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To conduct feasibility and cost analysis of portable MRI implementation in a remote setting where MRI access is otherwise unavailable.
Portable MRI (ultra-low field, 0.064T) was installed in Weeneebayko General Hospital, Moose Factory, Ontario. Adult patients, presenting with any indication for neuroimaging, were eligible for study inclusion. Scanning period was from November 14, 2021, to September 6, 2022. Images were sent via a secure PACS network for Neuroradiologist interpretation, available 24/7. Clinical indications, image quality, and report turnaround time were recorded. A cost analysis was conducted from a healthcare system’s perspective in 2022 Canadian dollars, comparing cost of portable MRI implementation to transporting patients to a center with fixed MRI.
Portable MRI was successfully implemented in a remote Canadian location. Twenty-five patients received a portable MRI scan. All studies were of diagnostic quality. No clinically significant pathologies were identified on any of the studies. However, based on clinical presentation and limitations of portable MRI resolution, it is estimated that 11 (44%) of patients would require transfer to a center with fixed MRI for further imaging workup. Cost savings were $854,841 based on 50 patients receiving portable MRI over 1 year. Five-year budget impact analysis showed nearly $8 million dollars saved.
Portable MRI implementation in a remote setting is feasible, with significant cost savings compared to fixed MRI. This study may serve as a model to democratize MRI access, offer timely care and improved triaging in remote areas where conventional MRI is unavailable.
OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.
This article presents a theory of reasoning about moral propositions that is based on four fundamental principles. First, no simple criterion picks out propositions about morality from within the larger set of deontic propositions concerning what is permissible and impermissible in social relations, the law, games, and manners. Second, the mechanisms underlying emotions and deontic evaluations are independent and operate in parallel, and so some scenarios elicit emotions prior to moral evaluations, some elicit moral evaluations prior to emotions, and some elicit them at the same time. Third, deontic evaluations depend on inferences, either unconscious intuitions or conscious reasoning. Fourth, human beliefs about what is, and isn’t, moral are neither complete nor consistent. The article marshals the evidence, which includes new studies, corroborating these principles, and discusses the relations between them and other current theories of moral reasoning.
Paediatricians play an integral role in the lifelong care of children with CHD, many of whom will undergo cardiac surgery. There is a paucity of literature for the paediatrician regarding the post-operative care of such patients.
The aim of this manuscript is to summarise essential principles and pertinent lesion-specific context for the care of patients who have undergone surgery or intervention resulting in a biventricular circulation.
Conclusions and relevance:
Familiarity with common issues following cardiac surgery or intervention, as well as key details regarding specific lesions and surgeries, will aid the paediatrician in providing optimal care for these patients.
Single ventricle CHD affects about 5 out of 100,000 newborns, resulting in complex anatomy often requiring multiple, staged palliative surgeries. Paediatricians are an essential part of the team that cares for children with single ventricle CHD. These patients often encounter their paediatrician first when a complication arises, so it is critical to ensure the paediatrician is knowledgeable of these issues to provide optimal care.
We reviewed the subtypes of single ventricle heart disease and the various palliative surgeries these patients undergo. We then searched the literature to detail the general paediatrician’s approach to single ventricle patients at different stages of surgical palliation.
Conclusions and relevance
Single ventricle patients undergo staged palliation that drastically changes physiology after each intervention. Coordinated care between their paediatrician and cardiologist is requisite to provide excellent care. This review highlights what to expect when these patients are seen by their paediatrician for either well child visits or additional visits for parental or patient concern.
Cognitive behavior therapy (CBT) is effective for most patients with a social anxiety disorder (SAD) but a substantial proportion fails to remit. Experimental and clinical research suggests that enhancing CBT using imagery-based techniques could improve outcomes. It was hypothesized that imagery-enhanced CBT (IE-CBT) would be superior to verbally-based CBT (VB-CBT) on pre-registered outcomes.
A randomized controlled trial of IE-CBT v. VB-CBT for social anxiety was completed in a community mental health clinic setting. Participants were randomized to IE (n = 53) or VB (n = 54) CBT, with 1-month (primary end point) and 6-month follow-up assessments. Participants completed 12, 2-hour, weekly sessions of IE-CBT or VB-CBT plus 1-month follow-up.
Intention to treat analyses showed very large within-treatment effect sizes on the social interaction anxiety at all time points (ds = 2.09–2.62), with no between-treatment differences on this outcome or clinician-rated severity [1-month OR = 1.45 (0.45, 4.62), p = 0.53; 6-month OR = 1.31 (0.42, 4.08), p = 0.65], SAD remission (1-month: IE = 61.04%, VB = 55.09%, p = 0.59); 6-month: IE = 58.73%, VB = 61.89%, p = 0.77), or secondary outcomes. Three adverse events were noted (substance abuse, n = 1 in IE-CBT; temporary increase in suicide risk, n = 1 in each condition, with one being withdrawn at 1-month follow-up).
Group IE-CBT and VB-CBT were safe and there were no significant differences in outcomes. Both treatments were associated with very large within-group effect sizes and the majority of patients remitted following treatment.
Evaluate the efficacy and long-term safety of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.
Patients requiring chronic treatment for schizophrenia, not on aripiprazole monotherapy, were cross-titrated from other antipsychotic(s) to aripiprazole in an oral conversion phase (Phase 1). All patients entered an oral aripiprazole stabilization phase (Phase 2). Patients meeting stability criteria entered an ARI-OM stabilization phase (Phase 3), with coadministration of oral aripiprazole for the first 2 weeks. Patients meeting stability criteria were randomized to ARI-OM or placebo once-monthly (placebo-OM) during a 52-week, double-blind maintenance phase (Phase 4). Primary endpoint was time-to-impending relapse. Safety and tolerability were also assessed.
710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo-OM=134). The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis. Time-to-impending relapse was significantly delayed with ARI-OM vs. placebo-OM (p< 0.0001, log-rank test). Discontinuations due to treatment-emergent adverse events (AEs) were: Phase 1, 3.8% (n=24/632); Phase 2, 3.0% (n=21/709); Phase 3, 4.9% (n=28/576); Phase 4, 7.1% (n=19/269). Most AEs were mild or moderate. Insomnia was the only AE >5% incidence in any phase. Headache, somnolence, and nausea had a peak first onset within the first 4 weeks of treatment. There were no unusual shifts in all phases in laboratory values, fasting metabolic parameters, weight, or objective scales of movement disorders.
ARI-OM significantly delayed time-to-impending relapse compared with placebo-OM and was well tolerated as maintenance treatment in schizophrenia1.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
Conodont fossils are highly valuable for Paleozoic biostratigraphy and for interpreting evolutionary change, but identifying and describing conodont morphologies, and characterizing gradual shape variation remain challenging. We used geometric morphometric (GM) analysis to conduct the first landmark-based morphometric analysis of the biostratigraphically useful conodont genus Neognathodus. Our objective is to assess whether previously defined morphotype groups are reliably distinct from one another. As such, we reevaluate patterns of morphologic change in Neognathodus P1elements, perform maximum-likelihood tests of evolutionary modes, and construct novel, GM-based biozonations through a Desmoinesian (Middle Pennsylvanian) section in the Illinois Basin. Our GM results record the entire spectrum of shape variability among Neognathodus morphotypes, thus alleviating the problem of documenting and classifying gradual morphologic transitions between morphotypes. Statistically distinct GM groups support previously established classifications of N. bassleri, N. bothrops, and N. roundyi. Statistically indistinct pairs of GM groups do not support literature designations of N. medadultimus and N. medexultimus, and N. dilatus and N. metanodosus, and we synonymize each pair. Maximum-likelihood tests of evolutionary modes provide the first statistical assessment of Neognathodus evolutionary models in the Desmoinesian. The most likely evolutionary models are an unbiased random walk or a general random walk. We name four distinct biozones through the Desmoinesian using GM results, and these align with previous biozonation structure based on the Neognathodus Index (NI), illustrating that Neognathodus-based biostratigraphic correlations would not change between GM or NI methods. The structural similarity between both biozonations showcases that determining GM-based biozones is not redundant, as this comparison validates using landmark-based GM work to construct viable biozonations for subsequent stratigraphic correlations. Although this study is limited to the Illinois Basin, our quantitative methodology can be applied broadly to test taxonomic designations of additional genera, interpret statistically robust evolutionary patterns, and construct valid biozones for this significant chordate group.
Small perturbations to a steady uniform granular chute flow can grow as the material moves downslope and develop into a series of surface waves that travel faster than the bulk flow. This roll wave instability has important implications for the mitigation of hazards due to geophysical mass flows, such as snow avalanches, debris flows and landslides, because the resulting waves tend to merge and become much deeper and more destructive than the uniform flow from which they form. Natural flows are usually highly polydisperse and their dynamics is significantly complicated by the particle size segregation that occurs within them. This study investigates the kinematics of such flows theoretically and through small-scale experiments that use a mixture of large and small glass spheres. It is shown that large particles, which segregate to the surface of the flow, are always concentrated near the crests of roll waves. There are different mechanisms for this depending on the relative speed of the waves, compared to the speed of particles at the free surface, as well as on the particle concentration. If all particles at the surface travel more slowly than the waves, the large particles become concentrated as the shock-like wavefronts pass them. This is due to a concertina-like effect in the frame of the moving wave, in which large particles move slowly backwards through the crest, but travel quickly in the troughs between the crests. If, instead, some particles on the surface travel more quickly than the wave and some move slower, then, at low concentrations, large particles can move towards the wave crest from both the forward and rearward sides. This results in isolated regions of large particles that are trapped at the crest of each wave, separated by regions where the flow is thinner and free of large particles. There is also a third regime arising when all surface particles travel faster than the waves, which has large particles present everywhere but with a sharp increase in their concentration towards the wave fronts. In all cases, the significantly enhanced large particle concentration at wave crests means that such flows in nature can be especially destructive and thus particularly hazardous.
The Numeniini is a tribe of 13 wader species (Scolopacidae, Charadriiformes) of which seven are Near Threatened or globally threatened, including two Critically Endangered. To help inform conservation management and policy responses, we present the results of an expert assessment of the threats that members of this taxonomic group face across migratory flyways. Most threats are increasing in intensity, particularly in non-breeding areas, where habitat loss resulting from residential and commercial development, aquaculture, mining, transport, disturbance, problematic invasive species, pollution and climate change were regarded as having the greatest detrimental impact. Fewer threats (mining, disturbance, problematic native species and climate change) were identified as widely affecting breeding areas. Numeniini populations face the greatest number of non-breeding threats in the East Asian-Australasian Flyway, especially those associated with coastal reclamation; related threats were also identified across the Central and Atlantic Americas, and East Atlantic flyways. Threats on the breeding grounds were greatest in Central and Atlantic Americas, East Atlantic and West Asian flyways. Three priority actions were associated with monitoring and research: to monitor breeding population trends (which for species breeding in remote areas may best be achieved through surveys at key non-breeding sites), to deploy tracking technologies to identify migratory connectivity, and to monitor land-cover change across breeding and non-breeding areas. Two priority actions were focused on conservation and policy responses: to identify and effectively protect key non-breeding sites across all flyways (particularly in the East Asian- Australasian Flyway), and to implement successful conservation interventions at a sufficient scale across human-dominated landscapes for species’ recovery to be achieved. If implemented urgently, these measures in combination have the potential to alter the current population declines of many Numeniini species and provide a template for the conservation of other groups of threatened species.
Geophysical granular flows, such as avalanches, debris flows, lahars and pyroclastic flows, are always strongly influenced by the basal topography that they flow over. In particular, localised bumps or obstacles can generate rapid changes in the flow thickness and velocity, or shock waves, which dissipate significant amounts of energy. Understanding how a granular material is affected by the underlying topography is therefore crucial for hazard mitigation purposes, for example to improve the design of deflecting or catching dams for snow avalanches. Moreover, the interactions with solid boundaries can also have important applications in industrial processes. In this paper, small-scale experiments are performed to investigate the flow of a granular avalanche over a two-dimensional smooth symmetrical bump. The experiments show that, depending on the initial conditions, two different steady-state regimes can be observed: either the formation of a detached jet downstream of the bump, or a shock upstream of it. The transition between the two cases can be controlled by adding varying amounts of erodible particles in front of the obstacle. A depth-averaged terrain-following avalanche theory that is formulated in curvilinear coordinates is used to model the system. The results show good agreement with the experiments for both regimes. For the case of a shock, time-dependent numerical simulations of the full system show the evolution to the equilibrium state, as well as the deposition of particles upstream of the bump when the inflow ceases. The terrain-following theory is compared to a standard depth-averaged avalanche model in an aligned Cartesian coordinate system. For this very sensitive problem, it is shown that the steady-shock regime is captured significantly better by the terrain-following avalanche model, and that the standard theory is unable to predict the take-off point of the jet. To retain the practical simplicity of using Cartesian coordinates, but have the improved predictive power of the terrain-following model, a coordinate mapping is used to transform the terrain-following equations from curvilinear to Cartesian coordinates. The terrain-following model, in Cartesian coordinates, makes identical predictions to the original curvilinear formulation, but is much simpler to implement.
To validate the ovine model of profound oropharyngeal dysphagia and compare swallowing outcomes of laryngotracheal separation with those of total laryngectomy.
Under real-time fluoroscopy, swallowing trials were conducted using the head and neck of two Dorper cross ewes and one human cadaver, secured in lateral fluoroscopic orientation. Barium trials were administered at baseline, pre- and post-laryngohyoid suspension, following laryngotracheal separation, and following laryngectomy in the ovine model.
Mean pre-intervention Penetration Aspiration Scale and National Institutes of Health Swallow Safety Scale scores were 8 ± 0 and 6 ± 0 respectively in sheep and human cadavers, with 100 per cent intra- and inter-species reproducibility. These scores improved to 1 ± 0 and 2 ± 0 post-laryngohyoid suspension (p < 0.01). Aerodigestive tract residue was 18.6 ± 2.4 ml at baseline, 15.4 ± 3.8 ml after laryngotracheal separation and 3.0 ± 0.7 ml after total laryngectomy (p < 0.001).
The ovine model displayed perfect intra- and inter- species reliability for the Penetration Aspiration Scale and Swallow Safety Scale. Less aerodigestive tract residue after narrow-field laryngectomy suggests that swallowing outcomes after total laryngectomy are superior to those after laryngotracheal separation.
When solid stands of foxtail millet are cut for swath grazing, the grazing season for cattle is extended and winter feeding costs reduced. The economic success of this practice depends on inexpensive weed control. Eight single- and double-rate herbicide combinations (g ai/ha) were evaluated and compared to a weed-free check: MCPA + bromoxynil (280 + 280 or 560 + 560); MCPA + clopyralid (560 + 100 or 1120 + 200); MCPA + fluroxypyr (562 + 108 or 1124 + 216); and MCPA + clopyralid + fluroxypyr (560 + 100 + 144 or 1120 + 200 + 288). This study was conducted at Indian Head, Saskatchewan (SK) in 2004, 2005, 2006, and 2007 and at Scott, SK, in 2006 and 2007. Crop injury and dry matter yield were measured. Results of the study indicate that crop injury exceeded 20% at only one out of six sites at 7 to 14 d after herbicide treatment. Double-rate MCPA + bromoxynil treatments had higher injury ratings than the weed-free check 7 to 14 d after treatment in all site years. As the growing season progressed, injury ratings tended to decline except at Scott in 2007, where injury ratings at the 21 to 35 d period were numerically greater than the other two rating periods. There were no differences among treatments for crop biomass production. We conclude that all four herbicide combinations at the labeled rate are safe to use on foxtail millet in Saskatchewan, and probably in other areas with similar environmental growing conditions.