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: 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.

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.

Ultrafast optical probing is a widely used method of underdense plasma diagnostic. In relativistic plasma, the motion blur limits spatial resolution in the direction of motion. For many high-power lasers the initial pulse duration of 30–50 fs results in a 10–15 μm motion blur, which can be reduced by probe pulse post-compression. Here we used the compression after compressor approach [Phys.-Usp. 62, 1096 (2019); JINST 17 P07035 (2022)], where spectral broadening is performed in thin optical plates and is followed by reflections from negative-dispersion mirrors. Our initially low-intensity probe beam was down-collimated for a more efficient spectral broadening and higher probe-to-self-emission intensity ratio. The setup is compact, fits in a vacuum chamber and can be implemented within a short experimental time slot. We proved that the compressed pulse retained the high quality necessary for plasma probing.

While there is a recognised role of optimising lifestyle behaviours such as diet and physical activity in the management of infertility, the best practice for lifestyle management of infertility remains unknown, and factors influencing the lifestyle behaviours of people with infertility are not well understood. The aim of this systematic review is to evaluate the barriers and enablers to a healthy lifestyle in people with infertility, from the perspectives of people with infertility and health professionals, in order to inform optimal behavioural change strategies for lifestyle management of infertility. Ovid MEDLINE(R), PsycINFO, EMBASE, EBM Reviews, and CINAHL Plus were searched from inception to 12th September 2022. Eligible studies were qualitative, quantitative or mixed-methods primary studies which explored barriers and/or enablers to lifestyle for infertility management, from the perspectives of people with infertility and/or health professionals. Two independent reviewers performed quality assessment, using the Centre for Evidence-Based Management Critical Appraisal of a Survey Tool (quantitative and mixed-methods studies) and the Critical Appraisal Skills Programme Qualitative Checklist (qualitative and mixed-methods studies). Data were analysed by inductive thematic analysis with themes mapped to the Capability, Opportunity, Motivation and Behaviour (COM-B) model(1) and Theoretical Domains Framework (TDF)(2). Relevant behaviour change techniques (BCTs)(3) to target the identified enablers and barriers were suggested. After screening 10703 citations and 82 full-texts, 22 studies were included (12 quantitative, 7 mixed-methods and 3 qualitative) with 18 studies including women with infertility (n = 2442), 10 including men with infertility (n = 1372) and 6 including health professionals (n = 261). From the perspectives of people with infertility, themes related to capability (e.g. strategies for behaviour change), opportunity (e.g. limited time, resources and money) and motivation (e.g. interplay between lifestyle and emotional state); themes mapped to 8 TDF domains. From the perspectives of health professionals, themes related to capability (e.g. identification of patients appropriate for lifestyle intervention), opportunity (e.g. mode of delivery) and motivation (e.g. professional responsibility); themes mapped to 6 TDF domains. 34 BCTs were identified across the suggested interventions. This systematic review found that several interacting factors influence lifestyle in people with infertility as well as health professional behaviour with regards to provision of lifestyle interventions for infertility. These factors can be targeted for optimisation of interventions. In light of the limited number of qualitative studies, there is a need for more qualitative research to gain deeper insights into the perspectives of people with infertility and health professionals for further exploration of the complex and interacting factors which shape lifestyle during the fertility journey.

OBJECTIVES/GOALS: The 'field effect' is a concept in pathology that pre-malignant tissue changes forecast health. Spatial transcriptomics could detect these changes earlier than histopathology, suggesting new early cancer screening methods. Knowing how normal tissue damage relates to cancer’s origin and progression may improve long-term outcomes. METHODS/STUDY POPULATION: We trained DEGAS, our machine learning framework, with prostate cancer data, combining both general cancer patterns and in-depth genetic information from individual tumors. The Tumor Cancer Genome Atlas (TCGA) shows how gene patterns in tumors relate to patient outcomes, emphasizing the differences between tumors from different patients (intertumor). On the other hand, spatial transcriptomics (ST) shows the genetic variety within a single tumor (intratumor) but has limited samples, making it hard to know which genetic differences are important for treatment. DEGAS bridges these areas by finding tissue sections that resemble those in TCGA profiles and are key indicators of patient survival. DEGAS serves as a valuable tool for generating clinically-important hypotheses. RESULTS/ANTICIPATED RESULTS: DEGAS identified benign-appearing glands in a normal prostate as being highly associated with poor progression-free survival. These glands have transcriptional signatures similar to high-grade prostate cancer. We confirmed this finding in a separate prostate cancer ST dataset. By integrating single cell (SC) data we demonstrated that cells annotated as cancerous in the SC data map to regions of benign glands in the ST dataset. We pinpoint several genes, chiefly Microseminoprotein-β (MSMB, PSP94), where reduced expression is highly correlated with poor progression-free survival. Cell type specific differential expression analysis further revealed that loss of MSMB expression associated with poor outcomes occurs specifically in luminal epithelia, the putative progenitor of prostate cancer. DISCUSSION/SIGNIFICANCE: DEGAS reveals that normal-appearing tissue can be highly-associated with tumor progression and underscores the importance of the 'field effect' in cancer research. Traditional analysis may miss such nuance, hiding key transitional cell states. Validating gene markers could boost early cancer detection and understanding of metastasis.

Background: Neurosurgery is a high-risk specialty with a low margin of error. We aim to assess the risk of neurosurgeons being involved in medicolegal cases in Canada. Methods: This retrospective descriptive study evaluated ten years (2012-2021) of closed legal cases, college cases, and hospital complaints against neurosurgeons with data from the CMPA. Included cases were cranial cases, VP shunts, or cases where a catheter or wire was inserted into the brain. Cases excluded angiography, radiation, ultrasound, or percutaneous procedures. Results: We identified 77 cases (66 urgent or emergent). Neurosurgeons had a significantly higher medicolegal risk than the CMPA surgeon membership, however lower risk compared to all physician specialties. Legal cases accounted for 69% with favourable outcomes in 52%. Forty-one cases involved post-operative complications and 16 cases involved VP shunts. Multiple surgeons or residents could be involved spanning age groups and years in practice. Thirty-four cases had a harmful incident, 41% of these severe. The majority of cases occurred at urban centers. The average case duration was 41 months. Conclusions: This study provides a recent medicolegal analysis of cranial neurosurgery in Canada. We identified areas of common complaints and hope the data can be used to mitigate risk surgical risk in the future.

Background: In meningiomas, CDKN2A/B deletions are associated with poor outcomes but are rare in most cohorts (1-5%). Large molecular datasets are therefore required to explore these deletions and their relationship to other prognostic CDKN2A alterations. Methods: We utilized multidimensional molecular data of 560 meningiomas from 5 independent cohorts to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Results: Meningiomas with either CDKN2A/B deletions (partial or homozygous loss) or an intact CDKN2A gene locus but elevated mRNA expression (CDKN2Ahigh) both had poor clinical outcomes. Increased CDKN2A mRNA expression was a poor prognostic factor independent of CDKN2A deletion. CDKN2A expression and p16 protein increased with tumor grade and more aggressive molecular and methylation groups. CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycling pathways dysregulated at different checkpoints. p16 immunohistochemistry was unreliable in differentiating between meningiomas with and without CDKN2A deletions, but increased positivity was associated with increased mRNA expression. CDKN2Ahigh meningiomas were associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. Conclusions: These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications.

This study assesses governments' long-term non-pharmaceutical interventions upon the coronavirus disease 2019 (COVID-19) pandemic in East Asia. It advances the literature towards a better understanding of when and which control measures are effective. We (1) provide time-varying case fatality ratios and focus on the elderly's mortality and case fatality ratios, (2) measure the correlations between daily new cases (daily new deaths) and each index based on multiple domestic pandemic waves and (3) examine the lead–lag relationship between daily new cases (daily new deaths) and each index via the cross-correlation functions on the pre-whitened series. Our results show that the interventions reduce COVID-19 infections for some periods before the period of the Omicron variant. Moreover, there is no COVID-19 policy lag in Taiwan between daily new confirmed cases and each index. As of March 2022, the case fatality ratios of the elderly group in Japan, Hong Kong and South Korea are 4.69%, 4.72% and 1.48%, respectively, while the case fatality ratio of the elderly group in Taiwan is 25.01%. A government's COVID-19 vaccination distribution and prioritisation policies are pivotal for the elderly group to reduce the number of deaths. Immunising this specific group as best as possible should undoubtedly be a top priority.

Background: Despite a higher prevalence of traumatic spinal cord injury (TSCI) amongst Canadian Indigenous peoples, there is a paucity of studies focused on Indigenous TSCI. We present the first Canada-wide study comparing TSCI amongst Canadian Indigenous and non-Indigenous peoples. Methods: This study is a retrospective analysis of prospectively-collected TSCI data from the Rick Hansen Spinal Cord Injury Registry (RHSCIR) from 2004-2019. We divided participants into Indigenous and non-Indigenous cohorts and compared them with respect to demographics, injury mechanism, level, severity, and outcomes. Results: Compared with non-Indigenous patients, Indigenous patients were younger, more female, less likely to have higher education, and less likely to be employed. The mechanism of injury was more likely due to assault or transportation-related trauma in the Indigenous group. The length of stay for Indigenous patients was longer. Indigenous patients were more likely to be discharged to a rural setting, less likely to be discharged home, and more likely to be unemployed following injury. Conclusions: Our results suggest that more resources need to be dedicated for transitioning Indigenous patients sustaining a TSCI to community living and for supporting these patients in their home communities. A focus on resources and infrastructure for Indigenous patients by engagement with Indigenous communities is needed.

The spatio-temporal variation of leaf chlorophyll content is an important crop phenotypic trait that is of great significance for evaluating crop productivity. This study used a soil-plant analysis development (SPAD) chlorophyll meter for non-destructive monitoring of leaf chlorophyll dynamics to characterize the patterns of spatio-temporal variation in the nutritional status of maize (Zea mays L.) leaves under three nitrogen treatments in two cultivars. The results showed that nitrogen levels could affect the maximum leaf SPAD reading (SPADmax) and the duration of high SPAD reading. A rational model was used to measure the changes in SPAD readings over time in single leaves. This model was suitable for predicting the dynamics of the nutrient status for each leaf position under different nitrogen treatments, and model parameter values were position dependent. SPADmax at each leaf decreased with the reduction of nitrogen supply. Leaves at different positions in both cultivars responded differently to higher nitrogen rates. Lower leaves (8th–10th positions) were more sensitive than the other leaves in response to nitrogen. Monitoring the SPAD reading dynamic of lower leaves could accurately characterize and assess the nitrogen supply in plants. The lower leaves in nitrogen-deficient plants had a shorter duration of high SPAD readings compared to nitrogen-sufficient plants; this physiological mechanism should be studied further. In summary, the spatio-temporal variation of plant nitrogen status in maize was analysed to determine critical leaf positions for potentially assisting in the identification of appropriate agronomic management practices, such as the adjustment of nitrogen rates in late fertilization.