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Correction: “Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10-/- mouse model of inflammatory bowel disease”
Get PDFMy journey as a nurse in Nepal and Canada: autoethnographic reflections
No full textIn this paper, I have tried to compare and contrast the status of disability in Nepal in terms of education, employment, accessibility, and health through my experiences of living in Nepal and moving to Canada. I start with what is now known from the many studies conducted in the field of disability in Nepal. Coming from a medical background, I challenged my understanding of the medical model of disability and brought my experiences to light from the perspective of the social model of disability.
Through my experiences and understanding of Nepalese society, I also discuss the religious concepts of disability in Nepal along with prevalent taboos and social beliefs about disability, and how discrimination is automatic due to these beliefs. I also present my experiences with education, employment, and health care and how accessibility is key in ensuring that everyone has access to these services.
Overall, my study highlights the need for continued efforts by the Nepal government and its external development partners (EDP’s) to improve the status of disabled people in Nepal. By prioritizing disability rights, investing in disability-inclusive policies and programs, and promoting social inclusion and awareness, the government can improve the quality of life for people with disabilities in Nepal. Furthermore, by prioritizing disability-inclusive medical education, healthcare professionals in Nepal can be equipped with the knowledge and skills necessary to provide quality healthcare services to people with disabilities. As the world continues to prioritize disability rights and inclusion, it is essential for countries such as Nepal to keep pace with global efforts.February 202
Sooner or later: development of the first-letter advantage and its importance
No full textHumans have developed adaptive mechanisms to efficiently process letters, not symbols or shapes, in crowded conditions. Fluent readers exhibit the highest accuracy for the first, most leftward letter in briefly presented letter strings, known as the first-letter advantage, which aids in word decoding and typically emerges by Grade 1 for most children. Dyslexic individuals display a first-letter advantage, but their accuracy across serial positions is lower than non-dyslexics. Research on how and when this phenomenon emerges, particularly in children with minimal reading skills and varying levels of reading risk, is limited. Numerous studies have used target-in-string tasks with varying string lengths to measure the first-letter advantage. The current study employed a two-alternative forced choice task using two-item strings to examine how 50 children (22 not at risk, 28 at risk) develop the first-letter advantage from kindergarten to Grade 1. In kindergarten, at-risk children showed similar accuracy in identifying letter and shape targets flanked by identical items, indicating a lack of letter-specific specialization. Not-at-risk children showed an advantage in identifying letter targets over shapes, achieving the highest accuracy when the letter target with a rightward flanker was on the left side of the screen—a first-letter advantage. In Grade 1, not-at-risk children maintained this advantage, while at-risk children still showed similar accuracy for letter and shape targets. Both groups improved in the first-letter advantage condition from kindergarten to Grade 1, but at-risk children remained less accurate overall. These findings suggest that children at risk for reading difficulties may not develop the same level of letter specialization as their peers, limiting the benefits of early reading experiences and highlighting the need for early identification and intervention.Research ManitobaOctober 202
Exploring new targeted therapies for sonic hedgehog (SHH) medulloblastoma
No full textMedulloblastoma (MB) is the most common malignant primary pediatric brain tumor. MB is split into four molecular subgroups, with each subgroup displaying different gene expression profiles, genomic alterations, and responses to treatment. One subgroup is referred to as Sonic Hedgehog (SHH) MB and is defined by activation of the SHH signaling pathway. The current standard of care for MB consists of surgery, cytotoxic chemotherapy, and radiation to the entire brain and spinal cord. In spite of improved clinical outcomes, up to 40% of patients succumb to their disease while survivors are left with pervasive physical and cognitive delays as a result of the aggressive treatment. SHH MB exhibits extensive intratumoral heterogeneity which accounts for the bulk of treatment failures. Few personalized therapies for SHH MB exist, as SHH pathway antagonists are predicted to be ineffective in younger patients with tumors harbouring mutations in downstream SHH pathway genes. Novel, targeted therapies that have the possibility to reduce toxicity and improve survival are needed. The Ogilvie lab identified CD271, a neurotrophin receptor found exclusively in SHH MB. CD271 is diagnostic and prognostic in SHH MB, providing a highly specific therapeutic target. A small molecule named NSC49652 was found to bind to CD271. Binding of NSC49652 to CD271 leads to conformational changes in the receptor, leading to apoptosis by activating c-Jun N-terminal kinases. I hypothesized that NSC49652 would reduce SHH MB tumorigenic properties in vitro and would increase the length of survival and decrease tumor volume in vivo. My studies reveal that NSC49652 significantly reduces tumorigenic properties in vitro. In two SHH MB cell lines, NSC49652 resulted in decreases in tumorsphere size, tumorsphere number, cell migration, and cell viability. NSC49652 induces a decrease in tumorsphere number, which indicates decreased self-renewal capacity of the cancer stem cells (CSCs) that give rise to new tumorspheres. NSC49652 also decreases tumor volume and increases survival in an in vivo model of SHH MB. My work reveals a novel role for NSC49652 and warrants further investigation for the use of NSC49652 as a potential combination therapy for SHH MB.Rady Faculty of Health Sciences Graduate Studentship AwardOctober 202
IRE1 Activation in Spinal Cord Development and Repair in the Zebrafish Model
Get PDFThe Unfolded Protein Response (UPR) is a cellular pathway that functions in the maintenance of proteostasis in response to endoplasmic reticulum (ER) stress. Recent studies implicate the IRE1 branch of the UPR in the development of the central nervous system (CNS) and in response to spinal cord injury (SCI). To date, studies have focused mainly on mammalian models and thus we know little about the role of the UPR in the CNS of other vertebrates. In this study, we take advantage of the many attributes of the zebrafish model, including its capacity for neurorepair, to investigate the activation of IRE1 during spinal cord development and following SCI. Using the Tg(xbp1s:eGFP) transgenic reporter fish that expresses GFP upon IRE1 activation, we show that IRE1 is strongly upregulated in early larvae compared to juveniles and adults. High levels of IRE1 expression are displayed at 4-days post fertilization (dpf) and drop off into adulthood. Interestingly, when exposed to the ER stress inducing drug Dithiothreitol (DTT), larvae at 4-dpf also show slight elevated levels of IRE1 activation compared to later stages of development, suggesting IRE1 is less inducible with age. We next established a larval SCI model to ask whether IRE1 expression was upregulated after SCI. We demonstrate that, in contrast to mammalian models, spinal cord IRE1 activity remains the same or slightly decreases following SCI
Exploring Canadian genetic healthcare providers’ perspectives on sponsored genetic testing
Get PDFSponsored genetic testing (SGT) programs consist of partnerships between clinical genetic testing laboratories and third-party organizations (generally biopharmaceutical companies) to offer genetic testing free of charge to a patient or healthcare system. To date, there is no research surrounding the use of SGT in Canada, or how it is perceived by professionals.
This study aims to learn about Canadian genetic healthcare providers’ (CGHPs’) views on SGT, along with their perceived benefits, limitations, and impacts of SGT within the Canadian healthcare system.
Certified genetic counsellors, medical geneticists, and laboratory geneticists practicing in Canada were invited to participate in semi-structed interviews. Interviews were recorded over Zoom, transcribed verbatim, and analyzed using interpretive description and thematic analysis. Codes were created inductively, and themes emerged across cases to capture participants’ perceptions.
Interviews were conducted with 18 CGHPs across six provinces. Some participants were ambivalent about SGT, and others either agreed or disagreed with its use in practice. Perspectives were categorized into four main themes: 1) adequate transparency surrounding data sharing 2) the desire for a workaround to improve access 3) consideration of budgets within a publicly funded healthcare system and 4) perspectives of non-genetics providers using SGT. Proponents noted that transparency regarding data sharing between the genetic testing laboratories and third-party companies was adequate, that SGT could provide increased access to genetic testing, and that SGT can help advocate for enhanced provincial funding of genetic services. Skeptics of SGT mentioned a lack of transparency regarding how patient data is shared and used, that a public system should be able to cover all patients who require genetic testing, and that there is a responsibility to consider how externally funded testing could be detrimental to future budget considerations. All participants had considerations for their non-genetics colleagues ordering SGT.
This exploratory study offers insights surrounding CGHPs’ views on SGT. It highlights the benefits and limitations regarding the use of SGT in Canada, along with a unique perspective into the challenges and nuances of using SGT within a publicly funded healthcare system.University of ManitobaOctober 202
Mechanisms of laminar organization of hippocampal excitatory synapses
No full textThe hippocampus has well-defined laminae with specified neuronal pathways. In the hippocampus, I investigated the developmental expression and functional roles of prominent synapse organizers, leucine-rich-repeat transmembrane neuronal proteins (LRRTMs). LRRTM1 and LRRTM2 are compartmentalised to the stratum radiatum (SR) and stratum lacunosum moleculare (SLM), respectively, with specific expression impacting synaptic architecture and cognitive behaviours. Using immunohistochemistry, I demonstrated that LRRTM1 and LRRTM2 exhibit distinct temporal and spatial expression patterns in the hippocampal laminae: LRRTM1 is predominantly localized in the SR, and LRRTM2 in the SLM. My findings indicate that LRRTM2 expression in the SLM corresponds with excitatory synapse formation and maturation in the cortical temporoammonic cortical inputs to the CA1. However, the functional significance of LRRTM2 compartmentalization in the SLM was not known. To this end, I conducted a suite of behavioural assays in mice lacking LRRTM2 in the dorsal CA1 (Lrrtm2-CA1-cKO). My studies revealed that Lrrtm2-CA1-cKO mice display anxiety-associated phenotype, but only in female mice.May 202
Incidence of serious infection among etanercept and infliximab initiators: safety comparison between biosimilars and bio-originators with Canadian population-based data
No full textBackground
Safety remains a significant concern for biologic drugs, and studies are needed to ensure a comparable safety profile for biosimilars and their legacy treatments. Using Canadian administrative health data from 2015–2019, we compared the incidence of serious infection between biosimilars and bio-originators initiators for etanercept and infliximab, two of the most commonly used biologics during this time.
Methods
We performed a retrospective cohort study using pan-Canadian data (except Quebec) from the National Prescription Drug Utilization Information System linked to hospitalization data. We studied new users of infliximab or etanercept (January/2015-December/2019) and compared incidence rates of serious infection, defined as those which required hospitalization, by using Cox regression models adjusted by biological sex, age at treatment initiation, prior corticosteroid or biologic, province, and calendar year.
Results
We studied 6,583 etanercept users (mean age 62) and 7,202 infliximab users (mean age 45). Hospitalization with infections occurred in 7% of infliximab and 2% of etanercept users. Comparing the risk of infection between biosimilar to bio-originator, the adjusted hazard ratio (95% confidence interval) was 1.33 (0.77, 2.30) for etanercept and 0.93 (0.72, 1.18) for infliximab.
Conclusions
Our study found no clear difference between etanercept and infliximab biosimilars and their bio-originators for infection incidence, suggesting a similar safety profile
NERD-seq: a novel approach of Nanopore direct RNA sequencing that expands representation of non-coding RNAs
No full textAbstract
Non-coding RNAs (ncRNAs) are frequently documented RNA modification substrates. Nanopore Technologies enables the direct sequencing of RNAs and the detection of modified nucleobases. Ordinarily, direct RNA sequencing uses polyadenylation selection, studying primarily mRNA gene expression. Here, we present NERD-seq, which enables detection of multiple non-coding RNAs, excluded by the standard approach, alongside natively polyadenylated transcripts. Using neural tissues as a proof of principle, we show that NERD-seq expands representation of frequently modified non-coding RNAs, such as snoRNAs, snRNAs, scRNAs, srpRNAs, tRNAs, and rRFs. NERD-seq represents an RNA-seq approach to simultaneously study mRNA and ncRNA epitranscriptomes in brain tissues and beyond
Association between early childhood caries and parental education and the link to the sustainable development goal 4: a scoping review
No full textBackground
The goal of the United Nations Sustainable Development Goal (SDG) 4 is to ensure inclusive and equitable quality education and promote lifelong learning opportunities for all. The aim of this scoping review was to map the current evidence on the association between the prevalence of early childhood caries (ECC) and parental education; and to identify possible pathways by which parental education may protect against ECC.
Methods
The two questions that guided this review were: what is the existing evidence on the association between maternal and paternal education and ECC; and what are the pathways by which parental education protects against ECC? The initial search was conducted in January 2023 in PubMed, Web of Science and Scopus. Articles published in English between January 2000 and October 2022 that reported on the association between parental education and ECC were screened, and the extracted data were compiled, summarized, and synthesized. Review papers and non-primary quantitative research papers were excluded from the full-text review. Open coding was applied to develop a conceptual framework.
Results
In total, 49 studies were included: 42 cross-sectional, 3 case-control and 4 cohort studies. The majority (91.8%) reported on the associations between ECC and maternal (n = 33), paternal (n = 3), and parental (n = 9) level of education, and 13 (26.7%) reported on the association between parental education and the severity of ECC. Mothers with more than primary school education (n = 3), post-secondary/college/tertiary education (n = 23), and more than 4–12 years of education (n = 12) had children with lower risk for ECC. Two studies reporting on parental education found an association between maternal but not paternal education and ECC. The review suggests that achieving the SDG 4.1 may reduce the risk of ECC. Possible pathways by which maternal education protects from ECC were feeding practices, oral hygiene practices, and the use of dental services.
Conclusion
The study findings suggests that higher maternal educational level may reduce the risk for the consumption of cariogenic diet, poor oral hygiene practices and poor use of dental services for caries prevention. However, the association between paternal education and ECC was not consistently observed, with significant associations less frequently reported compared to maternal education. Future studies are needed to define the magnitude and modifiers of the impact of maternal education on the risk for ECC