Rekindling Embers of the Past with Technologies of Today: Increasing LMS Adoption at an Ontario Secondary School

The motivation behind this organization improvement plan is to reap the benefits of online learning, enhance teaching and learning, and consequentially increase student achievement. This organizational improvement plan addresses a problem of practice in an Indigenous ministry inspected secondary school in Central, Canada. Indigenous people are achieving fewer and lower levels of educational attainment compared to non-Indigenious counterparts and Indigenious students in the community this OIP is situated are likewise at-risk of widening this gap (Statistics Canada, 2011; Deloitte, 2018). To narrow this gap, this school is centered on using technology to pay tribute to the past. Online learning offers organizations a variety of teaching and learning benefits. In pursuit of enhanced outcomes, more and more K-12 organizations are attempting to adopt a Learning Management System; however, instead of experiencing the promised potential of online learning, organizations are receiving frustrations and lackluster results. The leadership approach selected to drive forward change in this endeavour is the adaptive leadership approach complimented with characteristics of situational leadership. The change path model is selected as the framework for leading the process of organizational change. Additionally, the plan, do, study, act model serves as the model for change. Collectively the change path model in tandem with the plan, do, study, act model and former leadership approaches all work together to implement, evaluate, and communicate the change

Equitable and Inclusive Education for All? Public Funding for Denominational Schools in Ontario

Roman Catholic separate schools’ denominational right to receive public funding is a contentious issue in Ontario’s educational system. Ontario’s publicly funded denominational schools historically served a purpose at Confederation; however, in light of Ontario’s evolving demographics, publicly funding denominational schools today may no longer serve the needs of Ontario. The research problem in this study is expressed through growing problems reconciling Roman Catholic schools with diversity and current public views. Additionally, recent tensions, public views, and political consensus suggest it is time to revisit the existing policy. In order to understand both the history of denominational schools and the present context, this study conducted II policy analyses as its research design by completing 2 policy cycles. The first policy cycle determined that based upon Upper and Lower Canada’s pre-Confederation diversity, extending public funding to denominational schools at Confederation was an effective way of protecting minority rights; however, the analysis in the second policy cycle; which examined how equitable and inclusive denominational schools are today, concluded that the denominational school system no longer serves the diversity and equity needs of contemporary Ontario. Building on these findings, this study then explored two viable alternative educational arrangements for Ontario’s future educational system: publicly funding all faith-based schools, or publicly financing a one-school-system. To address the diversity issue in Ontario, transitioning toward publicly funding a one-school-system is found to be the most viable option

Next generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions

CLU, PICALM and CR1 were identified as genetic risk factors for late onset Alzheimer’s disease (AD) in two large genome wide association studies (GWAS) published in 2009, but the variants that convey this alteration in disease risk, and how the genes relate to AD pathology is yet to be discovered. A next generation sequencing (NGS) project was conducted targeting CLU, CR1 and PICALM, in 96 AD samples (8 pools of 12), in an attempt to discover rare variants within these AD associated genes. Inclusion of repetitive regions in the design of the SureSelect capture lead to significant issues in alignment of the data, leading to poor specificity and a lower than expected depth of coverage. A strong positive correlation (0.964, p<0.001) was seen between NGS and 1000 genome project frequency estimates. Of the ~170 “novel” variants detected in the genes, seven SNPs, all of which were present in multiple sample pools, were selected for validation by Sanger sequencing. Two SNPs were successfully validated by this method, and shown to be genuine variants, while five failed validation. These spurious SNP calls occurred as a result of the presence of small indels and mononucleotide repeats, indicating such features should be regarded with caution, and validation via an independent method is important for NGS variant calls

Next generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions

CLU, PICALM and CR1 were identified as genetic risk factors for late onset Alzheimer’s disease (AD) in two large genome wide association studies (GWAS) published in 2009, but the variants that convey this alteration in disease risk, and how the genes relate to AD pathology is yet to be discovered. A next generation sequencing (NGS) project was conducted targeting CLU, CR1 and PICALM, in 96 AD samples (8 pools of 12), in an attempt to discover rare variants within these AD associated genes. Inclusion of repetitive regions in the design of the SureSelect capture lead to significant issues in alignment of the data, leading to poor specificity and a lower than expected depth of coverage. A strong positive correlation (0.964, p<0.001) was seen between NGS and 1000 genome project frequency estimates. Of the ~170 “novel” variants detected in the genes, seven SNPs, all of which were present in multiple sample pools, were selected for validation by Sanger sequencing. Two SNPs were successfully validated by this method, and shown to be genuine variants, while five failed validation. These spurious SNP calls occurred as a result of the presence of small indels and mononucleotide repeats, indicating such features should be regarded with caution, and validation via an independent method is important for NGS variant calls

Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism

Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. Methods: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. Results: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. Conclusions: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia

A transcriptome-wide association study implicates specific pre- and post-synaptic abnormalities in schizophrenia

chizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in dorsolateral prefrontal cortex (P ≤ 9.43x10−6), including 20 novel genes. Genes whose expression correlate with schizophrenia were enriched for those involved in abnormal CNS synaptic transmission (PFDR = 0.02) and antigen processing and presentation of peptide antigen via MHC class I (PFDR = 0.02). Within the CNS synaptic transmission set, we identify individual significant candidate genes to which we assign direction of expression changes in schizophrenia. The findings provide strong candidates for experimentally probing the molecular basis of synaptic pathology in schizophrenia

Investigating splicing variants uncovered by next-generation sequencing the Alzheimer’s disease candidate genes, CLU, PICALM, CR1, ABCA7, BIN1, the MS4A locus, CD2AP, EPHA1 and CD33

Late onset Alzheimer’s disease (LOAD), the most common cause of late onset dementia, has a strong genetic component. To date, 21 disease-risk loci have been identified through genome wide association studies (GWAS). However, the causative functional variant(s) within these loci are yet to be discovered. This study aimed to identify potential functional splicing mutations in the nine original GWAS-risk genes: CLU, PICALM, CR1, ABCA7, BIN1, the MS4A locus, CD2AP, EPHA1 and CD33. Target enriched next generation sequencing (NGS) was used to resequence the entire genetic region for each of these GWAS-risk loci in 96 LOAD patients and in silico databases were used to annotate the variants for functionality. Predicted splicing variants were further functionally characterised using splicing prediction software and minigene splicing assays. Following in silico annotation, 21 variants were predicted to influence splicing and, upon further annotation, four of these were examined utilising the in vitro minigene assay. Two variants, rs881768 A>G in ABCA7 and a novel variant 11: 60179827 T>G in MS4A6A were shown, in these cell assays, to affect the splicing of these genes. The method employed in the paper successfully identified potential splicing variants in GWAS-risk genes. Further investigation will be needed to understand the full effect of these variants on LOAD risk. However, these results suggest a possible pipeline in order to identify putative functional variants as a result of NGS in disease-associated loci although improvements are needed within the current prediction programme in order to reduce the number of false positives

Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease

The cerebral deposition of Aß42, a neurotoxic proteolitic derivate of amyloid precursor protein (APP), is a central event in Alzheimer’s disease (AD)(Amyloid hypothesis). Given the key role of APP-Aß metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aß degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 435 sporadic and mainly late-onset AD cases and 801 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, which were nominally significant, were found to be very rare coding variants (MAF 0.3%-0.8%) that map to genes involved in APP processing (MEP1B), trafficking and recycling (SORL1), Aß extracellular degradation (ACE) and clearance (LRP1). Moreover, four genes (ECE1, LYZ, TTR and MME) have been found as nominally associated to AD using c-alpha and SKAT tests. We suggest that Aβ degradation and clearance, rather than Aβ production, may play a crucial role in the etiology of sporadic AD