Adapting our perspective: Applying Indigenous Knowledge to climate resilience planning in BC

Policymakers are increasingly recognizing the ways in which Indigenous Knowledge can complement Western science to improve our understanding of and response to important issues such as climate change. Despite this, there are few areas where Indigenous Knowledge is currently being applied in decision-making by non-Indigenous governments. The goal of this paper is to explore concrete ways that Indigenous Knowledge could be respectfully and appropriately included in climate adaptation decision-making at the provincial level. Based on a literature review, an environmental scan, expert interviews, and examples from across Canada, I first identify key principles that should guide government policies relating to Indigenous Knowledge. I then propose a framework with specific policy examples for how Indigenous Knowledge could be applied to climate adaptation and resilience planning in BC

Non‐steroidal anti‐inflammatory drugs for treatment of cancer cachexia: A systematic review

Cancer cachexia (CC) is a multifactorial syndrome driven by inflammation, defined by ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support. CC leads to progressive functional impairment, with its clinical management complicated and limited therapeutic options available. The objective of this review was to assess the efficacy and safety of non‐steroidal anti‐inflammatory drugs (NSAIDs) on patient‐centred outcomes in patients with CC. In 2013, two systematic reviews concluded that there was insufficient evidence to recommend NSAIDs for clinical management of CC outside of clinical trials. However, clinical trials of multi‐component CC interventions have included NSAIDs as an intervention component, so an up‐to‐date assessment of the evidence for NSAIDs in the treatment of CC is warranted. Four databases (MEDLINE, EMBASE, CENTRAL and CINAHL) and three trial registers (clinicaltrials.gov, WHO ICTRP and ISRCTN) were searched on 16 December 2022. Randomized controlled trials (RCTs) comparing any NSAID (any dose or duration) with a control arm, in adult patients with CC, reporting measures of body weight, body composition, nutrition impact symptoms, inflammation, physical function or fatigue, were eligible for inclusion. Primary outcomes (determined with patient involvement) were survival, changes in muscle strength, body composition, body weight and quality of life. Included studies were assessed for risk of bias using the Revised Cochrane risk‐of‐bias tool for randomized trials. Five studies were included, which investigated Indomethacin (n = 1), Ibuprofen (n = 1) and Celecoxib (n = 3). Four studies were judged to be at high risk of bias for all outcomes, with one study raising concerns for most outcomes. Considerable clinical and methodological heterogeneity amongst the studies meant that meta‐analysis was not appropriate. There was insufficient evidence to determine whether Indomethacin or Ibuprofen is effective or safe for use in patients with CC; RCTs with lower risk of bias are needed. Celecoxib studies indicated it was safe for use in this population at the doses tested (200–400 mg/day) but found contrasting results regarding efficacy, potentially reflecting heterogeneity amongst the studies. There is inadequate evidence to recommend any NSAID for CC. While current clinical trials for CC treatments are shifting towards multi‐component interventions, further research to determine the efficacy and safety of NSAIDs alone is necessary if they are to be included in such multi‐component interventions. Furthermore, the lack of data on patient‐determined primary outcomes in this review highlights the need for patient involvement in clinical trials for C

Increasing energetic demands on photoreceptors in diabetes corrects retinal lipid dysmetabolism and reduces subsequent microvascular damage

Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but they likely involve multiple cellular targets, including photoreceptors. Evidence suggests that dysregulated de novo lipogenesis in photoreceptors is a critical early target of diabetes. Following on this observation, the present study aimed to determine whether two interventions shown to improve diabetic retinopathy in mice-pharmacologic visual cycle inhibition and prolonged dark adaptation-reduce photoreceptor anabolic lipid metabolism. Elevated retinal lipid biosynthetic signaling was observed in two mouse models of diabetes, with both models showing reduced retinal AMP-activated kinase (AMPK) signaling, elevated acetyl CoA carboxylase (ACC) signaling, and increased activity of fatty acid synthase, which promotes lipotoxicity in photoreceptors. Although retinal AMPK-ACC axis signaling was dependent on systemic glucose fluctuations in healthy animals, mice with diabetes lacked such regulation. Visual cycle inhibition and prolonged dark adaptation reversed abnormal retinal AMPK-ACC signaling in mice with diabetes. Although visual cycle inhibition reduced the severity of diabetic retinopathy in control mice, as assessed by retinal capillary atrophy, this intervention was ineffective in fatty acid synthase gain-of-function mice. These results suggest that early diabetic retinopathy is characterized by glucose-driven elevations in retinal lipid biosynthetic activity, and that two interventions known to increase photoreceptor glucose demands alleviate disease by reversing these signals

Improving Completion Rates for Underrepresented Populations

Most experienced educators recognize that many students will not complete optional assignments, and often those students who need additional help do not seek assistance. Current research demonstrates that students in underrepresented populations (see definition below) are less likely to seek support than others because they see needing help as a confirmation that they don’t really “belong” in college in the first place. Research shows that those who do access currently optional supports such as tutoring are more likely to succeed, so this research group looked for ways to build structured connections between underrepresented students and resources. We found that our peers at various VCCS colleges had programs that were working to build these connections for our students, so in our resource-constrained environment, we chose to focus on what exists that works, is scalable, and could be implemented in stages as resources permit. Our proposal reflects increased resource allocation on both the academic support (tutoring) side and the student support (TRIO, Pathway to the Baccalaureate, Success Coaches) side to increase structured contact between the student and the support to decrease the “stigma” of seeking help. We propose this because in our roles as administrators and faculty we know that often our students need both academic support and holistic support

Wilms’ tumour antigen 1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a Phase II non-randomised clinical trial (WIN)

Background: In the UK almost 7000 people are diagnosed with leukaemia each year, but despite continuing advances in diagnosis and treatment with new drugs, such as the tyrosine kinase inhibitors, the majority of these patients will eventually die from their disease. Until quite recently, the only treatment to offer the possibility of long-term disease-free survival was allogeneic stem cell transplantation. However, this carries a substantial risk of mortality and is available to only a minority of patients.Objectives: The aim of the study was to test the hypothesis that molecular and clinical responses, induced by T lymphocytes (T cells), can be predicted by increases in the number of CD8+ (cluster of differentiation 8-positive) T cells specific for the vaccine-encoded T-cell epitopes. This project also aimed to build on the established programme of deoxyribonucleic acid (DNA) fusion-gene vaccination delivered by intramuscular injection, exploiting a unique experience with electroporation, to induce durable immune responses with the aim of controlling disease by precision attack of the tumour by CD8+ T cells.Method: A non-randomised, open-label, single-dose-level Phase II clinical trial in two patient groups [chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML)] on stable doses of imatinib. Human leucocyte antigen A2-positive (HLA A2+) patients were vaccinated with two DNA vaccines: (1) p.DOM–WT1-37 (epitope sequence: VLDFAPPGA); and (2) p.DOM–WT1-126 (epitope sequence: RMFPNAPYL). The HLA A2-negative patients formed an unvaccinated control group. The sample size for the HLA A2+ group was originally determined following Simon’s optimal Phase II trial design (Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10). This was changed to A’Hern’s single-stage design during the course of the trial (A’Hern RP. Sample size tables for single-stage phase II designs. Stat Med 2001;20:859–66), which was endorsed by the trial’s independent oversight committees.Results: The study included 12 patients with CML who were vaccinated and nine patients with CML who were unvaccinated as the control group. Both the vaccines and the electroporation were safe, with no new or unexpected toxicities. The evaluation adverse events of special interest (heart, bone marrow, renal) did not reveal safety concerns. Two BCR–ABL (breakpoint cluster region–Abelson murine leukaemia viral oncogene homolog 1) responses were observed, both of which were defined as a major response, with one in each group. Two Wilms’ tumour antigen 1 (WT1) molecular responses were observed in the vaccinated group and one was observed in the control group. At an immunological level, the vaccine performed as expected.Conclusions: The study met its primary decision-making target with one major molecular response in BCR–ABL transcript levels. Overall, the data showed, in this clinical setting, the immunogenicity and safety of the vaccine.Limitations: The study did not complete recruitment and there were multiple hurdles that contributed to this failure. This is disappointing given the robust induction immune responses against WT1 T-cell responses in 7 out of 10 evaluable patients.Future work: Evaluation of the p.DOM–WT1 vaccines in AML remains attractive clinically, but it is unlikely to be feasible at this time. Combination of the DNA vaccine approach with strategies to expand T-cell responses with immunomodulatory antibodies is in development.Funding details: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership, and Bloodwise

FASN-dependent de novo lipogenesis is required for brain development

Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multienzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors and reduced progenitor proliferation. Furthermore, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell-derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity in human brain organoids. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor-cell polarity and lipid metabolism

Glucose-mediated de novo lipogenesis in photoreceptors drives early diabetic retinopathy

Diabetic retinopathy (DR) is an increasingly frequent cause of blindness across populations; however, the events that initiate pathophysiology of DR remain elusive. Strong preclinical and clinical evidence suggests that abnormalities in retinal lipid metabolism caused by diabetes may account for the origin of this disease. A major arm of lipid metabolism, de novo biosynthesis, is driven by elevation in available glucose, a common thread binding all forms of vision loss in diabetes. Therefore, we hypothesized that aberrant retinal lipid biogenesis is an important promoter of early DR. In murine models, we observed elevations of diabetes-associated retinal de novo lipogenesis ∼70% over control levels. This shift was primarily because of activation of fatty acid synthase (FAS), a rate-limiting enzyme in the biogenic pathway. Activation of FAS was driven by canonical glucose-mediated disinhibition of acetyl-CoA carboxylase, a major upstream regulatory enzyme. Mutant mice expressing gain-of-function FAS demonstrated increased vulnerability to DR, whereas those with FAS deletion in rod photoreceptors maintained preserved visual responses upon induction of diabetes. Excess retinal de novo lipogenesis—either because of diabetes or because of FAS gain of function—was associated with modestly increased levels of palmitate-containing phosphatidylcholine species in synaptic membranes, a finding with as yet uncertain significance. These findings implicate glucose-dependent increases in photoreceptor de novo lipogenesis in the early pathogenesis of DR, although the mechanism of deleterious action of this pathway remains unclear

A Century of Grading Research: Meaning and Value in the Most Common Educational Measure

Grading refers to the symbols assigned to individual pieces of student work or to composite measures of student performance on report cards. This review of over 100 years of research on grading considers five types of studies: (a) early studies of the reliability of grades, (b) quantitative studies of the composition of K-12 report card grades, (c) survey and interview studies of teachers’ perceptions of grades, (d) studies of standards-based grading, and (e) grading in higher education. Early 20th century studies generally condemned teachers’ grades as unreliable. More recent studies of the relationships of grades to tested achievement and survey studies of teachers’ grading practices and beliefs suggest that grades assess a multidimensional construct containing both cognitive and non-cognitive factors reflecting what teachers value in student work. Implications for future research and for grading practices are discussed