Background: TERT promoter mutation (TPM) is an established biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival (PFS). TERT expression, however, has also been observed even in tumours with wildtype TERT promoters (TP-WT). This study aimed to examine TERT expression and clinical outcomes in meningiomas. Methods: TERT expression, TPM status, and TERT promoter methylation of a multi-institutional cohort of meningiomas (n=1241) was assessed through nulk RNA sequencing (n=604), Sanger sequencing of the promoter (n=1095), and methylation profiling (n=1218). 380 Toronto meningiomas were used for discovery, and 861 external institution samples were compiled as a validation cohort. Results: Both TPMs and TERTpromoter methylation were associated with increased TERT expression and may represent independent mechanisms of TERT reactivation. TERT expression was detected in 30.4% of meningiomas that lacked TPMs, was associated with higher WHO grades, and corresponded to shorter PFS, independent of grade and even among TP-WT tumours. TERT expression was associated with a shorter PFS equivalent to those of TERT-negative meningiomas of one higher grade. Conclusions: Our findings highlight the prognostic significance of TERT expression in meningiomas, even in the absence of TPMs. Its presence may identify patients who may progress earlier and should be considered in risk stratification models.

Background: Ischemic stroke is a major cause of morbidity and mortality in Canada. Since 2015, mechanical thrombectomy has been the standard of care for eligible large vessel occlusions (LVOs), though anesthetic strategies remain variable. Methods: We conducted a single-center retrospective review of patients undergoing mechanical thrombectomy for anterior circulation LVOs between 2021 and 2023. Patients were categorized by anesthetic strategy (general anesthesia vs. conscious sedation), and outcomes, including time to recanalization, angiographic results (mTICI), and 90-day functional status (mRS), were compared. Statistical analyses included Student’s t-test, Mann-Whitney U-test, and Fisher’s exact test. Results: Among 226 patients, 177 (78%) received general anesthesia and 49 (22%) underwent conscious sedation. Baseline characteristics including sex, age, NIHSS, ASPECTS, collaterals, and laterality were similar between groups. Conscious sedation was associated with a statistically significant shorter time from arrival to the angiography suite to groin puncture (p=0.007), but no differences in time to recanalization (p=0.893), angiographic outcomes (p=0.987), or 90-day functional status (p=0.795) were observed. Conclusions: Conscious sedation led to faster procedural initiation, though no difference in clinical or radiographic outcome was observed. Anesthetic choice should be individualized based on patient and physician factors in acute mechanical thrombectomy.

Background: The WHO grade of meningioma was updated in 2021 to include homozygous deletions of CDKN2A/B and TERT promotor mutations. Previous work including the recent cIMPACT-NOW statement have discussed the potential value of including chromosomal copy number alterations to help refine the current grading system. Methods: Chromosomal copy number profiles were inferred from from 1964 meningiomas using DNA methylation. Regularized Cox regresssion was used to identify CNAs independenly associated with post-surgical and post-RT PFS. Outcomes were stratified by WHO grade and novel CNAs to assess their potential value in WHO critiera. Results: Patients with WHO grade 1 tumours and chromosome 1p loss had similar outcomes to those with WHO grade 2 tumours (median PFS 5.83 [95% CI 4.36-Inf] vs 4.48 [4.09-5.18] years). Those with chromosome 1p loss and 1q gain had similar outcomes to those with WHO grade 3 cases regardless of initial grade (median PFS 2.23 [1.28-Inf] years WHO grade 1, 1.90 [1.23-2.25] years WHO grade 2, compared to 2.27 [1.68-3.05] years in WHO grade 3 cases overall). Conclusions: We advocate for chromosome 1p loss being added as a criterion for a CNS WHO grade of 2 meningioma and addition of 1q gain as a criterion for a CNS WHO grade of 3.

Background: Meningiomas exhibit considerable heterogeneity. We previously identified four distinct molecular groups (immunogenic, NF2-wildtype, hypermetabolic, proliferative) which address much of this heterogeneity. Despite their utility, the stochasticity of clustering methods and the requirement of multi-omics data limits the potential for classifying cases in the clinical setting. Methods: Using an international cohort of 1698 meningiomas, we constructed and validated a machine learning-based molecular classifier using DNA methylation alone. Original and newly-predicted molecular groups were compared using DNA methylation, RNA sequencing, whole exome sequencing, and clinical outcomes. Results: Group-specific outcomes in the validation cohort were nearly identical to those originally described, with median PFS of 7.4 (4.9-Inf) years in hypermetabolic tumors and 2.5 (2.3-5.3) years in proliferative tumors (not reached in the other groups). Predicted NF2-wildtype cases had no NF2 mutations, and 51.4% had others mutations previously described in this group. RNA pathway analysis revealed upregulation of immune-related pathways in the immunogenic group, metabolic pathways in the hypermetabolic group and cell-cycle programs in the proliferative group. Bulk deconvolution similarly revealed enrichment of macrophages in immunogenic tumours and neoplastic cells in hypermetabolic/proliferative tumours. Conclusions: Our DNA methylation-based classifier faithfully recapitulates the biology and outcomes of the original molecular groups allowing for their widespread clinical implementation.

Background: Nipocalimab is a human IgG1 monoclonal antibody targeting FcRn that selectively reduces IgG levels without impacting antigen presentation, T- and B-cell functions. This study describes the effect of nipocalimab on vaccine response. Methods: Open-label, parallel, interventional study randomized participants 1:1 to receive intravenous 30mg/kg nipocalimab at Week0 and 15mg/kg at Week2 and Week4 (active) or no drug (control). On Day 3, participants received Tdap and PPSV®23 vaccinations and were followed through Wk16. Results: Twenty-nine participants completed the study and are included (active, n=15; control, n=14). Participants with a positive anti-tetanus IgG response was comparable between groups at Wk2 and Wk16, but lower at Wk4 (nipocalimab 3/15 [20%] vs control 7/14 [50%]; P=0.089). All maintained anti-tetanus IgG above the protective threshold (0.16IU/mL) through Wk16. While anti-pneumococcal-capsular-polysaccharide (PCP) IgG levels were lower during nipocalimab treatment, the percent increase from baseline at Wk2 and Wk16 was comparable between groups. Post-vaccination, anti-PCP IgG remained above 50mg/L and showed a 2-fold increase from baseline throughout the study in both groups. Nipocalimab co-administration with vaccines was safe and well-tolerated. Conclusions: These findings suggest that nipocalimab does not impact the development of an adequate IgG response to T-cell–dependent/independent vaccines and that nipocalimab-treated patients can follow recommended vaccination schedules.

In recent years, the rapid convergence of artificial intelligence (AI) and low-altitude flight technology has driven significant transformations across various industries. These advancements have showcased immense potential in areas such as logistics distribution, urban air mobility (UAM) and national defense. By adopting the AI technology, low-altitude flight technology can achieve high levels of automation and operate in coordinated swarms, thereby enhancing efficiency and precision. However, as these technologies become more pervasive, they also raise pressing ethical or moral concerns, particularly regarding privacy, public safety, as well as the risks of militarisation and weaponisation. These issues have sparked extensive debates. In summary, while the integration of AI and low-altitude flight presents revolutionary opportunities, it also introduces complex ethical challenges. This article will explore these opportunities and challenges in depth, focusing on areas such as privacy protection, public safety, military applications and legal regulation, and will propose strategies to ensure that technological advancements remain aligned with ethical or moral principles.

Context effects occur when the preference between two alternatives is affected by the presence of an extra alternative. These effects are some of the most well studied phenomena in multi-alternative, multi-attribute decision making. Recent research in this area has revealed an intriguing pattern of results. On the one hand, these effects are robust and ubiquitous. That is, they have been demonstrated in many domains and different choice settings. On the other hand, they are fragile and they disappear or even reverse under different conditions. This pattern of results has spurred debate and speculation about the cognitive mechanisms that drive these choices. The attraction effect, where the preference for an option increases in the presence of a dominated decoy, has generated the most controversy. In this registered report, we systematically vary factors that are known to be associated with the attraction effect to build a solid foundation of empirical results to aid future theory development. We find a robust attraction effect across the different conditions. The strength of this effect is modulated by the display order (e.g., decoy top, target middle, competitor bottom) and mode (numeric vs. graphical) but not display layout (by-attribute vs. by-alternative).

In educational and psychological measurement when short test forms are used, the asymptotic normality of the maximum likelihood estimator of the person parameter of item response models does not hold. As a result, hypothesis tests or confidence intervals of the person parameter based on the normal distribution are likely to be problematic. Inferences based on the exact distribution, on the other hand, do not suffer from this limitation. However, the computation involved for the exact distribution approach is often prohibitively expensive. In this paper, we propose a general framework for constructing hypothesis tests and confidence intervals for IRT models within the exponential family based on exact distribution. In addition, an efficient branch and bound algorithm for calculating the exact p value is introduced. The type-I error rate and statistical power of the proposed exact test as well as the coverage rate and the lengths of the associated confidence interval are examined through a simulation. We also demonstrate its practical use by analyzing three real data sets.

Alzheimer’s disease (AD) is the most common progressive central nervous system neurodegenerative disease globally(1). At present, the treatment of AD involves only symptomatic medications which have continually demonstrated little efficacy(2). Hericium erinaceus (HE), commonly known as lion’s mane mushroom, has not yet been fully utilised among western pharmacology for its medicinal purposes, demonstrating a possible omittance of a highly beneficial neuro-altering substance. To date, studies that have investigated the potential medicinal properties of HE have found that various neuroprotective effects are exerted when following consumption(3). The aim of this review is to systematically investigate the neuroprotective pathways impacted by dietary supplementation of HE, determine specific bio-compounds responsible, and highlight the importance of continued research to determine the true potential relevance of this therapeutic treatment for AD.

Electronic databases were systematically searched for studies investigating the relationship between HE and AD. For inclusion in this review, human studies must have been of a clinical design involving adults >30 years that are healthy, have mild cognitive impairment, probably AD or memory deficits. Animal studies were required to involve interventions that directly impact AD-related mechanisms. The exclusion criteria involved any observational studies that involved participants with other neurological implications, or any studies that noted existing interventions (i.e., medications, post-surgery, dietary intervention). A study quality assessment was conducted for all qualified studies using Cochrane RoB2 tools. Data extraction was undertaken according to PRISMA guidelines.

A total of 16 studies (including 3 human clinical trials and 13 animal model studies) met the criteria for inclusion. All studies included either behavioural, biochemical, ophthalmic, and neuroimaging assessments which demonstrated to be directly influenced by HE intake and highlighted key mechanisms previously associated with neurohealth promotion or neuropathological decline. Behavioural and biochemical clinical trial results revealed statistical differences (p < 0.05) between result comparison between HE and control groups and various week intervals. Animal model behavioural and biochemical assessments demonstrated positive findings. Histological assessments of AD-induced rodents following HE administration revealed statistically significant results (p < 0.05) in cholinergic transmitter and NGF concentrations, β-amyloid peptide plaque accumulation, and microglia and astrocyte activation compared to control groups.

Evidence suggests that an intake of HE, specifically the compound erinacine-A may be an appropriate and relevant candidate for the future therapeutic treatment for the prevention and delayed progression of AD. Application of HE demonstrated numerous improvements in AD-related behaviour, biomarker parameters, histological features, and physiological mechanisms while neuroprotective and neurotrophic properties were also clearly established. Nevertheless, the review highlights the necessity for continued research specifically human clinical trials to contribute continued evidence surrounding the use of HE for AD, to provide direction for future research and provide constructive methods for the possible future targeting of AD populations.

This study conducts experimental investigations into wake-induced vibration (WIV) of a circular cylinder placed downstream of an oscillating cylinder. Surprisingly, it is observed that the previously identified WIV phenomenon, characterized by a sustained increase in amplitude at higher reduced velocities, does not occur when the upstream cylinder oscillates at large amplitudes. Instead, a different phenomenon, which we refer to as the ‘wake-captured vibration’, becomes dominant. The experiments reveal a negative correlation between the vortex-induced vibration amplitude response of the upstream cylinder and the WIV amplitude response of the downstream cylinder. Through a quasi-steady and linear instability analysis, the study demonstrates that the previously proposed wake-displacement mechanism may not be applicable for predicting the cylinder WIV response in the wake of an oscillating body. This is because the lift force gradients across the wake, measured through stationary cylinder experiments, decrease significantly when the upstream cylinder vibrates at higher amplitudes. Consequently, actively controlled vibration experiments are conducted to systematically map the hydrodynamic properties of the downstream cylinder vibrating in the wake of an oscillating cylinder. The findings align with observations from free-vibration experiments, and help to explain the amplitude and frequency response of WIV. Additionally, wake visualization through particle image velocimetry is conducted to provide further insights into the complex wake and vortex–body interactions.

A distributed cooperative guidance law without numerical singularities is proposed for the simultaneous attack a stationary target by multiple vehicles with field-of-view constraints. Firstly, the vehicle engagement motion model is transformed into a multi-agent model. Then, based on the state-constrained consensus protocol, a coordination control law with field-of-view (FOV) constraints is proposed. Finally, the cooperative guidance law has been improved to make it more suitable for practical application. Numerical simulations verified the effectiveness and robustness of the proposed guidance law in the presence of acceleration saturation, communication delays and measurement noise.

Background: Hyperacute stroke care demands rapid, coordinated care. Traditional metrics like Door-to-Needle time are pivotal but insufficient for capturing the complexity of endovascular stroke interventions. The SMILES collaboration aims to standardize and optimize protocols for door-to-intervention times, incorporating Crew Resource Management (CRM). Methods: The multidisciplinary initiative integrates both hospitals, ED, neurology, and QI teams. We employed a comprehensive approach: stakeholder engagement, simulation-based learning, process mapping, and literature review. Emphasis was placed on enhancing situational awareness, triage and prioritization, cognitive load management, role clarity, effective communication, and debriefing. Results: The collaboration led to PDSA cycles and development of refined stroke protocols. Interventions included: 1) A ’zero point survey’ for team pre-arrival briefings, enhancing situational awareness and role clarity; 2) Streamlined patient registration to reduce cognitive load and improve triage efficiency; 3) Direct transfer of patients to imaging. Additionally, digital tools were implemented to facilitate communication. Simulation sessions reinforced CRM principles, leading to improved team cohesion and operational performance. Conclusions: The SMILES initiative is grounded in CRM principles by standardizing protocols and emphasizing non-technical skills crucial for high-stakes environments. This improves outcomes but also fosters a culture of safety and efficiency. Future directions include an evaluation of these protocols’ impact on patient factors.

Background: Meningiomas are the most common intracranial tumor with surgery, dural margin treatment, and radiotherapy as cornerstones of therapy. Response to treatment continues to be highly heterogeneous even across tumors of the same grade. Methods: Using a cohort of 2490 meningiomas in addition to 100 cases from the prospective RTOG-0539 phase II clinical trial, we define molecular biomarkers of response across multiple different, recently defined molecular classifications and use propensity score matching to mimic a randomized controlled trial to evaluate the role of extent of resection, dural marginal resection, and adjuvant radiotherapy on clinical outcome. Results: Gross tumor resection led to improved progression-free-survival (PFS) across all molecular groups (MG) and improved overall survival in proliferative meningiomas (HR 0.52, 95%CI 0.30-0.93). Dural margin treatment (Simpson grade 1/2) improved PFS versus complete tumor removal alone (Simpson 3). MG reliably predicted response to radiotherapy, including in the RTOG-0539 cohort. A molecular model developed using clinical trial cases discriminated response to radiotherapy better than standard of care grading in multiple cohorts (ΔAUC 0.12, 95%CI 0.10-0.14). Conclusions: We elucidate biological and molecular classifications of meningioma that influence response to surgery and radiotherapy in addition to introducing a novel molecular-based prediction model of response to radiation to guide treatment decisions.

Background: Cerebrospinal fluid (CSF) leak is a common complication of minimally invasive tubular microdiscectomy (MIM). However, it is not known whether patients with CSF leak can be safely discharged home the same day. Methods: This is a retrospective cohort study of patients with incidental durotomy after MIM from January, 2009 to August, 2023. Patient demographic information, surgery information, CSF leak management, and postoperative outcomes were recorded. Results: There were 16 patients (53%) who were admitted to hospital and 14 (47%) patients discharged home the same day post CSF leak. There were no differences in patient demographics between the two groups at baseline. Twenty-nine out of 30 (97%) of the patients had onlay duraplasty, and one (3%) patient was repaired using sutures. The hospitalized group was kept on bed rest overnight or 24 hours. The discharge group was kept on best rest for 2 hours or mobilized immediately after surgery. The average length of admission for the hospitalized group was 2.4 ± 4.0 days. No patients in either group required readmission or revision surgery for CSF leak. Conclusions: Patients with CSF leak post minimally invasive tubular microdiscectomy can be safely discharged home the same day provided that duraplasty or primary repair was performed intraoperatively.