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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
Given the challenges in accurately identifying unexposed controls in case–control studies of diarrhoea, we examined diarrhoea incidence, subclinical enteric infections and growth stunting within a reference population in the Global Enteric Multicenter Study, Kenya site. Within ‘control’ children (0–59 months old without diarrhoea in the 7 days before enrolment, n = 2384), we examined surveys at enrolment and 60-day follow-up, stool at enrolment and a 14-day post-enrolment memory aid for diarrhoea incidence. At enrolment, 19% of controls had ⩾1 enteric pathogen associated with moderate-to-severe diarrhoea (‘MSD pathogens’) in stool; following enrolment, many reported diarrhoea (27% in 7 days, 39% in 14 days). Controls with and without reported diarrhoea had similar carriage of MSD pathogens at enrolment; however, controls reporting diarrhoea were more likely to report visiting a health facility for diarrhoea (27% vs. 7%) or fever (23% vs. 16%) at follow-up than controls without diarrhoea. Odds of stunting differed by both MSD and ‘any’ (including non-MSD pathogens) enteric pathogen carriage, but not diarrhoea, suggesting control classification may warrant modification when assessing long-term outcomes. High diarrhoea incidence following enrolment and prevalent carriage of enteric pathogens have implications for sequelae associated with subclinical enteric infections and for design and interpretation of case–control studies examining diarrhoea.
The links between low socioeconomic status and poor health are well established, yet despite adversity, some individuals with low socioeconomic status appear to avoid these negative consequences through adaptive coping. Previous research found a set of strategies, called shift-and-persist (shifting the self to stressors while persisting by finding meaning), to be particularly adaptive for individuals with low socioeconomic status, who typically face more uncontrollable stressors. This study tested (a) whether perceived social status, similar to objective socioeconomic status, would moderate the link between shift-and-persist and health, and (b) whether a specific uncontrollable stressor, unfair treatment, would similarly moderate the health correlates of shift-and-persist. A sample of 308 youth (Meanage = 13.0, range 8–17), physician diagnosed with asthma, completed measures of shift-and-persist, unfair treatment, asthma control, and quality of life in the lab, and 2 weeks of daily diaries about their asthma symptoms. Parents reported on perceived family social status. Results indicated that shift-and-persist was associated with better asthma profiles, only among youth from families with lower (vs. higher) parent-reported perceived social status. Shift-and-persist was also associated with better asthma profiles, only among youth who experienced more (vs. less) unfair treatment. These findings suggest that the adaptive values of coping strategies for youth with asthma depend on the family's perceived social status and on the stressor experienced.
Brain tumor behavior is driven by aberrations in the genome and epigenome. Many of these changes, such as IDH mutations in diffuse low-grade glioma (DLGG), are common amongst the same class of tumour and can be incorporated into the diagnostic criteria. However, any given tumor may have other, less common genomic aberrations that are essential for its biological behavior and may inform on underlying aberrant cellular pathways, and potential therapeutic agents. Precision oncology is a genomics-based approach which profiles these alterations to better manage cancer patients and has established itself within the practice of oncology and is slowly making its way into neuro-oncology. The BC Cancer’s Personalized OncoGenomics (POG) program has profiled 16 adult tumours originating from the central nervous system using whole genome and transcriptome analysis (WGTA), for the first time, within a meaningful clinical timeframe/setting. As expected, primary genomic drivers were consistent with their respective diagnoses, though secondary drivers were found to be unique to each tumour. Although these analyses did not result in altered clinical management for these patients, primarily due to availability of drug or clinical trials, they highlight the heterogeneity of secondary drivers in cancers and provide clinicians with meaningful biological information. Lastly, the data generated by POG has highlighted the frequency and complexity of novel driver fusions which are predicted to behave similarly to canonical driver events in their respective tumours. The information available to clinicians through POG has provided paramount knowledge into the biology of each unique tumour.
Background: The goal was to understand factors leading to prolonged wait times for neurological assessment of children with new onset seizures. A second objective was to develop an innovative approach to patient flow through and achieve a reduction in waiting times utilizing limited resources.
Audit of the referrals, flow through, wait times
Identification of bottlenecks
Development of triaging strategy:
Suspected Febrile seizures and non-epileptic events;
Suspected benign and absence epilepsies;
Suspected other Focal epilepsies, generalized epilepsies, epilepsy under 2 years
Initiation of early telephone contact and support
Development of a ketogenic diet
Results: Using a triaging strategy and focusing on timely access to investigations, wait times for clinic evaluations were shortened despite larger numbers of referrals (mean wait time reductions from 179 to 91 days). Limiting factors such increase in referral numbers, attrition in support staff, interfered with sustainability of reduced wait times achieved in the initial phase of the program. Conclusions: This pilot study highlights the effectiveness of an innovative triaging strategy and improvements in patient flow through in achieving the goals of reduction in wait times for clinical evaluation and timely investigations to improve care for children with new onset seizures. Insights into limitations of such strategies and factors determining sustainability are discussed.
The past 50 years have been a period of exciting progress in neuropsychological research on traumatic brain injury (TBI). Neuropsychologists and neuropsychological testing have played a critical role in these advances. This study looks back at three major scientific advances in research on TBI that have been critical in pushing the field forward over the past several decades: The advent of modern neuroimaging; the recognition of the importance of non-injury factors in determining recovery from TBI; and the growth of cognitive rehabilitation. Thanks to these advances, we now have a better understanding of the pathophysiology of TBI and how recovery from the injury is also shaped by pre-injury, comorbid, and contextual factors, and we also have increasing evidence that active interventions, including cognitive rehabilitation, can help to promote better outcomes. The study also peers ahead to discern two important directions that seem destined to influence research on TBI over the next 50 years: the development of large, multi-site observational studies and randomized controlled trials, bolstered by international research consortia and the adoption of common data elements; and attempts to translate research into health care and health policy by the application of rigorous methods drawn from implementation science. Future research shaped by these trends should provide critical evidence regarding the outcomes of TBI and its treatment, and should help to disseminate and implement the knowledge gained from research to the betterment of the quality of life of persons with TBI. (JINS, 2017, 23, 806–817)
The Square Kilometre Array will be an amazing instrument for pulsar astronomy. While the full SKA will be sensitive enough to detect all pulsars in the Galaxy visible from Earth, already with SKA1, pulsar searches will discover enough pulsars to increase the currently known population by a factor of four, no doubt including a range of amazing unknown sources. Real time processing is needed to deal with the 60 PB of pulsar search data collected per day, using a signal processing pipeline required to perform more than 10 POps. Here we present the suggested design of the pulsar search engine for the SKA and discuss challenges and solutions to the pulsar search venture.
Recently, in an intercomparison of the Hohenheim German oak chronology (Becker 1993) and the Göttingen chronology (Leuschner and Delorme 1988), an error was discovered in the former (Leuschner, in preparation). Due to an error in adding sections at 5241 bc, 41 yr are missing in the published Hohenheim chronology. After correction of the error, the two chronologies synchronize over their entire common length, back to 7200 bc.
Since the discovery of fading X-rays from Gamma-Ray Bursts (GRBs) with BeppoSAX (Piro et al. 1997, Costa et al. 1997), world-wide follow-up observations in optical band have achieved the fruitful results. The case of GRB 970228, there was an optical transient, coincides with the BeppoSAX position and faded (Paradijs et al. 1997, Sahu et al. 1997). These optical observations also confirmed the extended component, which was associated with the optical transient. The new transient are fading with a power-law function in time and the later observation of HST confirmed the extended emission is stable (Fruchter et al. 1997). This extended object seems to be a distant galaxy and strongly suggests to be the host.
The High Energy Transient Explorer 2 is a small scientific satellite designed to detect and localize gamma-ray bursts (GRBs). The coordinates of GRBs detected by HETE-2 will be distributed to interested ground-based observers within seconds of burst detection, thereby allowing detailed observations of the initial phases of GRBs. HETE-2 was launched successfully on October 9, 2000. The GRB positions will start to be delivered after a few months of the complete testing and calibration of the spacecraft system and the science instruments.
The capabilities of the X-ray Timing Explorer (XTE) are described with particular attention paid to current scientific problems it will address from galactic neutron star systems to active galactic nuclei. It features a low-background continuous 2-200 keV response with large apertures (a 0.63-m2 proportional counter array and a 0.16-m2 dual rocking NaI/CsI scintillation array). Rapid response (in hours) to temporal phenomena, e.g. transients, is obtained by virtue of a scanning all-sky monitor and rapid maneuverability. XTE will carry out detailed energy-resolved studies of phenomena close to neutron stars (e.g. QPO’s) because of its sub-millisecond timing (to 10 μs), its high telemetry rates (to 256 kb/s), and the high throughput of its data system (to ≳ 2 × 105 c s−1).
The mechanism providing the 35-day period found in optical and X-ray light curves of the eclipsing low-mass X-ray binary Her X-l is considered to be the precession of a tilted and twisted accretion disc about the neutron star. We have obtained spectrophotometric observations of this system. The majority of line absorption and emission originates on or near the mass-losing primary, with distributions over the inner face of the star consistent with irradiation from the environs of the compact object. After suitable corrections for heating, the neutron star is found have a mass of 1.6±0.3M⊙, in contrast to the last radial velocity study which found a value less than 1.0 M⊙ . Rotational velocity measurements, while insufficiently precise to reject the older mass estimate, suggest that the rotational period of HZ Her differs from the synchronous rate by no more than 20%. Using a recently determined figure for the effective temperature of the unheated face, the distance to Her X-l is estimated at 6.7±0.4kpc, higher than prior estimates. The systemic velocity is found to be –69±6km s−1. In order to to determine the plausibility of the twisted disc model we reconstruct the expected shadow of the disc across the heated inner face of the donor star to compare with observation. Large scale emission structure is reproduced, but the model fails to synthesize finer observational details. HeII λ4686 Å emission is detected and found to be distributed closely about the neutron star, and is a likely tracer of the accretion flow.
Objective: Idiopathic normal pressure hydrocephalus (INPH) is a neurological disorder presenting with gait, cognitive, and bladder symptoms in the context of ventricular enlargement. Although gait is the primary indicator for treatment candidacy and outcome, additional monitoring tools are needed. Line Tracing Test (LTT) and Serial Dotting Test (SDT), two psychomotor tasks, have been introduced as potential outcome measures but have not been widely studied. This preliminary study examined whether LTT and SDT are sensitive to motor dysfunction in INPH and determined if accuracy and time are important aspects of performance. Methods: Eighty-four INPH subjects and 36 healthy older adults were administered LTT and SDT. Novel error scoring procedures were developed to make scoring practical and efficient; interclass correlation showed good reliability of scoring procedures for both tasks (0.997; p<.001). Results: The INPH group demonstrated slower performance on SDT (p<.001) and made a greater number of errors on both tasks (p<.001). Combined Time/Error scores revealed poorer performance in the INPH group for original-LTT (p<.001), modified-LTT (p≤.001) and SDT (p<.001). Conclusions: These findings indicate LTT and SDT may prove useful for monitoring psychomotor skills in INPH. While completion time reflects impaired processing speed, reduced accuracy may suggest planning and self-monitoring difficulties, aspects of executive functioning known to be compromised in INPH. This is the first study to underscore the importance of performance accuracy in INPH and introduce practical/reliable error scoring for these tasks. Future work will establish reliability and validity of these measures and determine their utility as outcome tools. (JINS, 2016, 22, 341–349)
For the past decade, emergency preparedness campaigns have encouraged households to meet preparedness metrics, such as having a household evacuation plan and emergency supplies of food, water, and medication. To estimate current household preparedness levels and to enhance disaster response planning, the Virginia Department of Health with remote technical assistance from the Centers for Disease Control and Prevention conducted a community health assessment in 2013 in Portsmouth, Virginia.
Using the Community Assessment for Public Health Emergency Response (CASPER) methodology with 2-stage cluster sampling, we randomly selected 210 households for in-person interviews. Households were questioned about emergency planning and supplies, information sources during emergencies, and chronic health conditions.
Interview teams completed 180 interviews (86%). Interviews revealed that 70% of households had an emergency evacuation plan, 67% had a 3-day supply of water for each member, and 77% had a first aid kit. Most households (65%) reported that the television was the primary source of information during an emergency. Heart disease (54%) and obesity (40%) were the most frequently reported chronic conditions.
The Virginia Department of Health identified important gaps in local household preparedness. Data from the assessment have been used to inform community health partners, enhance disaster response planning, set community health priorities, and influence Portsmouth’s Community Health Improvement Plan. (Disaster Med Public Health Preparedness. 2016;10:193–198)
Early patterns of gut colonization may predispose children to adult disease. Exposures in utero and during delivery are associated with the infant gut microbiome. Although ~35% of women carry group B strep (GBS; Streptococcus agalactiae) during pregnancy, it is unknown if GBS presence influences the infant gut microbiome. As part of a population-based, general risk birth cohort, stool specimens were collected from infant’s diapers at research visits conducted at ~1 and 6 months of age. Using the Illumina MiSeq (San Diego, CA) platform, the V4 region of the bacterial 16S rRNA gene was sequenced. Infant gut bacterial community compositional differences by maternal GBS status were evaluated using permutational multivariate analysis of variance. Individual operational taxonomic units (OTUs) were tested using a zero-inflated negative binomial model. Data on maternal GBS and infant gut microbiota from either 1 (n=112) or 6-month-old stool (n=150) specimens was available on 262 maternal-child pairs. Eighty women (30.5%) were GBS+, of who 58 (72.5%) were given intrapartum antibiotics. After adjusting for maternal race, prenatal antifungal use and intrapartum antibiotics, maternal GBS status was statistically significantly associated with gut bacterial composition in the 6 month visit specimen (Canberra R2=0.008, P=0.008; Unweighted UniFrac R2=0.010, P=0.011). Individual OTU tests revealed that infants of GBS+ mothers were significantly enriched for specific members of the Clostridiaceae, Ruminococcoceae, and Enterococcaceae in the 6 month specimens compared with infants of GBS- mothers. Whether these taxonomic differences in infant gut microbiota at 6 months lead to differential predisposition for adult disease requires additional study.