The Canadian Neuromuscular Disease Registry 2010-2019: A Decade of Facilitating Clinical Research Througha Nationwide, Pan-NeuromuscularDisease Registry.

We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.

Efficient removal of arsenic using graphene-zeolite based composites.

Removing heavy metals from water can be considered an important problem of global magnitude due to their toxic and carcinogenic properties. The main aim of this presentation was to synthesize different composites of graphene (graphene oxide (GO) or reduced graphene oxide (RGO is referred to reduced graphene oxide, which was obtained using solvothermal method)) with Cu-exchanged zeolite A (Cu-ZEA) and nanoparticles of magnetite (Fe3O4) (including Fe3O4/RGO/, GO/Cu-ZEA, Fe3O4/RGO/Cu-ZEA and Fe3O4/GO/Cu-ZEA) for improving the properties of the individual components of mentioned composite and eventually investigate the composites' efficiency in arsenic adsorption. Among prepared composites, Fe3O4/RGO/Cu-ZEA composite had the highest efficiency in removing arsenic according to atomic absorption spectroscopy (AAS) results due to the high specific surface area, which was provided by the presence of Cu-ZEA and Fe3O4 in the structure of composite. Moreover, the adsorption kinetic investigation revealed that the adsorption of arsenate from aqueous suspension of Fe3O4/RGO/Cu-ZEA and Fe3O4/RGO composites followed a pseudo-second-order kinetic model.

Children born at 32 to 35 weeks with birth asphyxia and later cerebral palsy are different from those born after 35 weeks.

OBJECTIVE: The objectives of this study were to (1) establish the proportion of cerebral palsy (CP) that occurs with a history suggestive of birth asphyxia in children born at 32 to 35 weeks and (2) evaluate their characteristics in comparison with children with CP born at ⩾36 weeks with such a history. STUDY DESIGN: Using the Canadian CP Registry, children born at 32 to 35 weeks of gestation with CP with a history suggestive of birth asphyxia were compared with corresponding ⩾36 weeks of gestation children. RESULTS: Of the 163 children with CP born at 32 to 35 weeks and 738 born at ⩾36 weeks, 26 (16%) and 105 (14%) had a history suggestive of birth asphyxia, respectively. The children born at 32 to 35 weeks had more frequent abruptio placenta (35% vs 12%; odds ratio (OR) 4.1, 95% confidence interval (CI) 1.5 to 11.2), less frequent neonatal seizures (35% vs 72%; OR 0.20, 95% CI 0.08 to 0.52), more frequent white matter injury (47% vs 17%; OR 4.3, 95% CI 1.3 to 14.0), more frequent intraventricular hemorrhage (IVH) (40% vs 6%; OR 11.2, 95% CI 3.4 to 37.4) and more frequent spastic diplegia (24% vs 8%; OR 1.8, 95% CI 1.2 to 12.2) than the corresponding ⩾36 weeks of gestation children. CONCLUSIONS: Approximately 1 in 7 children with CP born at 32 to 35 weeks had a history suggestive of birth asphyxia. They had different magnetic resonance imaging patterns of injury from those born at ⩾36 weeks and a higher frequency of IVH. Importantly, when considering hypothermia in preterm neonates with suspected birth asphyxia, prospective surveillance for IVH will be essential.

Clinical profile of children with cerebral palsy born term compared with late- and post-term: a retrospective cohort study.

OBJECTIVE: To determine whether cerebral palsy (CP) risks factors, neurological subtype, severity and co-morbidities differ between early/full-term-born children with CP compared with those born late/post-term. DESIGN: Retrospective cohort study. SETTING: Children with CP born between 1998 and 2014, residing in Canada, and registered in the Canadian Cerebral Palsy Registry (CCPR) (n = 1691), a database with information from 15 participating centres across six Canadian provinces. POPULATION: Children with CP from the CCPR born at 37 weeks of gestation and later (n = 802). METHODS: The clinical profile of children with CP born at 37-40 weeks of gestation was compared with those born at 41 weeks and later using the Pearson chi-square test (or Fisher's exact test) for univariate analyses of categorical data. A P value <0.05 was considered significant a priori. MAIN OUTCOME MEASURES: CP neurological subtype, Gross Motor Function Classification System (GMFCS) severity, risk factors and co-morbidities. RESULTS: Neonatal encephalopathy was found in 23.9% of children with CP born early/full-term and in 33.6% of those born late/post-term (P = 0.026). Neonatal hyperbilirubinaemia was found in 10.2% of children born in the earlier period and in 2.6% of those born in the later period (P = 0.008). Apgar score at 5 minutes, but not 10 minutes, was significantly higher in the early/full-term group (9) compared with its late/post-term counterpart (7; P = 0.046). Rates of CP subtype, severity (GMFCS) and co-morbidities did not differ significantly between the two gestational periods. CONCLUSIONS: In children with CP, neonatal encephalopathy was significantly less frequent and neonatal hyperbilirubinaemia was significantly more frequent in those born early/full-term compared with their later-born counterparts. However, clinical outcomes of CP were not significantly different between these two gestational epochs. TWEETABLE ABSTRACT: Children with cerebral palsy born early/full-term have similar outcomes to those born late/post-term.

fMRI brain response during sentence reading comprehension in children with benign epilepsy with centro-temporal spikes.

INTRODUCTION: Children with benign epilepsy with centro-temporal spikes (BECTS) often have language problems. Abnormal epileptic activity is found in central and temporal brain regions, which are involved in reading and semantic and syntactic comprehension. Using functional magnetic resonance imaging (fMRI), we examined reading networks in BECTS children with a new sentence reading comprehension task involving semantic and syntactic processing. METHOD: Fifteen children with BECTS (age=11y 1m ± 16 m; 12 boys) and 18 healthy controls (age=11 y 8m ± 20 m; 11 boys) performed an fMRI reading comprehension task in which they read a pair of syntactically complex sentences and decided whether the target sentence (the second sentence in the pair) was true or false with respect to the first sentence. All children also underwent an exhaustive neuropsychological assessment. RESULTS: We demonstrated weaknesses in several cognitive domains in BECTS children. During the sentence reading fMRI task, left inferior frontal regions and bilateral temporal areas were activated in BECTS children and healthy controls. However, additional brain regions such as the left hippocampus and precuneus were activated in BECTS children. Moreover, specific activation was found in the left caudate and putamen in BECTS children but not in healthy controls. Cognitive results and accuracy during the fMRI task were associated with specific brain activation patterns. CONCLUSION: BECTS children recruited a wider network to perform the fMRI sentence reading comprehension task, with specific activation in the left dorsal striatum. BECTS cognitive performance differently predicted functional activation in frontal and temporal regions compared to controls, suggesting differences in brain network organisation that contribute to reading comprehension.

A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly.

We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. L-Serine is essential for neuronal survival and differentiation. Indeed, L-serine biosynthesis disorders affect brain development and cause severe ID. In the brain, L-serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of L-serine into neurons and the release of glia-borne L-serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID.

Placental pathology in asphyxiated newborns treated with therapeutic hypothermia.

OBJECTIVE: To describe the placental findings in asphyxiated newborns treated with hypothermia and to determine their association with the presence and severity of later brain injury. METHODS: Prospective cohort study of the placentas of asphyxiated newborns treated with hypothermia, in whom later brain injury was defined by brain imaging and/or autopsy results. RESULTS: Of the 142 asphyxiated newborns meeting the criteria for hypothermia, 73% had placenta and brain MRI/autopsy available for analysis. Fifty-one percent of these newborns developed brain injury. Sixty-five percent had microscopic placental findings involving the fetal vascular supply, which were comparable in asphyxiated newborns developing or not developing brain injury. Among the asphyxiated newborns with normal placental growth, the placental microscopic findings tended to be more common in those developing brain injury compared to those who did not: chorionic plate meconium in 50% compared to 36%, chorioamnionitis in 75% compared to 44%, and villitis of unknown etiology in 67% compared to 33%, but this did not reach statistical significance. CONCLUSIONS: Antenatal placental processes are common in term asphyxiated newborns treated with hypothermia. The placenta of each asphyxiated term newborn treated with hypothermia should be carefully examined to better understand its role in the progression from perinatal depression to brain injury.

Prevalence of cerebral palsy in Quebec: alternative approaches.

AIM: To provide an estimate of the period prevalence of cerebral palsy (CP) in the province of Quebec. METHODS: Children with CP were identified from three consecutive birth cohorts (1999-2001) from the Quebec CP Registry, covering 6 of the 17 administrative health regions of the province. Two inferential approaches were applied for period prevalence estimation, frequentist and bayesian. RESULTS: 228 children were identified with CP. Using a frequentist approach, the overall prevalence of CP was 1.84 per 1,000 children aged 9-11 years living in those areas in 2010 (95% CI 1.60-2.08). Using a bayesian approach taking into account the uncertainty about the registry's sensitivity in capturing all cases, the overall prevalence is higher at 2.30 per 1,000 children with a 95% CI (1.99-2.65). CONCLUSION: Using a bayesian approach to adjust for the registry's known high specificity and lower sensitivity, the prevalence estimate is in concordance with worldwide estimates and estimates using administrative databases in western Canadian provinces. Future studies are needed to validate the diagnosis of CP within administrative databases and to evaluate possible regional trends across Canada in both prevalence and health service utilization, which may highlight disparities in healthcare delivery.

Treatment comfort of adult neurologists in childhood onset conditions.

BACKGROUND: The majority of children with chronic neurodevelopmental disabilities are surviving to adulthood. Our goal was to assess how prepared and comfortable adult neurologists are in treating young adults with childhood onset chronic neurological conditions and evaluate the difficulty pediatric neurologists experience when transferring these patients to adult care. METHODS: We conducted a cross-sectional study using two postal surveys of all pediatric and adult neurologists in the province of Quebec, Canada. RESULTS: The response rate was 51.5%, with 119 neurologists completing the survey. Half of neurologists agreed that adult neurologists may not have adequate training in childhood onset disorders to prepare them to manage the disorders in adulthood, and 60% of pediatric neurologists reported having difficulty finding an adult provider for their patients. Adult neurologists were least comfortable treating patients with autism, chromosomal or metabolic disorders, and cognitive or behavioral disorders. CONCLUSION: Almost half of those surveyed believed that adult neurologists are not adequately trained to care for this growing patient population. Improving treatment comfort and knowledge among adult neurologists in childhood onset chronic neurological conditions may smooth the transition of these young adults from pediatric to adult care.

Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype.

OBJECTIVE: To describe the natural history of clinical and laboratory features associated with the m.3243A>G mitochondrial DNA point mutation. Natural history data are needed to obtain prognostic information and for clinical trial planning. METHODS: We included 85 matrilineal relatives from 35 families with at least 2 visits in this prospective cohort study. Thirty-one were fully symptomatic with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and 54 were carrier relatives. Evaluations included standardized questionnaires (medical history and daily living functioning), physical examination, neuropsychological testing, and a battery of imaging and laboratory tests. We evaluated changes in clinical and laboratory features over time and survival. Outcomes are reported over a follow-up period of up to 10.6 years (mean 3.8 ± 2.2 years for patients and 5.5 ± 3.0 for carrier relatives). RESULTS: Neurologic examination, neuropsychological testing, and daily living scores significantly declined in all patients with MELAS, whereas no significant deterioration occurred in carrier relatives. Cerebral MRI scores declined significantly in patients with MELAS. Magnetic resonance spectroscopy estimates of lactate in the lateral ventricles increased over time, and high lactate was associated with increased mortality. Symptom onset in childhood often was associated with worse outcome. Patients with MELAS had a greater death rate than carrier relatives. CONCLUSIONS: Patients with MELAS carrying the m.3243A>G mutation show a measurable decline in clinical and imaging outcomes. It is hoped that these data will be helpful in anticipating the disease course and in planning clinical trials for MELAS.

Distribution of insertion sequences associated with Tn1546 and clonal diversity of vancomycin-resistant enterococci isolated from patients in Tehran, Iran.

BACKGROUND AND OBJECTIVES: Infection with vancomycin-resistant enterococci (VRE) has caused a therapeutic problem. VanA and VanB resistant types are the predominant phenotypes among vancomycin resistant enetrococci. Transposon 1546 (Tn1546) harboring the vanA gene cluster, plays an important role in the horizontal transfer of vanA gene. In this study, we examined the phenotypic and genotypic diversity of a number of clinical VRE. MATERIALS AND METHODS: Twenty-four clinical VRE isolated from two university hospitals in Tehran were examined based on their antimicrobial susceptibility, Tn1546 related element organization and pulsed-field gel electrophoresis (PFGE) patterns. Integration of well-studied insertion sequence elements IS1216V, IS1542 and IS1251 was examined by PCR mapping and sequencing. RESULTS: From 24 isolates, 15 isolates with VanA phenotype and 9 isolates with VanB phenotype were identified which both groups interestingly possessed the vanA gene. According to PCR mapping, our isolates were assigned to 6 main groups. In 14 (58.3%) isolates, IS1216V was inserted in vanX-vanY region and/or in truncated left-hand of Tn1546-like elements. In 11 (45.8%) isolates, both IS1216V and IS1542 were inserted in vanX-vanY and orf2-vanR regions, respectively and none of them harbored IS1251. Interestingly, PFGE of the isolates showed a high degree of diversity. CONCLUSION: PCR mapping revealed that VanA elements in our isolates were highly heterogeneous. Overall, we found no correlation between transposon type and PFGE pattern. Genetic diversity of VRE provides practical information for epidemiological studies and our data showed horizontal transfer of VRE in this region.

Incidence and prevalence of amyotrophic lateral sclerosis in Canada: a systematic review of the literature.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease of unknown etiology. Although known to be rare, precise information on the frequency of ALS is essential to anticipate future demands on health resources and as baseline information for epidemiological studies. As part of a new ALS epidemiological initiative in Canada, we conducted a systematic review of published incidence and prevalence research in Canada. METHODS: Electronic searches and bibliographic reviews of pertinent publications were conducted. RESULTS: We identified 6 published studies from 4 Canadian provinces conducted between 1974 and 2004; 2 were available only as abstracts. Reported annual incidence rates were similar and study quality was generally good, but there was insufficient detail to adequately assess the methodological quality of 3 of the studies. The most recent studies reported an annual ALS age-adjusted incidence of 2.13 per 100,000 in Nova Scotia (2003-2004) and a crude mean annual incidence of 2.4 per 100,000 in Newfoundland and Labrador (2000-2004). CONCLUSIONS: There are limited data on the frequency of ALS in Canada. We found no studies from 6 of the Canadian provinces or from the territories. Future research is needed to estimate the frequency of occurrence of ALS in Canada.

The changing natural history of spinal muscular atrophy type 1.

BACKGROUND: Noninvasive ventilation has become increasingly available to spinal muscular atrophy (SMA) patients since the early 1990 s. This is expected to have improved survival for SMA type 1 patients. OBJECTIVE: To assess whether there has been a change in survival in patients with SMA type 1 between 1980 and 2006. METHODS: We used deidentified, family-reported data from participants in the International Spinal Muscular Atrophy Patient Registry and obtained additional clinical information through a mail-in questionnaire. One hundred forty-three patients with SMA type 1 were included in the analysis. Survival of patients born in 1995-2006 (n = 78) was compared with that of patients born in 1980-1994 (n = 65), using the Kaplan-Meier method and Cox proportional hazards models with age at death as the outcome. RESULTS: Patients born in 1995 though 2006 had significantly increased survival compared with those born in 1980-1994 (log-rank test, p < 0.001). In a Cox model, patients born in 1995-2006 had a 70% reduction in the risk of death compared with those born in 1980-1994 (hazard ratio [HR] 0.3, 95% CI 0.2-0.5, p < 0.001) over a mean follow-up of 49.9 months (SD 61.1, median 22.0). However, when controlling for demographic and clinical care variables, year of birth was no longer significantly associated with age at death (HR 1.0, 95% CI 0.6-1.8, p = 0.9), whereas ventilation for more than 16 h/d, use of a mechanical insufflation-exsufflation device, and gastrostomy tube feeding showed a significant effect in reducing the risk of death. CONCLUSION: Survival in spinal muscular atrophy type 1 patients has increased in recent years, in relation to the growing trend toward more proactive clinical care.

Tumor necrosis factor modulates fibroblast apoptosis, PMN recruitment, and osteoclast formation in response to P. gingivalis infection.

P. gingivalis is an important oral pathogen, which has been closely linked to periodontal disease as well as lesions of endodontic origin. Both infections are associated with a decrease in fibroblast numbers, formation of an inflammatory infiltrate, and bone resorption. The goal of this study was to investigate the role that the host response plays in the capacity of P. gingivalis to stimulate fibroblast apoptosis, PMN recruitment, and osteoclastogenesis. This was accomplished by the use of an in vivo calvarial model in mice with targeted deletion of TNF receptors p55 and p75 and matched wild-type mice. The results indicate that P. gingivalis induces fibroblast apoptosis in vivo and establish for the first time that this involves the stimulation of a host response. Moreover, bacteria-stimulated PMN recruitment and osteoclastogenesis were also dependent upon the host response. The results suggest that much of the damage caused by P. gingivalis infection, including fibroblast apoptosis, at least under some circumstances, results from stimulation of the host response rather than the direct effect of bacterial products. Furthermore, this may represent a more general mechanism by which bacterial challenge induces apoptosis of matrix-producing cells through the induction of TNF.