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The induction of long-term potentiation (LTP) in the dentate gyrus of the hippocampus is associated with a rapid and robust transcription of the immediate early gene Zif268 . We used a mutant mouse with a targeted disruption of Zif268 to ask whether this gene, which encodes a zinc finger transcription factor, is required for the maintenance of late LTP and for the expression of long-term memory. We show that whereas mutant mice exhibit early LTP in the dentate gyrus, late LTP is absent when measured 24 and 48 hours after tetanus in the freely moving animal. In both spatial and non-spatial learning tasks, short-term memory remained intact, whereas performance was impaired in tests requiring long-term memory. Thus, Zif268 is essential for the transition from short- to long-term synaptic plasticity and for the expression of long-term memories.

Purpose Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients. Methods Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed. Results Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn’t statistically significant. Conclusion Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.

Genomic translocations have been implicated in cancer. In this study, we performed a screen for genetic translocations in gliomas based on exon-level expression profiles. We identified a translocation in the contactin-associated protein-like 2 ( CASPR2) gene, encoding a cell adhesion molecule. CASPR2 mRNA was fused to an expressed sequence tag that likely is part of the nuclear receptor coactivator 1 gene. Despite high mRNA expression levels, no CASPR2 fusion protein was detected. In a set of 25 glioblastomas and 22 oligodendrogliomas, mutation analysis identified two additional samples with genetic alterations in the CASPR2 gene and all three identified genetic alterations are likely to reduce CASPR2 protein expression levels. Methylation of the CASPR2 gene was also observed in gliomas and glioma cell lines. CASPR2-overexpressing cells showed decreased proliferation rates, likely because of an increase in apoptosis. Moreover, high CASPR2 mRNA expression level is positively correlated with survival and is an independent prognostic factor. These results indicate that CASPR2 acts as a tumor suppressor gene in glioma.

Background: We have recently demonstrated that expression profiling is a more accurate and objective method to classify gliomas than histology. Similar to most expression profiling studies, our experiments were performed using fresh frozen (FF) glioma samples whereas most archival samples are fixed in formalin and embedded in paraffin (FFPE). Identification of the same, expression-based intrinsic subtypes in FFPE-stored samples would enable validation of the prognostic value of these subtypes on these archival samples. In this study, we have therefore determined whether the intrinsic subtypes identified using FF material can be reproduced in FFPE-stored samples. Methods: We have performed expression profiling on 55 paired FF-FFPE glioma samples using HU133 plus 2.0 arrays (FF) and Exon 1.0 ST arrays (FFPE). The median time in paraffin of the FFPE samples was 14.1 years (range 6.6–26.4 years). Results: In general, the correlation between FF and FFPE expression in a single sample was poor. We then selected the most variable probe sets per gene ( n =17 583), and of these, the 5000 most variable probe sets on FFPE expression profiles. This unsupervised selection resulted in a better concordance ( R 2 =0.54) between expression of FF and FFPE samples. Importantly, this probe set selection resulted in a correct assignment of 87% of FFPE samples into one of seven intrinsic subtypes identified using FF samples. Assignment to the same molecular cluster as the paired FF tissue was not correlated to time in paraffin. Conclusion: We are the first to examine a large cohort of paired FF and FFPE samples. We show that expression data from FFPE material can be used to assign samples to intrinsic molecular subtypes identified using FF material. This assignment allows the use of archival material, including material derived from large-randomised clinical trials, to determine the predictive and/or prognostic value of ‘intrinsic glioma subtypes’ on Exon arrays. This would enable clinicians to provide patients with an objective and accurate diagnosis and prognosis, and a personalised treatment strategy.

Introduction: Improving public access and training for epinephrine auto-injectors (EAIs) can reduce time to initial treatment in anaphylaxis. Effective use of EAIs by the public requires bystanders to respond in a timely and proficient manner. We wished to examine optimal methods for effective training and skill retention for public use of EAIs. Methods: In this prospective, stratified randomized study, 154 participants at 15 sites receiving installation of public EAIs were randomized to one of three experimental education interventions: A) didactic poster (POS) teaching; B) poster with video teaching (VID), and C) Poster, video, and simulation training (SIM). Participants were tested by participation in a standardized simulated anaphylaxis scenario at 0-months, immediately following training, and again at follow-up at 3 months. Participants responses were videoed and assessed by blinded raters. Patient recorded experience measures (PREMs) assessed participant-patient interaction for every scenario. Data that was non-normally distributed was analyzed using non-parametric testing (Kruskall-Wallis-Rank Sum-Test). Results: Initial analysis showed differences between group baseline characteristics for age and first aid training; with a multivariable analysis providing the effect size of these differences. PREM data and video assessment data were not normally distributed. Analysis of PREM data revealed significantly higher scores in the SIM group at 0-months (median=6.5, IQR=5; p=0.05) and 3-months (median=5, IQR=3; p<0.01), compared to those groups that did not receive SIM. Video assessment performance scores show trends in higher skills and knowledge retention for SIM participants at 3-months; full data analysis will be performed at a later date. Final video assessment analysis will involve a weighted scoring system, using a consensus process, and an inter-rater agreement analysis. Conclusion: Simulation training improves interaction, essential skills, and retention of knowledge in simulated anaphylaxis response with public EAIs compared to non-simulation-based training.

Introduction: With hospital occupancy rates frequently approaching 100%, even small variations in daily admission numbers can have a large impact. The ability to predict variance in emergency admission rates would provide administrators with a significant advantage in managing hospital daily bed requirements. There is a growing interest in patterns of hospital admissions, and many EDs utilize historical admission patterns to attempt to predict daily bed requirements. Previous studies have utilized patient demographics and past medical history to develop an admission likelihood model. We wished to examine the predictive strength of individual CEDIS presenting complaints (PC) on admission likelihood Methods: Using a database analysis of over 285,000 ED presentations (2013-2017), we calculated visit frequencies and admission rates by PC. Using a logistic regression analysis PCs were ordered from high to medium predictive strength. Results: Of 285,155 presentations, there were 38,090 hospital admissions, a rate of 13.36%. Based on the number of visit frequencies and admission rates, the PCs demonstrating high predictive strength were Direct Referral (effect=0.36, binomial CI: 0.28 to 0.44); Shortness of Breath (0.32: 0.26 to 0.41); General Weakness; Weakness/Query CVA; & Chest Pain Cardiac Features (each 0.30: 0.25 to 0.42); Altered level of consciousness (0.24: 0.16 to 0.31); and Confusion (0.18: 0.08 to 0.26). With our sample size, all remaining CEDIS PCs had low predictive value (the effect is <0.1), or were not predictive at all. Conclusion: We have demonstrated that, for our population, certain PCs are associated with an increased likelihood of admission and have quantified this effect using logistic regression analysis. Variance from the average daily admission rate may be predicted, in our population, by identifying these PCs at registration.We plan to develop a tool, based on this data and implemented at registration, to predict cumulative likely daily admission requirements as patients present over a 24hr period.

Introduction: Deliberate practice (DP) is the evolution of practice using continually challenging and focused practice on a particular task. DP involves immediate feedback, time for problem-solving and evaluation, and opportunities for repeated performance. Mircroskills training breaks down larger tasks into multiple smaller subtasks and then adds opportunities for feedback and adjustment for each subtask. Microskills training is routinely used to achieve excellence in competitive sports, martial arts, military operations, and music. Endotracheal intubation is a complex task with a clinically significant complication and failure rate. Methods: Two doctors and three nurses developed stepwise team microskills checklist from case review, simulations and published evidence. The checklist was tested, evaluated and developed during four days of simulation faculty team training. The final 36 item checklist was used to facilitate skills training for doctors, nurses, respiratory therapists and ACPs in one level 2, and two level 3 trauma centers from April 2017 to October 2017. The microskills checklist was used in four phases: 1. Group discussion of each microskill step 2. Groups of three team members; operator, assistant and microskill facilitator (using the checklist) to enable the deliberate analysis of the teams current performance. Each subtask is performed with immediate peer and where necessary faculty feedback. Changes are recorded. 3. Total task run though without interruption. Changes are recorded. 4. Repetition and feedback using different team members, manikins, including time pressure. User satisfaction surveys were collected after the skills training session Results: Results. Teams were composed of Registered Nurses (8), Physicians (9), and Respiratory Therapists (2). All of the teams experienced a change in practice. The median number of microskills changed for MDs 13/30, RNs 7/16. The commonest changes in practice were patient positioning (all teams). All professions agreed strongly that the approach produces a positive change in practice (median score 4.8/5). Conclusion: Microskills checklist facilitate endotracheal intubation with a bougie skill development in interprofessional teams in this provisional analysis.

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR), a method of cardiopulmonary bypass, is increasingly being used to supplement traditional CPR to improve outcomes for cardiac arrest (CA). CA and particularly out of hospital CA (OHCA) have poor outcomes. Prior to development of a 3 phase ECPR program in a Canadian regional hospital, we wished to identify and optimize a practical selection process (inclusion and exclusion criteria) for patients who may benefit from ECPR. Methods: Using a locally modified Delphi technique, we followed a literature review to construct a proposed set of evidence based criteria with a questionnaire, where inclusion and exclusion criteria were scored by a selected group of 13 experts. Following 3 rounds, and additional review by an international expert in the field of ECPR, consensus was achieved for patient selection criterion. Results: First round responses achieved 87.5% agreement for selection of exclusion criteria. Inclusion criteria had agreement 62.5%. Responses to the second round for selection of inclusion criteria were unanimous at 100% with the exception of age parameters (<65 years vs. <70 years). The third and final set of criteria achieved 100% consensus though subsequent expert review refined a single exclusion criteria (asystole). Agreed inclusion criteria were: witnessed CA, age <70, refractory arrest, no flow time <10min, total downtime <60min, and a cardiac or select non-cardiac etiology (PE, drug OD, poisoning, hypothermia). Exclusion criteria were : unwitnessed arrest, asystole, certain etiologies (uncontrolled bleeding, irreversible brain damage, trauma), and comorbidities (severe disability limiting ADLs, standing DNR, palliation). Simplified criteria for EMS transport included witnessed OHCA, age, and no flow time. Conclusion: Selection criteria of candidates for ECPR are important components for any program. Expert consensus review of current evidence is an effective method for development of ECPR selection criteria.

Introduction: Traditionally, out of hospital cardiac arrests (CA) have poor outcomes. Incorporation of extracorporeal cardiopulmonary resuscitation (ECPR) is being used increasingly to supplement ACLS to provide better outcomes for patients. Current literature suggests potentially improved outcomes, including neurological function. We assessed the feasibility of introduction of ECPR to a regional hospital using a 4-phase study. We report phase-1, an estimation of the number of potential candidates for ECPR in our setting. Methods: Following development and agreement on local criteria for selection of patients for ECPR using a modified Delphi Technique, inclusion and exclusion criteria were applied retrospectively, to a database comprising 4 years of emergency department (ED) cardiac arrests (n=395). This provided estimates of the number of patients who would have qualified for EMS transport for ECPR and initiation of ECPR in the ED. Results: Application of criteria would result in 20.0% (95% CI 16.2-24.3%) of CA being transported to the ED for ECPR (mean 18.5 patients per year). In the ED 4.6% (95% CI 2.83-7.26%) would be eligible to receive ECPR (4.3 patients per year). Incorporating downtime criteria, 3.0% (95% CI 1.6-5.3%) qualify. After considering local in-house cardiac catheterization hours 9.4% (95% CI 6.8-12.9%) and 5.4% (95% CI 3.5-8.2%), without and with EMS rhythm assumptions respectively, would be eligible for transport. For placement on pump, 3.0% (95% CI 1.6-5.3%) and 2.4% (95% CI 1.2-4.6%), without and with use of total downtime respectively, were eligible. Conclusion: If historical patterns of CA were to continue, we believe that an ECPR program may be feasible in our regional hospital setting, with a small number of selected cardiac arrest patients meeting eligibility for transportation and initiation of ECPR. These numbers suggest that an ECPR program would not be resource intensive, yet would be sufficiently busy to maintain adequate team competency.

Introduction: Electrocardiographic (ECG) rhythms are used during resuscitation (ACLS) to guide resuscitation, and often to determine futility. Survival rates to hospital discharge have been reported to be higher for patients with PEA than asystole in out-of-hospital cardiac arrest. This study examines how well the initial ECG cardiac rhythm represents actual cardiac activity as determined by point of care ultrasound (PoCUS). Methods: A database review was completed for patients arriving to a tertiary ED in asystole or PEA arrest, from 2010 to 2014. Patients under 19y or with a previous DNR were excluded. Patients were grouped into those with cardiac activity (PEA) and asystole on ECG; as well as whether cardiac activity was seen on PoCUS during the arrest. Data was analyzed for visualized cardiac activity on PoCUS. Results: 186 patients met the study criteria. Those with asystole on ECG were more likely to have no cardiac activity than those with PEA (Odds 7.21 for initial PoCUS; 5.45 for any PoCUS). The sensitivity of ECG rhythm was 80.49% and 82.12%, specificity was 77.91% and 54.28%, positive predictive value was 94.28% and 88.57%, and negative predictive value was 30.43% and 41.30% for cardiac activity on initial PoCUS and on any PoCUS respectively. The positive and negative likelihood ratios for ECG were 3.47 and 0.25 for activity on initial PoCUS. The positive and negative likelihood ratios for activity on any PoCUS were 1.78 and 0.33. Conclusion: Our results suggest that although most patients with asystole on ECG demonstrate no cardiac activity, a small number actually had activity on PoCUS. This supports the use of PoCUS during cardiac arrest, in addition to ECG, to identify patients with ongoing mechanical cardiac activity.