The interaction of helminth infections with type 2 diabetes (T2D) has been a major area of research in the past few years. This paper, therefore, focuses on the systematic review of the effects of helminthic infections on metabolism and immune regulation related to T2D, with mechanisms through which both direct and indirect effects are mediated. Specifically, the possible therapeutic role of helminths in T2D management, probably mediated through the modulation of host metabolic pathways and immune responses, is of special interest. This paper discusses the current possibilities for translating helminth therapy from basic laboratory research to clinical application, as well as existing and future challenges. Although preliminary studies suggest the potential for helminth therapy for T2D patients, their safety and efficacy still need to be confirmed by larger-scale clinical studies.

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: 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: We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation model compatible with newer methylation arrays. Methods: The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. A nomogram was generated by incorporating our methylation predictor with WHO grade and extent of resection. Results: A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and a retrospective cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperformed 2021 WHO grade in predicting postoperative recurrence. Dichotomizing into grade-specific risk subgroups was predictive of outcome within both WHO grades 1 and 2 tumours (log-rank p<0.05). Multivariable Cox regression demonstrated benefit of adjuvant radiotherapy in high-risk cases specifically, reinforcing its informative role in clinical decision making. Conclusions: This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms 2021 WHO grading in predicting time to recurrence. This will help improve prognostication and inform patient selection for RT.

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.

This study explored mental workload recognition methods for carrier-based aircraft pilots utilising multiple sensor physiological signal fusion and portable devices. A simulation carrier-based aircraft flight experiment was designed, and subjective mental workload scores and electroencephalogram (EEG) and photoplethysmogram (PPG) signals from six pilot cadets were collected using NASA Task Load Index (NASA-TLX) and portable devices. The subjective scores of the pilots in three flight phases were used to label the data into three mental workload levels. Features from the physiological signals were extracted, and the interrelations between mental workload and physiological indicators were evaluated. Machine learning and deep learning algorithms were used to classify the pilots’ mental workload. The performances of the single-modal method and multimodal fusion methods were investigated. The results showed that the multimodal fusion methods outperformed the single-modal methods, achieving higher accuracy, precision, recall and F1 score. Among all the classifiers, the random forest classifier with feature-level fusion obtained the best results, with an accuracy of 97.69%, precision of 98.08%, recall of 96.98% and F1 score of 97.44%. The findings of this study demonstrate the effectiveness and feasibility of the proposed method, offering insights into mental workload management and the enhancement of flight safety for carrier-based aircraft pilots.

Manned lunar landers must ensure astronaut safety while enhancing payload capacity. Due to traditional landers being weak in high-impact energy absorb and heavy payload capacity, a Starship-type manned lunar lander is proposed in this paper. Firstly, a comprehensive analysis was conducted on the traditional cantilever beam cushioning mechanism for manned lander. Subsequently, a 26-ton manned lander and its landing mechanism were designed, and a rigid-flexible coupling dynamic analysis was performed on the compression process of the primary and auxiliary legs. Secondly, the landing performance of the proposed Starship-type manned lunar lander was compared with the traditional 14-ton manned lander in multiple landing conditions. The results indicate that under normal conditions, the largest acceleration of the proposed 26-ton Starship-type manned lander decreases more than 13.1%. It enables a significant increase in payload capacity while mitigating impact loads under various landing conditions.

Rogue waves (RWs) can form on the ocean surface due to the well-known quasi-four-wave resonant interaction or superposition principle. The first is known as the nonlinear focusing mechanism and leads to an increased probability of RWs when unidirectionality and narrowband energy of the wave field are satisfied. This work delves into the dynamics of extreme wave focusing in crossing seas, revealing a distinct type of nonlinear RWs, characterised by a decisive longevity compared with those generated by the dispersive focusing (superposition) mechanism. In fact, through fully nonlinear hydrodynamic numerical simulations, we show that the interactions between two crossing unidirectional wave beams can trigger fully localised and robust development of RWs. These coherent structures, characterised by a typical spectral broadening then spreading in the form of dual bimodality and recurrent wave group focusing, not only defy the weakening expectation of quasi-four-wave resonant interaction in directionally spreading wave fields, but also differ from classical focusing mechanisms already mentioned. This has been determined following a rigorous lifespan-based statistical analysis of extreme wave events in our fully nonlinear simulations. Utilising the coupled nonlinear Schrödinger framework, we also show that such intrinsic focusing dynamics can be captured by weakly nonlinear wave evolution equations. This opens new research avenues for further explorations of these complex and intriguing wave phenomena in hydrodynamics as well as other nonlinear and dispersive multi-wave systems.

Liouville-type theorems for the steady incompressible Navier–Stokes system are investigated for solutions in a three-dimensional (3-D) slab with either no-slip boundary conditions or periodic boundary conditions. When the no-slip boundary conditions are prescribed, we prove that any bounded solution is trivial if it is axisymmetric or $ru^r$ is bounded, and that general 3-D solutions must be Poiseuille flows when the velocity is not big in $L^\infty$ space. When the periodic boundary conditions are imposed on the slab boundaries, we prove that the bounded solutions must be constant vectors if either the swirl or radial velocity is independent of the angular variable, or $ru^r$ decays to zero as $r$ tends to infinity. The proofs are based on the fundamental structure of the equations and energy estimates. The key technique is to establish a Saint-Venant type estimate that characterizes the growth of the Dirichlet integral of non-trivial solutions.

We present the first results from a new backend on the Australian Square Kilometre Array Pathfinder, the Commensal Realtime ASKAP Fast Transient COherent (CRACO) upgrade. CRACO records millisecond time resolution visibility data, and searches for dispersed fast transient signals including fast radio bursts (FRB), pulsars, and ultra-long period objects (ULPO). With the visibility data, CRACO can localise the transient events to arcsecond-level precision after the detection. Here, we describe the CRACO system and report the result from a sky survey carried out by CRACO at 110-ms resolution during its commissioning phase. During the survey, CRACO detected two FRBs (including one discovered solely with CRACO, FRB 20231027A), reported more precise localisations for four pulsars, discovered two new RRATs, and detected one known ULPO, GPM J1839 $-$10, through its sub-pulse structure. We present a sensitivity calibration of CRACO, finding that it achieves the expected sensitivity of 11.6 Jy ms to bursts of 110 ms duration or less. CRACO is currently running at a 13.8 ms time resolution and aims at a 1.7 ms time resolution before the end of 2024. The planned CRACO has an expected sensitivity of 1.5 Jy ms to bursts of 1.7 ms duration or less and can detect $10\times$ more FRBs than the current CRAFT incoherent sum system (i.e. 0.5 $-$2 localised FRBs per day), enabling us to better constrain the models for FRBs and use them as cosmological probes.

The dynamic behaviour of helicopter during water impact, considering variations in initial downward velocity and pitching angle, have been investigated numerically and theoretically in the present study. The air-water two-phase flows are simulated by solving unsteady Reynolds-averaged Navier-Stokes equations enclosed by standard $k - \omega $ turbulence model. A treatment for computational domain in combination with a global dynamic mesh technique is applied to deal with the relative motion between the helicopter and water. Results indicate that the initial downward velocity of helicopter exhibits behaviour similar to that of a V-shaped body impacting on water, as does the initial pitching angle. To extend the theoretical approach for predicting the kinematic parameters during helicopter ditching, a shape factor capturing the combined effect of various attributes and an average deadrise angle for asymmetric wedges are also introduced.

Vaccines have revolutionised the field of medicine, eradicating and controlling many diseases. Recent pandemic vaccine successes have highlighted the accelerated pace of vaccine development and deployment. Leveraging this momentum, attention has shifted to cancer vaccines and personalised cancer vaccines, aimed at targeting individual tumour-specific abnormalities. The UK, now regarded for its vaccine capabilities, is an ideal nation for pioneering cancer vaccine trials. This article convened experts to share insights and approaches to navigate the challenges of cancer vaccine development with personalised or precision cancer vaccines, as well as fixed vaccines. Emphasising partnership and proactive strategies, this article outlines the ambition to harness national and local system capabilities in the UK; to work in collaboration with potential pharmaceutic partners; and to seize the opportunity to deliver the pace for rapid advances in cancer vaccine technology.

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.

Background: After a transient ischemic attack (TIA) or minor stroke, the long-term risk of subsequent stroke is uncertain. Methods: Electronic databases were searched for observational studies reporting subsequent stroke during a minimum follow-up of 1 year in patients with TIA or minor stroke. Unpublished data on number of stroke events and exact person-time at risk contributed by all patients during discrete time intervals of follow-up were requested from the authors of included studies. This information was used to calculate the incidence of stroke in individual studies, and results across studies were pooled using random-effects meta-analysis. Results: Fifteen independent cohorts involving 129794 patients were included in the analysis. The pooled incidence rate of subsequent stroke per 100 person-years was 6.4 events in the first year and 2.0 events in the second through tenth years, with cumulative incidences of 14% at 5 years and 21% at 10 years. Based on 10 studies with information available on fatal stroke, the pooled case fatality rate of subsequent stroke was 9.5% (95% CI, 5.9 – 13.8). Conclusions: One in five patients is expected to experience a subsequent stroke within 10 years after a TIA or minor stroke, with every tenth patient expected to die from their subsequent stroke.