, detection survey efforts to locate incipient infestations of V. dubia in sagebrush steppe communities should focus on moist areas and sites susceptible to invasion by T. caput-medusae.
We present the first data release of the SkyMapper Southern Survey, a hemispheric survey carried out with the SkyMapper Telescope at Siding Spring Observatory in Australia. Here, we present the survey strategy, data processing, catalogue construction, and database schema. The first data release dataset includes over 66 000 images from the Shallow Survey component, covering an area of 17 200 deg2 in all six SkyMapper passbands uvgriz, while the full area covered by any passband exceeds 20 000 deg2. The catalogues contain over 285 million unique astrophysical objects, complete to roughly 18 mag in all bands. We compare our griz point-source photometry with Pan-STARRS1 first data release and note an RMS scatter of 2%. The internal reproducibility of SkyMapper photometry is on the order of 1%. Astrometric precision is better than 0.2 arcsec based on comparison with Gaia first data release. We describe the end-user database, through which data are presented to the world community, and provide some illustrative science queries.
We present early results from the first near-IR imaging of the weak X-ray sources discovered in the recent Chandra/ACIS-I survey towards the Galactic Centre (GC) (Wang et al. 2002). These ~800 discrete sources, which contribute significantly to the GC X-ray emission, represent an important and previously unknown population within the Galaxy. From our VLT observations we will identify likely IR counterparts to a sample of the hardest sources, which are most likely X-ray binaries. With these data we can place constraints on the nature of the discrete weak X-ray source population of the GC. Once the data analysis is complete we will discuss our results in the context of binary population synthesis models.
The SPICA mid- and far-infrared telescope will address fundamental issues in our understanding of star formation and ISM physics in galaxies. A particular hallmark of SPICA is the outstanding sensitivity enabled by the cold telescope, optimised detectors, and wide instantaneous bandwidth throughout the mid- and far-infrared. The spectroscopic, imaging, and polarimetric observations that SPICA will be able to collect will help in clarifying the complex physical mechanisms which underlie the baryon cycle of galaxies. In particular, (i) the access to a large suite of atomic and ionic fine-structure lines for large samples of galaxies will shed light on the origin of the observed spread in star-formation rates within and between galaxies, (ii) observations of HD rotational lines (out to ~10 Mpc) and fine structure lines such as [C ii] 158 μm (out to ~100 Mpc) will clarify the main reservoirs of interstellar matter in galaxies, including phases where CO does not emit, (iii) far-infrared spectroscopy of dust and ice features will address uncertainties in the mass and composition of dust in galaxies, and the contributions of supernovae to the interstellar dust budget will be quantified by photometry and monitoring of supernova remnants in nearby galaxies, (iv) observations of far-infrared cooling lines such as [O i] 63 μm from star-forming molecular clouds in our Galaxy will evaluate the importance of shocks to dissipate turbulent energy. The paper concludes with requirements for the telescope and instruments, and recommendations for the observing strategy.
The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement component 4 (C4) gene. This structural variation generates varying levels of C4 RNA expression, and genetic information from the MHC region can now be used to predict C4 RNA expression in the brain. Increased predicted C4A RNA expression is associated with the risk of SZ, and C4 is reported to influence synaptic pruning in animal models.
Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predicted C4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples.
We observed that increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predicted C4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected).
These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4’s developmental role.
The mainstay of management of epistaxis refractory to first aid and cautery is intranasal packing. This review aimed to identify evidence surrounding nasal pack use.
A systematic review of the literature was performed using standardised methodology.
Twenty-seven eligible articles were identified relating to non-dissolvable packs and nine to dissolvable packs. Nasal packing appears to be more effective when applied by trained professionals. For non-dissolvable packs, the re-bleed rates for Rapid Rhino and Merocel were similar, but were higher with bismuth iodoform paraffin paste packing. Rapid Rhino packs were the most tolerated non-dissolvable packs. Evidence indicates that 96 per cent of re-bleeding occurs within the first 4 hours after nasal pack removal. Limited evidence suggests that dissolvable packs are effective and well tolerated by patients. There was a lack of evidence relating to: the duration of pack use, the economic effects of pack choice and the appropriate care setting for non-dissolvable packs.
Rapid Rhino packs are the best tolerated, with efficacy equivalent to nasal tampons. FloSeal is easy to use, causes less discomfort and may be superior to Merocel in anterior epistaxis cases. There is no strong evidence to support prophylactic antibiotic use.
Housed pigs are exposed chronically to aerial pollutants, principally dust and ammonia, at concentrations that may affect performance, possibly by raising the incidence and prevalence of multi-factorial respiratory diseases. Tolerable limits for aerial pollutants are unknown. The aim of this experiment was to test the hypothesis that chronic exposure of weaner pigs to controlled concentrations of aerial dust and ammonia lead to slower growth and lower feed intake compared with controls kept in ‘fresh air’.
A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.
This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes.
The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.
The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.
The Taipan galaxy survey (hereafter simply ‘Taipan’) is a multi-object spectroscopic survey starting in 2017 that will cover 2π steradians over the southern sky (δ ≲ 10°, |b| ≳ 10°), and obtain optical spectra for about two million galaxies out to z < 0.4. Taipan will use the newly refurbished 1.2-m UK Schmidt Telescope at Siding Spring Observatory with the new TAIPAN instrument, which includes an innovative ‘Starbugs’ positioning system capable of rapidly and simultaneously deploying up to 150 spectroscopic fibres (and up to 300 with a proposed upgrade) over the 6° diameter focal plane, and a purpose-built spectrograph operating in the range from 370 to 870 nm with resolving power R ≳ 2000. The main scientific goals of Taipan are (i) to measure the distance scale of the Universe (primarily governed by the local expansion rate, H0) to 1% precision, and the growth rate of structure to 5%; (ii) to make the most extensive map yet constructed of the total mass distribution and motions in the local Universe, using peculiar velocities based on improved Fundamental Plane distances, which will enable sensitive tests of gravitational physics; and (iii) to deliver a legacy sample of low-redshift galaxies as a unique laboratory for studying galaxy evolution as a function of dark matter halo and stellar mass and environment. The final survey, which will be completed within 5 yrs, will consist of a complete magnitude-limited sample (i ⩽ 17) of about 1.2 × 106 galaxies supplemented by an extension to higher redshifts and fainter magnitudes (i ⩽ 18.1) of a luminous red galaxy sample of about 0.8 × 106 galaxies. Observations and data processing will be carried out remotely and in a fully automated way, using a purpose-built automated ‘virtual observer’ software and an automated data reduction pipeline. The Taipan survey is deliberately designed to maximise its legacy value by complementing and enhancing current and planned surveys of the southern sky at wavelengths from the optical to the radio; it will become the primary redshift and optical spectroscopic reference catalogue for the local extragalactic Universe in the southern sky for the coming decade.
The immune system not only provides protection against infectious disease but also contributes to the etiology of neoplastic, atopic, and cardiovascular and metabolic diseases. Prenatal and postnatal nutritional and microbial environments have lasting effects on multiple aspects of immunity, indicating that immune processes may play important roles in the developmental origins of disease. The objective of this study is to evaluate the association between birth weight and the distribution of leukocyte (white blood cell) subsets in peripheral blood in young adulthood. Postnatal microbial exposures were also considered as predictors of leukocyte distribution. Participants (n=486; mean age=20.9 years) were drawn from a prospective birth cohort study in the Philippines, and analyses focused on the following cell types: CD4 T lymphocytes, CD8 T lymphocytes, B lymphocytes, natural killer cells, monocytes, granulocytes. Higher birth weight was a strong predictor of higher proportion of CD4 T lymphocytes (B=0.12, s.e.=0.041, P=0.003), lower proportion of CD8 T lymphocytes (B=−0.874, s.e.=0.364, P=0.016), higher CD4:CD8 ratio (B=1.964, s.e.=0.658, P=0.003), and higher B lymphocytes (B=0.062, s.e.=0.031, P=0.047). Measures of microbial exposure in infancy were negatively associated with proportions of B lymphocytes and granulocytes, and lower CD4:CD8 ratio. Leukocytes are the key regulators and effectors of innate and specific immunity, but the origins of variation in the distribution of cell type across individuals are not known. Our findings point toward nutritional and microbial exposures in infancy as potentially important determinants of immune-phenotypes in adulthood, and they suggest that leukocyte distribution is a plausible mechanism through which developmental environments have lasting effects on disease risk in adulthood.