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 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.

Background: We’ve adopted a novel approach that combines cellular barcoding with CRISPR/Cas-9 technology and single-cell RNA sequencing known as continuous lineage tracing to track the development, treatment and inevitable recurrence of glioblastoma. Methods: Patient derived glioma initiating cell lines were engineered with expressed DNA barcodes with CRISPR/Cas-9 targets and engrafted into NOD scid-mice. Clonal and relationships are surmised through identification of expressed barcodes, and cells were characterized by their transcriptional profiles. Phylogenetic lineage trees are created using lineage reconstructive algorithms to define cell fitness and expansion. Results: Our work has revealed a significant amount of intra-clonal cell state heterogeneity, suggesting that tumour cells engage in phenotype switching prior to therapeutic intervention. Phylogenetic lineage trees allowed us to define a gene signature of cell fitness. GBMs exist along a transcriptional gradient between undifferentiated but “high-fit” cells and terminally differentiated, “low-fit” cells, lending further evidence that these tumours consist of pools of cells that are capable of recapitulating the tumour microenvironment after treatment. Conclusions: We have successfully engineered a set of glioma initiating tumours with a novel lineage tracing technique, creating a powerful tool for real-time tracing of tumour growth through the analysis of highly detailed singe-cell RNA sequencing data with associated clonal and phylogenetic relationships.

The rupture of a liquid film, where a thin liquid layer between two other fluids breaks and forms holes, commonly occurs in both natural phenomena and industrial applications. The post-rupture dynamics, from initial hole formation to the complete collapse of the film, are crucial because they govern droplet formation, which plays a significant role in many applications such as disease transmission, aerosol formation, spray drying nanodrugs, oil spill remediation, inkjet printing and spray coating. While single-hole rupture has been extensively studied, the dynamics of multiple-hole ruptures, especially the interactions between neighbouring holes, are less well understood. Here, this study reveals that when two holes ‘meet’ on a curved film, the film evolves into a spinning twisted ribbon before breaking into droplets, distinctly different from what occurs on flat films. We explain the formation and evolution of the spinning twisted ribbon, including its geometry, orbits, corrugations and ligaments, and compare the experimental observations with models. We compare and contrast this phenomena with its counterpart on planar films. While our experiments are based on the multiple-hole ruptures in corona splash, the underlying principles are likely applicable to other systems. This study sheds light on understanding and controlling droplet formation in multiple-hole rupture, improving public health, climate science and various industrial applications.

Improving neonatal piglet survival is a key driver for improving pig production and enhancing animal welfare. Gestational diabetes is a risk factor for neonatal morbidities in humans, such as hypoglycaemia and respiratory distress(1). There is limited knowledge on the association of gestational diabetes with neonatal survival in commercial pigs. An early study suggested that the diabetic condition of late-gestating sows was positively correlated with the first-week newborn piglet mortality(2). Genetic selection in recent decades for heavier birth weight may have increased the prevalence or severity of gestational diabetes in pigs, considering the positive correlation between gestational diabetes and birth weight. We hypothesised that the diabetic condition of late gestating sows positively correlates with the neonatal piglet mortality rate in sows with modern genetics. Mixed-parity sows (1.5 ± 1.6 parity for mean ± standard deviation (SD); Large White × Landrace) from a commercial piggery in Australia were randomly selected and participated in an oral glucose tolerance test (OGTT) during two seasons (118 sows in winter and 118 sows in summer). On the d109 day of gestation, sows were fed 3.0 g dextrose per kg of metabolic body weight after fasting overnight. Tail blood glucose concentrations were measured using a glucometer (Accu-Chek ®, Roche Diabetes Care Australia Pty) at −10, 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120 minutes relative to dextrose feeding. The glucose increment (2.5 ± 1.29 mM for mean ± SD) during OGTT was calculated using the maximum concentration substrating the fasting concentration of blood glucose. The 24-hour piglet mortality rate (5% ± 8.8% for mean ± SD) was calculated as the ratio between piglets that died during the first 24 hours and the total number of born alive on a litter basis. The effect of sow glucose increment, season (winter vs summer), glucose increment × season, number of piglets born alive, and sows parity on the 24-h piglet mortality rate as analysed using a Generalised Linear Model (SPSS 27th Version, IBM SPSS Statistics, Armonk). Results showed that the 24-hour piglet mortality rate was numerically higher in winter than in summer although insignificant (5.7% vs 4.2%, p = 0.41). The glucose increment of gestating sows was positively correlated with the 24-hour piglet mortality rate during winter but not summer, as evidenced by an interaction trend between glucose increment and season (p = 0.059). The regression coefficient suggested that every extra unit (mM) of glucose increment during OGTT corresponded to a 1.4% increase in the 24-hour piglet mortality rate in winter. In conclusion, the diabetic condition of late-gestating sows is a risk factor for neonatal piglet mortality in winter. Developing nutritional strategies to mitigate the diabetic condition of late-gestating sows may benefit neonatal piglet survival.

Oral supplementation with probiotics, prebiotics, and synbiotics is a novel potential complementary therapy for addressing overweight and obesity through gut microbiota modulation. This systematic review provides a comprehensive summary of the existing evidence to guide future research. Literature searches were conducted in four databases to identify human trials published until May 2024 that examined the impact of probiotic, prebiotic, or synbiotic interventions on faecal microbiota composition changes in overweight and obese participants from Latin American and Caribbean populations (LACPs). Of the 13,090 identified records, five randomised controlled trials (RCTs) from Brazil, Mexico, and Chile met the inclusion criteria for this review. The included RCTs evaluated different forms of therapies over short-term interventions (6 or 8 weeks), with sample sizes ranging from 21 to 39 participants across the studies. Variations in the reported outcomes were observed due to differences in supplement formulation, dosage, population characteristics, and methodological heterogeneity. The findings indicate that the available data are inadequate to establish definitive conclusions regarding the impact of biotic treatments on gut microbiota profiles in LACP. Further research with larger sample sizes and precise microbiota analysis is required to elucidate the implications of dietary interventions on gut microbiota in obesity and related disorders.

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.

The depth-integrated horizontal momentum equations and continuity equation are employed to develop a new model. The vertical velocity and pressure can be expressed exactly in terms of horizontal velocities and free-surface elevation, which are the only unknowns in the model. Dividing the water column into elements and approximating horizontal velocities using linear shape function in each element, a set of model equations for horizontal velocities at element nodes is derived by adopting the weighted residual method. These model equations can be applied for transient or steady free-surface flows by prescribing appropriate lateral boundary conditions and initial conditions. Here, only the wave–current–bathymetry interaction problems are investigated. Theoretical analyses are conducted to examine various linear wave properties of the new models, which outperform the Green–Naghdi-type models for the range of water depth to wavelength ratios and the Boussinesq-type models as they are capable of simulating vertically sheared currents. One-dimensional horizontal numerical models, using a finite-difference method, are applied to a wide range of wave–current–bathymetry problems. Numerical validations are performed for nonlinear Stokes wave and bichromatic wave group propagation in deep water, sideband instability, regular wave transformation over a submerged shoal and focusing wave group interacting with linearly sheared currents in deep water. Very good agreements are observed between numerical results and laboratory data. Lastly, numerical experiments of wave shoaling from deep to shallow water are conducted to further demonstrate the capability of the new model.

With the over-use of tetracycline (TC) and its ultimate accumulation in aquatic systems, the demand for TC removal from contaminated water is increasing due to its severe threat to public health. Clay minerals have attracted great attention as low-cost adsorbents for controlling water pollution. The objective of the present study was to measure the adsorption behavior and mechanisms of TC on allophane, a nanosized clay mineral with a hollow spherical structure; to highlight the advantage of the allophane nanostructure, a further objective was to compare allophane with halloysite and montmorillonite, which have nanostructures that differ from allophane. Structural features and surface physicochemical properties were characterized by transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), zeta potential, N2-physisorption, and acid–base titration. The adsorption data showed that TC adsorption followed the pseudo-second order and Langmuir models. The adsorption was pH dependent, as all three clay minerals performed better under neutral to weakly alkaline conditions and maintained high adsorption performance in the presence of co-existing Na+/K+/Ca2+/Mg2+ cations. Regeneration of the adsorbent was excellent, with efficiencies exceeding 75% after five recycles. By comparison, allophane always exhibited the greatest adsorption capacity, up to 796 mg g–1 at ~pH 9. The TC adsorption on allophane and halloysite was dominated by inner-sphere complexation, together with a small amount of electrostatic adsorption, while that on montmorillonite involved mainly interlayer cation exchange. The findings provide insights into the effects of nanostructures of clay minerals on their TC adsorption performance and highlight the huge potential of allophane as an efficient and inexpensive adsorbent for TC removal.

In this paper, a brand-new adaptive fault-tolerant non-affine integrated guidance and control method based on reinforcement learning is proposed for a class of skid-to-turn (STT) missile. Firstly, considering the non-affine characteristics of the missile, a new non-affine integrated guidance and control (NAIGC) design model is constructed. For the NAIGC system, an adaptive expansion integral system is introduced to address the issue of challenging control brought on by the non-affine form of the control signal. Subsequently, the hyperbolic tangent function and adaptive boundary estimation are utilised to lessen the jitter due to disturbances in the control system and the deviation caused by actuator failures while taking into account the uncertainty in the NAIGC system. Importantly, actor-critic is introduced into the control framework, where the actor network aims to deal with the multiple uncertainties of the subsystem and generate the control input based on the critic results. Eventually, not only is the stability of the NAIGC closed-loop system demonstrated using Lyapunov theory, but also the validity and superiority of the method are verified by numerical simulations.