bluuebunny/crossref_metadata_2025 huggingface dataset:
P.043 Volumetric analysis of low-grade glioma growth in serially-imaged patients
Authors: Gui C , Lau JC , Kosteniuk SE , Megyesi JF
Published: June 2018

Background: Diffuse low-grade gliomas (LGGs) are infiltrative, slow-growing primary brain tumors that remain relatively asymptomatic for long periods of time before progressing to aggressive high-grade gliomas. Methods: We retrospectively identified LGG patients that were stably managed by observation with numerous (≥ 8) serial magnetic resonance imaging (MRI) studies. Tumour volumes were measured by manual segmentation on imaging to study the growth of the lesion. Patient demographic information, tumour characteristics, and histological data were collected from electronic medical records. Results: Of 74 LGG patients, 10 (13.5%) patients were included in the study. The number of MRIs acquired ranged from 8 to 18 (median, 11) over a median of 79.7 months (range, 39.8-113.8 months). Tumor diameter increased at a median rate of 2.17 mm/year in a linear trajectory. Cox regression analysis revealed that initial tumour volume predicted time to clinical intervention, and Mann-Whitney U test found that patients diagnosed prior to age 50 had significantly slower-growing tumors. Clinical intervention was more likely for tumours larger than 73.8 mL. Conclusions: We retrospectively analyzed the natural history of LGGs in patients with numerous serial MRIs managed at a single institution. Comparisons to the literature suggest that this is a subset of particularly slow-growing and low-risk tumours.
P.044 Salvage therapy in recurrent pediatric medulloblastoma: A single centre experience
Authors: Kameda-Smith MM , Wang A , Adile A , Manoranjan B , Voth R , Sergeant A , Maharaj A , Ajani O , Yarascavitch B , Alyman C , Samaan C , Farrokhyar F , Duckworth J , Singh SK , Fleming A
Published: June 2018

Background: Children diagnosed with medulloblastoma (MB) that are refractory to upfront therapy or experience recurrence have very poor prognoses. Reports of phase I and II studies for these children exist, but bear significant treatment related morbidity and mortality. Methods: A retrospective review of children diagnosed with a pediatric MB from 2002-2015 from the McMaster Pediatric Brain Tumour Study Group (PBTSG) captured a number of pediatric recurrent MB. Results: Over the 13-year period, 31 children with a histological diagnosis of MB were treated. At two years, 21 (67.7%) of 31 patients were free of recurrence and 25 (80.6%) survived. Thirteen children had recurrent or treatment refractory MB. mean time to recurrence was 14.6 months. The mean follow-up for survivors of recurrent MB was 4.0 years. In 3 recurrent MB, the disease had significantly progressed and the patients palliated. For the remaining children, therapy offered included surgery, radiation, and chemotherapy agents either in isolation or in varying combinations. Conclusions: Recurrent MB in our cohort carried a poor prognosis despite administration of salvage therapy. Though there is standardization of the upfront treatment exists, we observed great heterogeneity in the treatment of our 13 patients experiencing recurrence. A greater understanding of the biology of recurrent MB has the potential to guide salvage therapy.
P.048 Correlation of preoperative serum lactate, MR spectroscopy and frozen tissue lactate levels as a biomarker for giomas – a prospective clinical study
Authors: Khan OH , Nolt JK , Cousins JP , Agnihotri S , Vachhrajani S , Venkatraghavan L , Zadeh G
Published: June 2018

Background: Lactate, a by-product of glycolysis, has been well established as a marker of poor tissue perfusion. Elevated lactate production is observed in tumor glycolysis known as the Warburg effect. We have previously shown that serum lactate correlated with brain tumor grade. In this prospective study we aimed to determine if the preoperative serum lactate correlated with preoperative MR spectroscopy and in lactate levels in the fresh frozen tissue samples. Methods: Twenty-one glioma patients (13 male, 8 female) ages 34 – 86 underwent craniotomy at a single institution by lead author. Tumor pathology revealed a Glioblastoma (n=16), grade II (oligodendroglioma n=1) and Grade III Glioma (anaplastic astrocytoma n=4). Preoperative spectroscopy was performed on 18 patients. A fellowship trained neuro-radiologist (JPC) was blinded to the serum and tissue lactate levels and graded the spectroscopy lactate levels as low or elevated. Results: There was direct correlation of spectroscopy tissue lactate levels with serum lactate levels. Pre-operative serum lactate (range 6.6- 29.9 mg/dl) was directly correlated with the fresh frozen tissue lactate levels (range 0.1 – 0.39 ug/mg; Pearson r=0.6 p = 0.0021). Conclusions: This study supports that serum lactate correlates with spectroscopy and tissue lactate levels.
P.051 5-hydroxymethylcytosine profiling identifies differential targeting in IDH1 mutant versus IDH1 wild-type high-grade gliomas
Authors: Glowacka W , Jain H , Okura M , Maimaitiming A , Nejad R , Yasin M , Farooq H , Aldape K , Kongkham PN
Published: June 2018

Background: Gliomas demonstrate epigenetic dysregulation highlighted by the Glioma CpG-Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. IDH1 mutation perturbs the balance between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) by inhibiting TET-mediated active demethylation. The role 5hmC plays in IDH1 mutant tumors remains poorly understood. Methods: We profiled 5hmC in high grade IDH1 mutant (n = 12) and wild-type (n = 9) tumors on the Illumina MethylationEPIC Beadchip. We examined regions with high 5hmC abundance (top 1% probes), and differentially hydroxymethylated regions (DHMR). 5hmC profiles were correlated with gene expression. Results: Mean 5hmC b-values were 4.6%% and 3.8% for IDH1 mutant and wild-type tumors, respectively. Top 1% and DHMR probes demonstrated increased 5hmC among IDH1 mutants. 5hmC enriched for enhancer and super-enhancers. Among G-CIMP target genes, 22/50 were hydroxymethylated in our IDH1 mutant cohort, suggesting that 5hmC contributes to their overall methylation. Gene expression was associated with gene body 5hmC. 48 genes differentially expressed between IDH1 cohorts showed a positive Spearman correlation between 5hmC and gene expression, in particular for genes upregulated in IDH1 mutants. Conclusions: Locus-specific gain of 5hmC, targeting regulatory regions and associated with over-expressed genes, suggests a significant role for 5hmC in IDH1 mutant HGG.
P.052 Case Report: Brentuximab associated toxic neuropathy
Authors: Hunter G , Omene E
Published: June 2018

Background: A 28 year old male with a previous diagnosis of Ewing’s Sarcoma in 2008, and a revised diagnosis to Hodgkin’s lymphoma in 2016, presented to the Neurology service 6 months after starting the novel monoclonal antibody, Brentuximab. Concurrent therapy included adriamycin, vincristine and daunorubicin. He was referred for progressive weakness and sensory symptoms starting in the legs and spreading to the arms over 6 months. Methods: Examination demonstrated distal symmetric weakness with power of 3 proximally and distally in the lower extremities. Reflexes were absent at the ankles and severely reduced at the patella. Gait was consistent with a sensory ataxia, and there was pseudoathetosis of the left hand. Results: MRI demonstrated no relevant abnormalities. Electrophysiology was consistent with a motor predominant, distal symmetric sensorimotor axonal neuropathy. Conclusions: A review of the literature demonstrated that the monoclonal antibody brentuximab has a high incidence (48%; n = 89) of a reversible distal symmetric polyneuropathy. The mechanism likely relates to microtubule dysfunction by the conjugated compound monomethyl auristatin E. This case adds to the existing body of literature around a severe but potentially reversible neuropathy, resulting from the new monoclonal antibody brentuximab, which may also serve as a model of disease in neuropathy with a well elucidated mechanism of toxicity.
P.055 Epidemiologic features of pituitary adenoma patients requiring surgical treatment: large North American patient population based study
Authors: Alkherayf F , Banaz F , Lasso A , Mohajeri S , Masoudian P , Lamothe A , Agbi C , Caulley L , Alshardan M , Kilty S
Published: June 2018

Background: The surgical treatment of pituitary adenoma has evolved greatly over the decades. In order to better understand the patient population and their surgical treatment, we conducted an institutional review for pituitary adenoma surgery using the endoscopic endonasal trans-sphenoidal (EETS) approach. Methods: A retrospective review of all EETS cases for pituitary tumor resection was performed between November 2009 and June 2016. Patient characteristics, tumor type, endocrine data, operation characteristics were extracted from medical records. Preoperative MRI images were reviewed. The SIPAP classification was applied to the pituitary tumors. Postoperative patient data were extracted for the available follow-up period. Results: 232 cases were identified. Functional tumors were present in 29% of the cohort. Complete excision was most common for functioning tumors (49%) compared to nonfunctioning tumors (26%). There were no major vascular injuries. Hormone replacement with cortisol was required transiently in 70% of patients, with thyroid hormone replacement occurring in 40% of the cohort. Conclusions: From this large North American cohort nearly 30% of operated pituitary tumors were functioning. More commonly, these tumors were completely resected compared to the nonfunctioning group. The most commonly replaced hormone following EETS surgery was cortisol and this was largely transient.
P.061 Reliability of EEG reactivity in assessement of comatose patients under standardized protocol
Authors: AlKhateeb M , Norton L , Gofton T , AlThenayan E , Debicki D
Published: June 2018

Background: Electroencephalography (EEG) is a routine clinical tool that is used to evaluate thalamocortical function in comatose patients. The presence or absence of reactivity in background EEG patterns to afferent stimuli is believed to be an important indicator of clinical outcome. At present, there are no guidelines or standardized testing protocols for the assessment of EEG reactivity in critically ill patients. Moreover, the inter-rater reliability of subjectively identifying presence or absence of reactivity is known to be poor. Methods: Here we report the implementation of a clinical protocol formalizing the use of afferent stimuli – name-calling, clapping, nasal tickle, central painful stimuli and tracheal suction – administered during the routine EEG evaluation of behaviourally unresponsive patients in the critical care units at London Health Sciences Centre. EEGs were evaluated by qualified electroencephalographers. Results: This retrospective observational study of consecutive patients describes the inter-rater reliability of detecting presence or absence of EEG reactivity since implementation of the clinical protocol. Moreover it evaluates the relationship between EEG reactivity and clinical outcome to determine its reliability as a prognostic tool. Conclusions: The implementation of clinical protocols to standardize testing parameters may improve the ability to provide a reliable neurologic prognosis for critically ill patients in a comatose and behaviourally unresponsive state.
P.069 Respiratory dysfunction and sleep disordered breathing in children with Myasthenia Gravis
Authors: Qashqari HF , Narang I , Katzberg H , Vezina K , Khayat A , Chrestian N , Vajsar J
Published: June 2018

Background: Myasthenia Gravis ( MG) is an autoimmune disease that affects the neuromuscular junction. It typically presents with fluctuating muscle weakness which can affect respiratory muscles. Data about the prevalence of sleep disordered breathing in children with MG and the benefits of non-invasive ventilation outside the setting of MG crisis has not been studied so far. Methods: Eleven children between 3 and 18 years old with confirmed MG were recruited from the The Hospital for Sick Children Neuromuscular clinic in a prospective observational study. Informed consent was obtained and patients underwent PFTs, MIP/MEP, SNIP, FVC and standard polysomnography testing’s. Results: In our study, we found that 2/11 children had abnormal Apnea Hypopnea index (AHI) and were diagnosed with obstructive sleep apnea (OSA). One of them has juvenile ocular MG with mild to moderate OSA and the second child has congenital MG with mild OSA. CPAP therapy was initiated for both patients. Conclusions: In our cohort, obstructive sleep apnea rate was significantly higher in children with MG than the known prevalence in general pediatric population ( 18% vs 2-3% ). Early diagnosis and management of OSA can have great impact on children’s health and quality of life. A larger study is needed to validate our findings.
P.070 Autosomal dominant MARS mutation linked to severe early onset CMT2U
Authors: McMillan HJ , Gillespie MK , Kernohan KD , Myer-Schuman R , Antonellis A , Boycott KM
Published: June 2018

Background: Methionyl-tRNA synthetase (MARS) links methionine to its cognate tRNA required for translation. MARS mutations have been linked to adult-onset CMT2U. Methods: The proband had weakness in her first year of life, sitting at 11 months and walking at 20 months old. At 4 years old she was areflexic with distal > proximal weakness. Nerve conduction studies showed normal median and sural sensory responses with absent common peroneal, low median and tibial motor amplitudes. EMG noted denervation and quadriceps biopsy revealed neurogenic atrophy. Genetic testing for spinal muscular atrophy and sequencing of MNF2, RAB7A, LMNA, MPZ, HSPB1, NEFL, GADP1, TRPV4, HSPB8, GJB1 and PLEK8G5 were negative. She stopped walking at 9 years old and could not raise her arms above her head at 11 years old. Results: Exome sequencing identified MARS: c.1189G>A; p.Ala397Thr. To determine the functional consequences of p.A397T-MARS, yeast complementation assays were performed. Wild type or mutant MARS were cloned into yeast lacking the endogenous MARS ortholog. Wild-type MARS supported robust cellular growth, while the p.A397T-MARS insert did not support cellular growth confirming deleterious effect of this variant. Conclusions: Our patient’s phenotype was similar to children with motor-predominant GARS mutations. Functional data notes this MARS variant to be damaging and predictive of a severe, early-onset phenotype.
P.078 Health-related quality of life and fatigue in children with Duchenne muscular dystrophy: A three-year longitudinal study
Authors: Bhullar G , Wei Y , El-Aloul B , Speechley K , Miller M , Campbell C
Published: June 2018

Background: Longitudinal data on health-related quality of life (HRQOL) and fatigue in paediatric Duchenne muscular dystrophy (DMD) are limited. Recently, fatigue was reported to be the greatest predictor of poor HRQOL in paediatric DMD. Understanding the trajectory of HRQOL and its relationship with fatigue may facilitate the development of improved therapeutic strategies. Our objective was to describe three-year changes in HRQOL and fatigue in children with DMD. Methods: Patients identified via the Canadian Neuromuscular Disease Registry received mailed questionnaires (2013–2016). HRQOL was assessed using the PedsQLTM GCS and NMM domains, and fatigue was assessed using the MFS domain (patient- and parent-report). Mean three-year change in scores were computed. Pearson correlations were computed between three-year change in HRQOL and fatigue. Results: Mean decline in MFS scores for patient- and parent-reports were 1.03 and 1.19, respectively. Mean decline in GCS scores for patient- and parent-report were 1.75 and 4.13, respectively. Mean change in NMM scores for patient- and parent-report were 0.72 and -8.36, respectively. Change in MFS score was associated with changes in GCS (r=0.72, p<0.001) and NMM scores (r=0.84, p<0.001) by patient-report. Conclusions: Children with DMD experience worse fatigue and HRQOL over time. Parents perceive a greater decline in HRQOL over time compared to patients.
P.079 Development of a performance model for virtual reality tumor resections
Authors: Sawaya R , Alsideiri G , Bugdadi A , Winkler-Schwartz A , Azarnoush H , Bajunaid K , Sabbagh AJ , Del Maestro R
Published: June 2018

Background: This work proposes a hypothetical model that integrates human factors (e.g. inherent ability and acquired expertise) and task factors (e.g. pre-procedural data, visual and haptic information) to better understand the hand ergonomics adaptation needed for optimal safety and efficiency during simulated brain tumor resections. Methods: Hand ergonomics of neurosurgeons, residents and medical students were assessed during simulated brain tumors resection on the NeuroVR virtual reality neurosurgical simulation platform. Spatial distribution of time expended, force applied, and tumor volume removed, and other metrics were analyzed in each tumor quadrant (Q1 to Q4). Results: Significant differences were observed between the most favorable hand ergonomics condition (Q2) and the unfavorable hand ergonomics condition (Q4). Neurosurgeons applied more total force, more mean force, and removed less tumor per unit of force applied in Q4. However, total volume removed was not significant between the two quadrants indicating hand ergonomics adaptation in order to maximize tumor removal. In comparison, hand ergonomics of medical students remained unchanged in all quadrants, indicating a learning phenomenon. Conclusions: Neurosurgeons are more capable of adapting their hand ergonomics during simulated brain tumor resections. Our proposed hypothetical model integrates our findings with the literature and highlights the importance of experience in the acquisition of adaptive hand ergonomics.
P.082 An evidence-based supportive and palliative care curriculum for Canadian neurology residents
Authors: Gofton TE , Stewart S , Yeung Laiwah J , Schulz VN , Sarpal A
Published: June 2018

Background: Graduating residents require general palliative care skills. In Canada, there is no standardized palliative care curriculum for specialty trained residents. The objective of this research is to develop an evidence-based palliative care curriculum designed to provide neurology residents with the general palliative care skills required for providing patient care along the continuum of life. Methods: A needs assessment was performed in Neurology at Western University using qualitative analysis techniques. Residents completed the following:. A curricular outline was developed based on the Kolb learning style inventory (LSI), a knowledge pre-test, the Palliative Medicine Comfort and Confidence Survey and a review of the literature. Two iterations of the curriculum have been developed. Results: Residents identified a need for additional training in supportive and palliative care skills. Based on the Kolb LSI, 9/16 (56.3%) of neurology residents are “accommodators”. General principles identified for inclusion included: symptom management, communication, psychosocial aspects of care, care coordination and access, and myths and pitfalls in palliative care. Conclusions: This project is designed to identify the current palliative educational needs for Neurology residents. The results suggest that specialty trained residents are receptive to embedding training in the principles of palliative care within their training programs.
P.098 Primary closure versus expansile patch angioplasty for carotid endarterectomy: a single center series
Authors: Zagzoog N , Attar A , Elgheriani A , Farrokhyar F , Martyniuk A , Almenawer S
Published: June 2018

Background: Carotid endarterectomy (CEA) is a common treatment option for patients presenting with carotid stenosis; however, the optimal method for arterial closure remains unclear. Therefore, we examined our single center series to compare primary closure versus patch angioplasty for carotid endarterectomy. Methods: We reviewed all patients who underwent CEA from 2008 to 2016. Closure method was entirely based on the surgeon style (i.e., all patients treated by vascular surgeons underwent patch angioplasty and all individuals managed by neurosurgeons undergone primary closure). Data were reported as frequencies and outcomes as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Results: A total of 713 patients were included (349 in the primary closure group and 364 in the patch group). Underlying baseline characteristics were similar between both groups. The risk of transient ischemic attack (OR, 7.08; 95%CI, 0.41-2.84; P=0.872), stroke (OR, 1.14; 95%CI, 0.58-2.22; P=0.697), myocardial infarction (OR, 1.10; 95% CI, 0.39-3.07; P=0.851), cranial nerve palsy (OR, 1.79; 95%CI, 0.65-4.91; P=0.248), and post-operative neck hematoma (OR, 1.04; 95%CI, 0.48-2.24; P=0.923) didn’t differ significantly between the two closure options. Conclusions: Our findings suggest that primary closure and expansile angioplasty have similar safety and efficacy profiles as treatment closure options among patients undergoing CEA.
P.113 Down Syndrome: robust neurophysiological perspectives
Authors: Norton J , Auer R , Almubarak S
Published: June 2018

Background: Down Syndrome (DS) has a mosaicism of presentations, but a number of common features. Cerebral evoked potentials (somatosensory, visual and auditory) can be higher in amplitude in DS. The aim of this study is to explore the value of the neurophysiological amplitude of three different modalities in DS individuals undergoing spinal surgery, or epilepsy evaluation. Methods: Standard procedure of EEG evaluation was conducted. We routinely monitor somatosensory (SSEP) and motor evoked potentials (MEP), using peripheral nerves stimulation and transcranial electrical stimulation during surgery. We report findings from 14 DS individuals age-matched to 14 individuals with idiopathic scoliosis Results: The amplitude of the SSEP is significantly higher in DS individuals than in age-matched controls using the same parameters. SSEP;10.2±2.5µV vs 2.4±2.3µV (p<0.05, paired t-test). The threshold for eliciting MEPs was also significantly lower in DS in comparison to controls, 175±20V vs 629±100V, (p<0.05, paired t-test). Interictal EEG showed high amplitude spike and waves, and greater intracortical coherence in DS with epilepsy than non-DS patients Conclusions: Robust neurophysiological findings showed high amplitude sensory evoked potentials, low threshold motor evoked potentials, and high amplitude spikes and wave, all reflect a common process of increased neuronal synchronicity and oscillatory behaviour in Down Syndrome.
P.114 Twice negative PCR in a patient with HSV-1 Encephalitis
Authors: Roberts J , Jewett G , Raymond T , Couillard P , Peters S
Published: June 2018

Case Description: A 64 year-old male presented with left-sided weakness and altered level of consciousness after a suspected seizure. MR Brain demonstrated right mesial temporal lobe diffusion restriction. Empiric antiviral and antibiotic treatments were initiated despite CSF negative for HSV/VZV and enteroviruses. Lumbar puncture on admission day five was unchanged and empiric treatments were discontinued. On day 13 he deteriorated into status epilepticus necessitating ICU transfer. A third lumbar puncture demonstrated elevated protein and HSV-1 positive PCR. Acyclovir was restarted with guarded prognosis. Discussion: Detection of HSV-1 in CSF is considered the diagnostic gold standard for HSV-1 encephalitis. The validated multiplex assay used in Alberta, Canada has a 95% level of detection significantly better than the recommended threshold for HSV laboratory diagnosis. Previous reports have indicated that CSF PCR may be negative early in the disease course. Others have suggested that initially negative/follow up positive HSV PCR cases may represent secondary reactivation or release from underlying tissue damage. Consideration of the full clinical picture is crucial in patients with HSV negative PCR. Continuation of antiviral therapy may be appropriate in select HSV PCR negative patients.
P.121 Preoperative predictors of poor postoperative pain control: systematic review and meta-analysis
Authors: Yang M , Hartley RL , Leung AA , Ronksley PE , Jette (New York) N , Casha S , Riva-Cambrin J
Published: June 2018

Background: Inadequate postoperative pain control is common and is associated with negative clinical outcomes. The objective is to identify preoperative predictors of poor postoperative pain control in the adult population undergoing inpatient surgery. Methods: Meta-analysis was performed according to MOOSE guidelines. Studies were included if they evaluated postoperative pain using a validated instrument in adults undergoing inpatient surgery and reported a measure of association between poor postoperative pain control and at least one preoperative predictor. Measures of association were pooled using random effects models. Results: A total of 33 studies representing 59,259 patients were included. Significant preoperative predictors of poor postoperative pain included sleeping difficulties (OR 2.32 [95% CI 1.46-3.69]), history of depressive symptoms (OR 1.71 [95% CI 1.32-2.22]), use of preoperative analgesia (OR 1.54 [95% CI 1.18-2.03]), smoking (OR 1.33 [95% CI 1.09-1.61]), -female sex (OR 1.29 [95% CI 1.17-1.43]), presence of preoperative pain (OR 1.21 [95% CI 1.10-1.32]], history of anxiety symptoms (OR 1.22 [95% CI 1.09-1.36)], younger age (OR 1.18 [95% CI 1.05-1.32)], and higher BMI (OR 1.02 [95% CI 1.01-1.03]). Conclusions: Nine significant predictors of poor postoperative pain control were identified and these should be recognized as important factors when developing pre- and peri-operative strategies to improve pain outcomes.
P.130 Canadian physician attitudes towards long term EEG monitoring in the neonatal intensive care unit
Authors: Buttle SG , Sell E , Lemyre B , Pohl D
Published: June 2018

Background: Long-term EEG monitoring (LTEM), including amplitude-integrated (aEEG) or conventional EEG (cEEG), is increasingly being used in critically ill neonates. Despite an abundance of studies regarding the clinical utility of LTEM, much is unknown regarding provider attitudes toward this tool. We aimed to evaluate neurologist and neonatologist opinions regarding LTEM in the NICU and describe current Canadian practices. Methods: A 15-item questionnaire was developed with input from neonatologists and pediatric neurologists at two Canadian centres. The questionnaire was piloted at our hospital and subsequently distributed to Canadian neonatologists and pediatric neurologists. Results: All 16 local respondents use LTEM in the NICU. Neonatologists were more likely to combine aEEG and cEEG, and monitor for longer durations than pediatric neurologists. However, most pediatric neurologists would like to monitor more (71%), compared to neonatologists who were more likely to say that current monitoring practices are sufficient. High rates of neonatologists (88%) and neurologists (85%) are interested in attending an education session on LTEM. Conclusions: Preliminary data suggests neonatologists and pediatric neurologists differ in their approach to LTEM. Results from our national questionnaire will be analyzed shortly, and may inform the development of educational materials as well as future studies that involve multi-centre efforts.
GP.04 Smart human neural stem cells to degrade scar and optimize regeneration after traumatic cervical spinal cord injury
Authors: Ahuja CS , Khazaei M , Chan P , Bhavsar J , Yao Y , Lou Z , Wang J , Fehlings M
Published: June 2018

Background: Human induced pluripotent stem cell-derived neural stem cells (hiPS-NSCs) represent an exciting therapeutic approach for traumatically spinal cord injury (SCI). Unfortunately, most patients are the in chronic injury phase where a dense perilesional chondroitin sulfate proteoglycan (CSPG) scar significantly hinders regeneration. CSPG-degrading enzymes can enhance NSC-mediated recovery, however, nonspecific intrathecal administration causes off-target effects. We aimed to genetically engineer hiPS-NSCs to express a scar-degrading ENZYME into their local environment to enhance functional recovery. Methods: A bicistronic scar-degrading ENZYME and RFP reporter vector was non-virally integrated into hiPS-NSCs and monoclonalized. ENZYME activity was assessed by WST-1 and DMMB biochemical assays and an in vitro CSPG spot assay with hiPS-NSC-derived neurons. To assess in vivo efficacy, T-cell deficient rats (N=60) with chronic (8wk) C6-7 SCIs were randomized to receive (1)SMaRT cells, (2)hiPS-NSCs, (3)vehicle, or (4)sham surgery. Results: SMaRT cells retained key hiPS-NSC characteristics while stably expressing ENZYME. The expressed ENZYME could appropriately degrade in vitro and ex vivo CSPGs. While blinded neurobehavioural and immunohistochemical assessments are ongoing at 40wks post-injury, an interim analysis demonstrated human cells extending remarkably long (≥20,000µm) axons along host white matter tracts. Conclusions: This work provides exciting proof-of-concept data that genetically-engineered SMaRT cells can degrade CSPGs and human NSCs can extend long-distance processes in chronic SCI.
A.06 Trends in hospital admission and in-hospital mortality for atrial fibrillation related stroke in Canada
Authors: Jewett GA , Lindsay P , McQuiggan J , Zagorski B , Kamal N , Kapral MK , Demchuk AM , Hill MD , Yu AY
Published: June 2018

Background: Atrial fibrillation (AF) is associated with increased risk of ischemic stroke. In Canada, the contemporary burden of AF-related stroke is incompletely characterized. Our objective was to determine temporal trends in hospital admissions and in-hospital mortality for AF-related stroke in Canada from 2007 to 2015. Methods: We conducted a retrospective cohort study using Canadian national administrative data to identify admissions to hospital for stroke with comorbid AF between 2007 and 2015. We analyzed temporal trends in age- and sex-standardized proportion of admissions with comorbid AF and associated in-hospital mortality. Results: There were 222,100 admissions to hospital for ischemic (182,990) or hemorrhagic (39,110) stroke. The age-sex adjusted proportion of ischemic stroke admissions with comorbid AF increased from 16.2% to 20.5% (p for trend = 0.02) between 2007 and 2015, and was stable among hemorrhagic stroke. In-hospital mortality for ischemic stroke with comorbid AF decreased from 21.6% to 15.0% (p for trend = 0.001). Conclusions: Rates of hospital admission for ischemic stroke with comorbid AF have increased, while associated in-hospital mortality has decreased. These results identify AF as an important continued focus for stroke prevention. Our findings provide insight into current trends and highlight the need for continued focus on AF-related stroke.
B.01 Neonatal Neuro-Critical Care (NNCC) program associated with improved short term outcomes in neonates significant Hypoxic Ischemic Encephalopathy (HIE)
Authors: Roychoudhury S , Esser M , Buchhalter J , Bello-Espinosa L , Zein H , Howlett A , Thomas S , Murthy P , Appendino J , Metcalfe C , Lind J , Oliver N , Kozlik S , Mohammad K
Published: June 2018

Background: Despite advances in neonatal care, neonates with moderate to severe HIE are at high risk of mortality and morbidity. we report the impact of a dedicated NNCC team on short term mortality and morbidities. Methods: A retrospective cohort study on neonates with moderate to serve HIE between July 1st 2008 and December 31st 2017. primary outcome : a composite of death and/or brain injury on MRI. Secondary outcomes: rate of cooling, length of hospital stay, anti-seizure medication burden, and use of inotropes. A regression analysis was done adjusting for gestational age, birth weight, gender, out-born status, Apgar score at 10 minutes, cord blood pH, and HIE clinical staging Results: 216 neonates were included, 109 before NNCC implementation, and 107 thereafter. NNCC program resulted in reduction in the primary outcome (AOR: 0.28, CI: 0.14-0.54, p<0.001) and brain injury (AOR: 0.28, CI: 0.14-0.55, p<0.001). It decreased average length of stay/infants by 5 days (p=0.03), improved cooling rate (73% compared to 93% , p <0.001), reduced: seizure misdiagnosis (71% compared to 23%, P <0.001), anti-seizure medication burden (P = 0.001), and inotrope use (34% compared to 53%, p=0.004) Conclusions: NNCC program decreased mortality and brain injury , shortened the length of hospital stay and improved care of neonates with significant HIE.
B.04 Insight into the mesial frontal negative motor area: The girl with a very unusual interest in having her back patted
Authors: Mailo JA , Hung R , Tang-Wai R
Published: June 2018

Background: Currently, there is limited insight in to the function of the mesial frontal negative motor area (NMA) and the anatomic structures implicated in its function. Methods: We present a patient with a Rett-like phenotype, refractory frontal lobe epilepsy, and reflexogenic seizures in which backpatting induced atonic seizures with a semiology resembling the patient falling asleep. The patient underwent video EEG monitoring and ictal/interictal SPECT imaging capturing the reflexogenic seizures. Iterative reconstruction was performed, with images co-registered to previously acquired MRI with subtraction Ictal-Interictal imaging co-registered to MRI. Results: Interictally, the patient’s EEG showed a slow background and right frontal spikes. Ictally, the patient had numerous subclinical frontal seizures. The reflexogenic seizures had an ictal pattern at the vertex (Cz) with the ictal SPECT imaging, showing hyperperfusion in the right mesial frontal region, both paramedian precentral and postcentral gyri, and right basal ganglia. Conclusions: Our findings support the hypothesis that the negative motor area may be activated by the primary sensory cortex; moreover, the ictal SPECT now suggests involvement of the basal ganglia in the NMA’s function.
B.05 Nusinersen in infants who initiate treatment in a presymptomatic stage of spinal muscular atrophy (SMA): interim results from the Phase 2 NURTURE study
Authors: De Vivo DC , Bertini E , Hwu W , Foster R , Bhan I , Gheuens S , Farwell W , Reyna SP , Vajsar J
Published: June 2018

Background: NURTURE (NCT02386553) is an ongoing open-label single-arm efficacy/safety study of intrathecal nusinersen in infants who initiate treatment in a presymptomatic stage of spinal muscular atrophy (SMA). Methods: Enrolled infants were age ≤6 weeks at first dose, clinically presymptomatic, had genetically diagnosed SMA, and 2 or 3 copies of SMN2. Primary endpoint is time to death or respiratory intervention (≥6 hours/day continuously for ≥7 days or tracheostomy). Results: As of July 5, 2017, 25 infants (2 copies SMN2, n=15;3 copies, n=10) were enrolled. All infants were alive. Two infants (both with 2 copies SMN2) required respiratory intervention (but not tracheostomy or permanent ventilation) during an acute, reversible viral infection and thus met the primary -endpoint. At last visit, 22/24 (92%) infants had achieved WHO motor milestones sitting without support and 8/16 (50%;2 SMN2, n=3/11;3 SMN2, n=5/5) on study >13 months achieved walking alone. AEs were reported in 24/25 (96%) infants; most 20/25 (80%) had AEs that were mild/moderate in severity; 9 had serious AEs. Four infants had an AE possibly related to study drug, which resolved despite continued treatment. No new safety concerns were identified. Conclusions: Nusinersen continued to benefit infants who initiated treatment in a presymptomatic stage of SMA.

Study Support: Biogen
B.06 Safety and efficacy of nusinersen in infants/children with spinal muscular atrophy (SMA): part 1 of the phase 2 EMBRACE study
Authors: Shieh PB , Acsadi G , Mueller-Felber W , Crawford TO , Richardson R , Natarajan N , Castro D , Gheuens S , Bhan I , Gambino G , Sun P , Farwell W , Reyna SP , Vajsar J
Published: June 2018

Background: EMBRACE (NCT02462759) Part 1 is a randomized, double-blind, sham-procedure controlled study assessing safety/tolerability of intrathecal nusinersen (12-mg equivalent dose) in symptomatic infants/children with SMA who were not eligible to participate in ENDEAR or CHERISH. Methods: Eligible participants had onset of SMA symptoms at ≤6 months with 3 SMN2 copies; onset at ≤6 months, age >7 months and 2 copies; or onset at >6 months, age ≤18 months, and 2/3 copies. Safety/tolerability was the primary endpoint. Exploratory endpoints included Hammersmith Infant Neurological Examination Section 2 (HINE-2) motor milestone attainment, change in ventilator use, and growth. Results: EMBRACE Part 1 was terminated early based on positive results from ENDEAR. Safety/tolerability was similar to previous trials. More nusinersen-treated (11/14;79%) vs. sham–treated individuals (2/7;29%) were HINE-2 motor milestone responders. Between Day 183 and 302, mean (SD) hours of ventilator use changed by +1.236 (3.712) hours in nusinersen-treated (n=12) and +2.123 (3.023) hours in sham–treated individuals (n=7). Similar increases in weight and body length were observed in nusinersen-treated and sham–treated individuals by Day 183. Conclusions: In EMBRACE Part 1, nusinersen demonstrated a favorable benefit-risk profile. These results add to the aggregated efficacy, safety/tolerability data of nusinersen in SMA.

Study Supported by: Ionis and Biogen
B.07 Review of patients with Spinal Muscular Atrophy treated with Nusinersen in Ontario
Authors: Remtulla S , Zapata-Aldana E , Gonorazky H , Boyd J , Scholtes C , Hicks R , Leung A , Dowling J , Vajsar J , McMillan H , Tarnopolsky M , Campbell C
Published: June 2018

Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. In June 2017, Health Canada approved Nusinersen, currently the only available drug for SMA. Since 2016, patients in Ontario have been treated clinically with Nusinersen through different access programs. Methods: Retrospective case series of patients with SMA treated clinically with Nusinersen in Ontario, describing clinical characteristics and logistics of intrathecal Nusinersen administration. Results: Twenty patients have been treated across four centres. To date, we have reviewed 8 cases at one centre (seven SMA Type I, one SMA Type II). Age at first dose ranged from 3-156 months and disease duration 9-166 months. Patients had received 4-7 doses at last evaluation. Three patients with scoliosis (2 with spinal rods) required fluoroscopy-guided radiologist administration, and 4 required general anesthesia. No complications/adverse events were reported. At last follow up, 5/8 families reported improved daily activities. Of 5 patients with baseline and follow up motor function testing, 3 demonstrated improved scores. One patient died due to respiratory decline at age 9 months, despite improved motor outcome scores. Conclusions: We describe the first Canadian post-marketing experience with Nusinersen. Timely dissemination of this information is needed to guide clinicians, hospital administrators, and policy-makers.
Area change of glaciers across Northern Ellesmere Island, Nunavut, between ~1999 and ~2015
Authors: WHITE ADRIENNE , COPLAND LUKE
Published: June 2018

Using a variety of optical satellite scenes, this study quantifies the change in the areal extent of 1773 glaciers across Northern Ellesmere Island between ~1999 and ~2015. Our results show that the regional ice coverage decreased by 1705.3 km2over the ~16-year period, a loss of ~5.9%. Ice shelves had the greatest losses relative to their size, of ~42.4%. Glaciers feeding into ice shelves reduced in area by 4.7%, while tidewater glaciers reduced in area by 3.3%. Marine-terminating glaciers with floating ice tongues reduced in area by 4.9%, and 19 of these 27 ice tongues disintegrated, causing these glaciers to retreat to their grounding lines. Land-terminating glaciers lost 4.9% of their 1999 area, including the complete loss of three small ice caps (<1.5 km2). Our study highlights the high sensitivity of the ice cover of Northern Ellesmere Island to recent climate warming and the continued losses that are likely to occur in the future. In particular, the ice masses most susceptible to further losses are marine-terminating glaciers with floating termini and small land-terminating ice caps at low elevations.
Nutritional status and human milk intake of exclusively breast-fed infants at high altitude in La Paz, Bolivia
Authors: Urteaga Noelia , San Miguel José Luis , Aguilar Ana María , Muñoz Maruska , Slater Christine
Published: June 2018

Breast-feeding habits are related to the nutritional status and the risk of illness and death in children under 2 years of age. For the first 6 months, infants should be exclusively breast-fed. This study aimed to evaluate the relationship between the infant’s nutritional status and human milk intake by breast-fed infants at high altitude. A quantitative, descriptive, correlational study was conducted including mother/baby pairs of infants aged 2–6 months. The amount of human milk consumed by the infants was assessed by the deuterium oxide dose-to-mother technique. The lipid content of human milk was measured by creamatocrit, and anthropometric measurements were performed. A total of eighteen mother/baby pairs were assessed. The mean human milk intake was 888 (sd 149) g/d, and the intake of water from other sources was 24·3 (sd 29·8) g/d. The lipid content in human milk was 41 (sd 12) g/l. The infant’s nutritional indicators were normal in all cases. A moderate positive correlation was found between milk volume and z scores weight-for-length r 0·58 (P=0·01), BMI-for-age r 0·56 (P=0·01) and weight-for-age r 0·45 (P=0·05). There was no correlation with length-for-age z score. The mean of breast milk intake in this study was similar to that found in other studies in the world. The lipid content is comparable to similar studies and was within the normal range. Children older than 3 months showed signs of stunting despite adequate volume and lipid content of breast milk.
Phytic acid improves intestinal mucosal barrier damage and reduces serum levels of proinflammatory cytokines in a 1,2-dimethylhydrazine-induced rat colorectal cancer model
Authors: Liu Cuiping , Chen Chen , Yang Fuguo , Li Xin , Cheng Lixue , Song Yang
Published: June 2018

Phytic acid (PA) has been demonstrated to have a potent anticarcinogenic activity against colorectal cancer (CRC). Defects of the intestinal mucosal barrier and inflammation processes are involved in the development and progression of CRC. In the present study, we evaluated the effect of PA on the intestinal mucosal barrier and proinflammatory cytokines. After a 1-week acclimatisation period, sixty Wistar male rats were divided into the following five groups, with twelve rats per group: the control group (CG), model group (MG), low-PA-dose group (0·25 g/kg per d), middle-PA-dose group (0·5 g/kg per d), and high-PA-dose group (1 g/kg per d). 1,2-Dimethylhydrazine (DMH) at a dosage of 30 mg/kg of body weight was injected weekly to induce CRC for 18 weeks. We examined the expression of genes related to the intestinal mucosal barrier in the model. The results demonstrated that tumour incidence was decreased following PA treatment. The mRNA and protein expression of mucin 2 (MUC2), trefoil factor 3 (TFF3) and E-cadherin in the MG were significantly lower than those in the CG (P<0·05). The mRNA and protein expression of claudin-1 in the MG were significantly higher than those in the CG (P<0·05). PA elevated the mRNA and protein expression of MUC2, TFF3 and E-cadherin, and diminished the mRNA and protein expression of claudin-1. Furthermore, PA decreased serum levels of proinflammatory cytokines, which included TNF-α, IL-1βand IL-6. In conclusion, this study suggests that PA has favourable effects on the intestinal mucosal barrier and may reduce serum proinflammatory cytokine levels.
Reforming Everywhere and All at Once: Transitioning to Free Labor across the British Empire, 1837–1838
Authors: Boehme Kate , Mitchell Peter , Lester Alan
Published: June 2018

In late 1837 and early 1838 the British imperial government was preparing for an empire-wide transition from bonded to nominally free labor. This article builds upon recent scholarship that promotes a holistic, global approach to this transition, by narrowing the temporal frame and expanding the spatial. We emphasize interconnectivity and simultaneity rather than chronological succession, and we analyze the governance, rather than the experience, of this transition. Our approach is founded upon analysis of correspondence passing from every British colonial site through the Colonial Office in 1837–1838. We suggest that this hub of imperial government sought to reconcile the persistence of different conditions in each colony with the pursuit of three overarching policy objectives: redistributing labor globally; distinguishing between the moral debts owed to different kinds of bonded labor, and managing tradeoffs between security, economy, and morality. We conclude that the governance of the transition to free labor is best conceived as an assemblage of material and expressive elements of different spatial scales, whose interactions were complex and indeterminate. Through these specific governmental priorities and a particular communications infrastructure, these elements were brought into critical alignment at this moment to shape a significant transition in relations between people across the world.
Access to awareness of direct gaze is related to autistic traits
Authors: Madipakkam Apoorva Rajiv , Rothkirch Marcus , Dziobek Isabel , Sterzer Philipp
Published: June 2018

Background

The atypical processing of eye contact is a characteristic hallmark of autism spectrum disorder (ASD). The severity of these symptoms, however, is thought to lie on a continuum that extends into the typical population. While behavioural evidence shows that differences in social cognitive tasks in typically developed (TD) adults are related to the levels of autistic-like traits, it remains unknown whether such a relation exists for the sensitivity to direct gaze.

Methods

In two experiments, we measured reaction times to detect the faces with direct and averted gaze, suppressed from awareness, i.e. the access to awareness. In experiment 1, we tested N = 19 clinically diagnosed adults with ASD and N = 22 TD matched controls, while in experiment 2, we tested an independent sample of N = 20 TD adults.

Results

In line with the literature, experiment 1 showed preferential processing of direct gaze in the TD group but not in the ASD group. Importantly, we found a linear relationship in both experiments between the levels of autistic traits within the groups of TD participants and their sensitivity to direct gaze: with increasing autistic characteristics, there was a decrease in sensitivity to direct gaze.

Conclusion

These results provide the first evidence that differences in gaze processing and the sensitivity to direct gaze are already present in individuals with subclinical levels of autistic traits. Furthermore, they lend support to the continuum view of the disorder and could potentially help in an earlier diagnosis of individuals at high risk for autism.