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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
Targeted screening for carbapenem-resistant organisms (CROs), including carbapenem-resistant Enterobacteriaceae (CRE) and carbapenemase-producing organisms (CPOs), remains limited; recent data suggest that existing policies miss many carriers.
Our objective was to measure the prevalence of CRO and CPO perirectal colonization at hospital unit admission and to use machine learning methods to predict probability of CRO and/or CPO carriage.
We performed an observational cohort study of all patients admitted to the medical intensive care unit (MICU) or solid organ transplant (SOT) unit at The Johns Hopkins Hospital between July 1, 2016 and July 1, 2017. Admission perirectal swabs were screened for CROs and CPOs. More than 125 variables capturing preadmission clinical and demographic characteristics were collected from the electronic medical record (EMR) system. We developed models to predict colonization probabilities using decision tree learning.
Evaluating 2,878 admission swabs from 2,165 patients, we found that 7.5% and 1.3% of swabs were CRO and CPO positive, respectively. Organism and carbapenemase diversity among CPO isolates was high. Despite including many characteristics commonly associated with CRO/CPO carriage or infection, overall, decision tree models poorly predicted CRO and CPO colonization (C statistics, 0.57 and 0.58, respectively). In subgroup analyses, however, models did accurately identify patients with recent CRO-positive cultures who use proton-pump inhibitors as having a high likelihood of CRO colonization.
In this inpatient population, CRO carriage was infrequent but was higher than previously published estimates. Despite including many variables associated with CRO/CPO carriage, models poorly predicted colonization status, likely due to significant host and organism heterogeneity.
In 2014/2015, International Medical Corps (IMC) operated two Ebola Treatment Units (ETUs) in Liberia and three in Sierra Leone when the Ebola virus disease epidemic killed over 11,000 people across Liberia, Sierra Leone and Guinea. As Ebola cases declined in Liberia, IMC Psychosocial teams transitioned to working in communities highly affected by the epidemic. This article describes IMC's experience with developing and implementing a community-based mental health and psychosocial group intervention in a rural, severely affected Liberian town – Mawah – where 46 out of approximately 800 community members were infected, 39 of whom died. In this paper, we present how the group intervention, named ‘Social Reconnection Groups’, was developed and implemented. We then discuss intervention strengths, challenges, key lessons learnt and recommendations for how Social Reconnection Groups can be adapted for use in similar settings.
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.
Introduction: Survival from cardiac arrest has been linked to the quality of resuscitation care. Unfortunately, healthcare providers frequently underperform in these critical scenarios, with a well-documented deterioration in skills weeks to months following advanced life support courses. Improving initial training and preventing decay in knowledge and skills are a priority in resuscitation education. The spacing effect has repeatedly been shown to have an impact on learning and retention. Despite its potential advantages, the spacing effect has seldom been applied to organized education training or complex motor skill learning where it has the potential to make a significant impact. The purpose of this study was to determine if a resuscitation course taught in a spaced format compared to the usual massed instruction results in improved retention of procedural skills. Methods: EMS providers (Paramedics and Emergency Medical Technicians (EMT)) were block randomized to receive a Pediatric Advanced Life Support (PALS) course in either a spaced format (four 210-minute weekly sessions) or a massed format (two sequential 7-hour days). Blinded observers used expert-developed 4-point global rating scales to assess video recordings of each learner performing various resuscitation skills before, after and 3-months following course completion. Primary outcomes were performance on infant bag-valve-mask ventilation (BVMV), intraosseous (IO) insertion, infant intubation, infant and adult chest compressions. Results: Forty-eight of 50 participants completed the study protocol (26 spaced and 22 massed). There was no significant difference between the two groups on testing before and immediately after the course. 3-months following course completion participants in the spaced cohort scored higher overall for BVMV (2.2 ± 0.13 versus 1.8 ± 0.14, p=0.012) without statistically significant difference in scores for IO insertion (3.0 ± 0.13 versus 2.7± 0.13, p= 0.052), intubation (2.7± 0.13 versus 2.5 ± 0.14, p=0.249), infant compressions (2.5± 0.28 versus 2.5± 0.31, p=0.831) and adult compressions (2.3± 0.24 versus 2.2± 0.26, p=0.728) Conclusion: Procedural skills taught in a spaced format result in at least as good learning as the traditional massed format; more complex skills taught in a spaced format may result in better long term retention when compared to traditional massed training as there was a clear difference in BVMV and trend toward a difference in IO insertion.
Pluralism has become a buzzword in International Relations. It has emerged in a number of linked literatures and has drawn the support of an unusual coalition of scholars: advocates of greater methodological diversity; those who feel that IR has degenerated into a clash of paradigmatic “-isms”; those who favor a closer relationship between academics and policy-makers; and those who wish to see greater reflexivity within the field. Perhaps unsurprisingly, no single vision of pluralism unites these scholars; they appear to be using the term in divergent ways. Accordingly, our aim is threefold. First, we wish to highlight this odd state of affairs, by placing it in disciplinary and intellectual context. Second, we distinguish between plurality—the de facto recognition that IR has become a more diverse field—and pluralism—a normative position which values that diversity, given the public vocation of social science. Finally, we lay out a more consistent understanding and defense of pluralism in those latter terms. We argue that, properly understood, pluralism entails a position of epistemological skepticism: the straightforward claim that no single knowledge system, discipline, theory, or method can claim singular access to truth.
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.
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)
All antipsychotic medications carry warnings of increased mortality for older adults, but little is known about comparative mortality risks between individual agents.
To estimate the comparative mortality risks of commonly prescribed antipsychotic agents in older people living in the community.
A retrospective, claims-based cohort study was conducted of people over 65 years old living in the community who had been newly prescribed risperidone, olanzapine, quetiapine, haloperidol, aripiprazole or ziprasidone (n = 136 393). Propensity score-adjusted Cox proportional hazards models assessed the 180-day mortality risk of each antipsychotic compared with risperidone.
Risperidone, olanzapine and haloperidol showed a dose–response relation in mortality risk. After controlling for propensity score and dose, mortality risk was found to be increased for haloperidol (hazard ratio (HR) = 1.18, 95% CI 1.06–1.33) and decreased for quetiapine (HR = 0.81, 95% CI 0.73–0.89) and olanzapine (HR = 0.82, 95% CI 0.74–0.90).
Significant variation in mortality risk across commonly prescribed antipsychotics suggests that antipsychotic selection and dosing may affect survival of older people living in the community.
the maternally inherited MTTL1 A3243G mutation in the mitochondrial genome causes MelaS (Mitochondrial encephalopathy lactic acidosis with Stroke-like episodes), a condition that is multisystemic but affects primarily the nervous system. Significant intra-familial variation in phenotype and severity of disease is well recognized.
retrospective and ongoing study of an extended family carrying the MTTL1 A3243G mutation with multiple symptomatic individuals. tissue heteroplasmy is reviewed based on the clinical presentations, imaging studies, laboratory findings in affected individuals and pathological material obtained at autopsy in two of the family members.
there were seven affected individuals out of thirteen members in this three generation family who each carried the MTTL1 A3243G mutation. the clinical presentations were varied with symptoms ranging from hearing loss, migraines, dementia, seizures, diabetes, visual manifestations, and stroke like episodes. three of the family members are deceased from MelaS or to complications related to MelaS.
the results of the clinical, pathological and radiological findings in this family provide strong support to the current concepts of maternal inheritance, tissue heteroplasmy and molecular pathogenesis in MelaS. neurologists (both adult and paediatric) are the most likely to encounter patients with MelaS in their practice. genetic counselling is complex in view of maternal inheritance and heteroplasmy. newer therapeutic options such as arginine are being used for acute and preventative management of stroke like episodes.