Background: The complement C5 inhibitor (C5IT), ravulizumab, is approved in Canada for the treatment of anti-acetylcholine receptor antibody-positive (AChR-Ab+) generalized myasthenia gravis (gMG). Updated effectiveness and safety results from the ongoing MG SPOTLIGHT Registry (NCT04202341) are reported. Methods: MGFA classification and MG-ADL total scores were assessed in patients who received ravulizumab only (ravu-only) or transitioned from eculizumab to ravulizumab (ecu-to-ravu), with data available prior to C5IT initiation (“pre-C5IT”) and ≥1 assessment post-initiation (“post-ravu”). Results: Of 52 patients with 2 post-ravu assessments, average treatment duration was 10.4 months at last assessment (LA). Mean±SD MG-ADL scores improved (pre-C5IT: 7.6±3.6; LA: 3.4±3.3), as did the proportions of patients with minimal symptom expression (MSE, MG-ADL≤1) (pre-C5IT: 1/52 [2%]; LA: 17/52 [33%]) and MGFA classification 0-II (pre-C5IT: 18/45 [40%]; LA: 40/45 [89%]). In the ravu-only subgroup, outcomes improved (pre-C5IT vs LA): MG-ADL, 6.3±3.0 vs 4.0±3.4; MGFA 0-II, 9/14 [64%] vs 12/14 [86%]. The ecu-to-ravu subgroup sustained continued gradual improvement from last eculizumab assessment to LA: MG-ADL, 4.4±4.2 vs 3.0±2.8; MGFA 0-II, 19/21 [90%] vs 20/21 [95%]. Ravulizumab was well tolerated; no meningococcal infections were reported. Conclusions: These results demonstrate the long-term effectiveness and safety of ravulizumab in routine clinical practice in patients with gMG.

Background: Meningiomas are the most common intracranial tumors. Radiotherapy (RT) serves as an adjunct following surgical resection; however, response varies. RTOG-0539 is a prospective, phase 2, trial that stratified patients risk groups based on clinical and pathological criteria, providing key benchmarks for RT outcomes. This is the first study that aims to characterize the molecular landscape of an RT clinical trial in meningiomas. Methods: Tissue from 100 patients was analyzed using DNA methylation, RNA sequencing, and whole-exome sequencing. Copy number variations and mutational profiles were assessed to determine associations with meningioma aggressiveness. Tumors were molecularly classified and pathway analyses were conducted to identify biological processes associated with RT response. Results: High-risk meningiomas exhibited cell cycle dysregulation and hypermetabolic pathway upregulation. 1p loss and 1q gain were more frequent in aggressive meningiomas, and NF2 and non-NF2 mutations co-occurred in some high-risk tumors. Molecular findings led to the reclassification of several cases, highlighting the limitations of histopathologic grading alone. Conclusions: This is the first study to comprehensively characterize the molecular landscape of any RT trial in meningioma, integrating multi-omic data to refine treatment stratification. Findings align with ongoing genomically driven meningioma clinical trials and underscore the need for prospective tissue banking to enhance biomarker-driven treatment strategies.

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: The combination of PARP inhibitor and immune checkpoint inhibitors have been proposed as a potentially synergistic combinatorial treatment in IDH mutant glioma, targeting dysregulated homologous recombination repair pathways. This study analyzed the cell-free DNA methylome of patients in a phase 2 trial using the PARP inhibitor Olaparib and the PD-1 inhibitor Durvalumab. Methods: Patients with recurrent high-grade IDH-mutant gliomas were enrolled in a phase II open-label study (NCT03991832). Serum was collected at baseline and monthly and cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed. Binomial GLMnet models were developed and model performance was assessed using validation set data. Results: 29 patients were enrolled between 2020–2023. Patients received olaparib 300mg twice daily and durvalumab 1500mg IV every 4 weeks. The overall response rate was 10% via RANO criteria. 144 plasma samples were profiled with cfMeDIP-seq along with 30 healthy controls. The enriched circulating tumour DNA methylome during response periods exhibited a highly specific signature, accurately discriminating response versus failure (AUC 0.98 ± 0.03). Additionally, samples that were taken while on treatment were able to be discriminated from samples off therapy (AUC 0.74 ± 0.11). Conclusions: The cell-free plasma DNA methylome exhibits highly specific signatures that enable accurate prediction of response to therapy.

Objectives: Activities that require active thinking, like occupations, may influence cognitive function and its change over time. Associations between retirement and dementia risk have been reported, however the role of retirement age in these associations is unclear. We assessed associations of occupation and retirement age with cognitive decline in the US community-based Atherosclerosis Risk in Communities (ARIC)cohort.

Methods: We included 14,090 ARIC participants, followed for changes in cognition during up to 21 years. Information on current or most recent occupation was collected at ARIC baseline (1987–1989; participants aged 45–64 years) and categorized according to the 1980 US Census protocols and the Nam-Powers-Boyd occupational status score. Follow-up data on retirement was collected during 1999–2007 and classified as retired versus not retired at age 70. Trajectories of global cognitive factor scores from ARIC visit 2 (1990–1992) to visit 5 (2011–2013) were presented, and associations with occupation and age at retirement were studied using generalized estimating equation models, stratified by race and sex, and adjusted for demographics andcomorbidities.

Results: Mean age (SD) at first cognitive assessment was 57.0 (5.72) years. Higher occupational status and white- collar occupations were significantly associated with higher cognitive function at baseline. Occupation was associated with cognitive decline over 21 years only in women, and the direction of the effect on cognitive function differed between black and white women: in white women, the decline in cognitive function was greater in homemakers and low status occupations, whereas in black women, less decline was found in homemakers and low (compared to high) occupational status. Interestingly, retirement on or before age 70 was associated with less 21-year cognitive decline in all race-sex strata, except for blackwomen.

Conclusions: Associations between occupation, retirement age and cognitive function substantially differed by race and sex. Further research should explore reasons for the observed associations and race-sex differences.

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.

To accelerate high-intensity heavy-ion beams to high energy in the booster ring (BRing) at the High-Intensity Heavy-Ion Accelerator Facility (HIAF) project, we take the typical reference particle 238U35+, which can be accelerated from an injection energy of 17 MeV/u to the maximal extraction energy of 830 MeV/u, as an example to study the basic processes of longitudinal beam dynamics, including beam capture, acceleration, and bunch merging. The voltage amplitude, the synchronous phase, and the frequency program of the RF system during the operational cycle were given, and the beam properties such as bunch length, momentum spread, longitudinal beam emittance, and beam loss were derived, firstly. Then, the beam properties under different voltage amplitude and synchronous phase errors were also studied, and the results were compared with the cases without any errors. Next, the beam properties with the injection energy fluctuation were also studied. The tolerances of the RF errors and injection energy fluctuation were dictated based on the CISP simulations. Finally, the effect of space charge at the low injection energy with different beam intensities on longitudinal emittance and beam loss was evaluated.

The effects of surfactants on a mechanically generated plunging breaker are studied experimentally in a laboratory wave tank. Waves are generated using a dispersively focused wave packet with a characteristic wavelength of $\lambda _0 = 1.18$ m. Experiments are performed with two sets of surfactant solutions. In the first set, increasing amounts of the soluble surfactant Triton X-100 are mixed into the tank water, while in the second set filtered tap water is left undisturbed in the tank for wait times ranging from 15 min to 21 h. Increasing Triton X-100 concentrations and longer wait times lead to surfactant-induced changes in the dynamic properties of the free surface in the tank. It is found that low surface concentrations of surfactants can dramatically change the wave breaking process by changing the shape of the jet and breaking up the entrained air cavity at the time of jet impact. Direct numerical simulations (DNS) of plunging breakers with constant surface tension are used to show that there is significant compression of the free surface near the plunging jet tip and dilatation elsewhere. To explore the effect of this compression/dilatation, the surface tension isotherm is measured in all experimental cases. The effects of surfactants on the plunging jet are shown to be primarily controlled by the surface tension gradient ($\Delta \mathcal {E}$) while the ambient surface tension of the undisturbed wave tank ($\sigma _0$) plays a secondary role.

The target backsheath field acceleration mechanism is one of the main mechanisms of laser-driven proton acceleration (LDPA) and strongly depends on the comprehensive performance of the ultrashort ultra-intense lasers used as the driving sources. The successful use of the SG-II Peta-watt (SG-II PW) laser facility for LDPA and its applications in radiographic diagnoses have been manifested by the good performance of the SG-II PW facility. Recently, the SG-II PW laser facility has undergone extensive maintenance and a comprehensive technical upgrade in terms of the seed source, laser contrast and terminal focus. LDPA experiments were performed using the maintained SG-II PW laser beam, and the highest cutoff energy of the proton beam was obviously increased. Accordingly, a double-film target structure was used, and the maximum cutoff energy of the proton beam was up to 70 MeV. These results demonstrate that the comprehensive performance of the SG-II PW laser facility was improved significantly.

Background: Toxoplasma gondii is a protozoan parasite with the ability to infect any nucleated cell in humans. Most immunocompetent infected individuals are asymptomatic. Latent toxoplasma can become reactivated in immunocompromised individuals though this is exceptionally rare in HIV-negative individuals. Methods: We present the case of a 47-year-old male with chronic immunosuppression secondary to marginal zone lymphoma and steroid therapy. Results: The patient presented to hospital with a 1-week history of word-finding difficulties, intermittent right facial numbness and leg weakness, and tonic-clonic seizures. CT head showed a left temporal heterogenous mass measuring 2.8 × 2.8 × 3.5 cm. Biopsy of the lesion showed Multiple tachyzoites and rare bradyzoites with strong positivity for the toxoplasma specific immunostain. The patient was treated with trimethoprim/sulfamethoxazole which resulted in complete neurologic recovery. Conclusions: Our literature review included 32 cases of cerebral toxoplasmosis in HIV-negative patients with an overall mortality rate of 48%. Cerebral toxoplasmosis has a predilection for immunosuppressed patients with an underlying hematologic malignancy (74%, n= 23). Successful treatment requires early recognition of the disease and prompt treatment with sulfamethoxazole and trimethoprim, pyrimethamine, or sulfadiazine. Patients who recover from acute toxoplasmosis should remain on lifelong suppressive antibiotic therapy to prevent relapse.

Meat quality is not only influenced by breed but also rearing environment. The aim of this study was to evaluate the influence of different housing environments on growth performance, carcase traits, meat quality, physiological response pre-slaughter and fatty acid composition in two pig breeds. A total of 120 growing pigs at 60-70 days of age were arranged in a 2 × 2 factorial design with the breeds (Duroc × Landrace × Large White [D × L × LW] and Duroc × Landrace × Min pig [D × L × M]) and environmental enrichment (barren concrete floor or enriched with straw bedding) as factors. Each treatment was performed in triplicate with ten pigs per replicate. The pigs housed in the enriched environment exhibited a higher average daily gain, average daily feed intake, saturated fatty acid percentage and backfat depth than the pigs reared in the barren environment. Plasma cortisol levels were lower and growth hormone higher in enriched compared to barren pens. The D × L × M pigs showed lower cooking loss compared with the D × L × LW pigs. Moreover, the D × L × M pigs exhibited poor growth performance but had a better water-holding capacity. Only carcase traits and meat quality interaction effects were observed. We concluded that an enriched environment can reduce preslaughter stress and improve the growth performance of pigs and modulate the fatty acid composition of pork products.