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Lasers have been proven to be precise tools for bone ablation. Applying no mechanical stress to the patient, they are potentially very suitable for microsurgery on fragile structures such as the inner ear. However, it remains challenging to control the laser-bone ablation without injuring embedded soft tissue. In this work, we demonstrate a closed-loop control of a short-pulsed CO2 laser to perform laser cochleostomy under the monitoring of an optical coherence tomography (OCT) system. A foresighted detection of the bone-endosteum-perilymph boundary several hundred micrometers before its exposure has been realized. Position and duration of the laser pulses are planned based on the residual bone thickness distribution. OCT itself is also used as a highly accurate tracking system for motion compensation between the target area and the optics. During ex vivo experimental evaluation on fresh porcine cochleae, the ablation process terminated automatically when the thickness of the residual tissue layer uniformly reached a predefined value. The shape of the resulting channel bottom converged to the natural curvature of the endosteal layer without injuring the critical structure. Preliminary measurements in OCT scans indicated that the mean absolute accuracy of the shape approximation was only around 20 μm.

Hot spot mutations in the promoter region of telomerase reverse transcriptase ( TERT ) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age ( p  < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss ( p  < 0.0001), but inversely associated with loss of ATRX expression ( p  < 0.0001) and IDH1/IDH2 mutations ( p  < 0.0001). TERT promoter mutations are typically found in adult patients and occur in a highly tumor type-associated distribution.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition characterised by inattention and impulsivity. While its effects on academic and occupational functioning are well established, less is known about how ADHD traits relate to financial behaviours, particularly in high-risk contexts such as online trading. This cross-sectional study examined associations between ADHD traits and financial decision-making in a sample of 945 active online traders. Participants were assessed using a validated self-report scale for ADHD traits and standardised measures of financial risk tolerance (FRT), trading activity, and portfolio performance. The median participant age was 34 years, with 74.5% identifying as male. Based on self-report, 5.7% of participants met DSM-5 symptom criteria suggestive of ADHD, though no clinical diagnosis was made. Participants with ADHD traits demonstrated significantly higher FRT and greater speculative risk-taking. ADHD traits correlated positively with FRT and negatively with portfolio returns. Regression analyses revealed that increased trading frequency, speculative risk-taking, and higher return expectations predicted greater ADHD trait expression, while higher actual portfolio returns and higher investment risk scores were associated with lower ADHD traits. Though causality cannot be inferred, traits like inattention and impulsivity might contribute to suboptimal decision-making in volatile financial settings. Clinicians should consider this in their assessments, promote awareness and support prevention of poor investment decisions. Further longitudinal studies are needed, alongside targeted financial guidance for individuals with elevated ADHD traits.

Spirulina is a multicellular cyanobacterium that is consumed as a dietary supplement. The content of trace elements (B, Ba, Li, Ni, Sr, V) and toxic metals (Al, Cd, Pb) was determined in 24 spirulina samples marketed in two different formulations (tablets and powder) by ICP-OES (inductively coupled plasma optical emission spectrometry). The highest element concentration was found in the powder presentation, except for Li. The powder presentation element levels (mg/kg dry weight) were Al (28.1), Sr (10.3), B (1.73), Li (1.47), Ba (1.25), Ni (0.63), Pb (88.1 μg/kg dw), Cd (37.2 μg/kg dw), and V (22.9 μg/kg dw). Considering an adult with a body weight of 68.48 kg and the posology guidelines (14 tablespoons per week), the consumption of powdered spirulina contributes greatly to the Al intake by 2.04% of its TWI (tolerable weekly intake) set at 1 mg/kg body weight/week, followed by Cd with 1.05% of its TWI set at 2.5 μg/kg bw/week. Pb intake represents 1.05% of the BMDL (benchmark dose) level associated with nephrotoxicity and 0.44% of the BMDL associated with cardiovascular effects. This assessment suggests that spirulina consumption does not pose risks to the consumer as far as exposure to toxic metals (Al, Cd, Pb) is concerned. However, the presence of trace elements and toxic metals in spirulina preparations should be monitored to ensure its quality and safety.

Glioblastoma, the most aggressive primary brain cancer, has a dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we systematically screened repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling more than 2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug–target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of more than 1 million compounds with high patient validation accuracy. Deep multimodal profiling confirmed Ca 2+ -driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the anti-depressant vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology. A single-cell ex vivo screening of repurposable drugs in glioblastoma and machine learning of drug–target networks show that anti-tumor neuroactive drugs converge on the AP-1/BTG pathway, based on which prediction models and experimental in vivo and in silico validation identify the anti-depressant vortioxetine as a potential therapeutic agent.

Microbial organisms have key roles in numerous physiological processes in the human body and have recently been shown to modify the response to immune checkpoint inhibitors 1 , 2 . Here we aim to address the role of microbial organisms and their potential role in immune reactivity against glioblastoma. We demonstrate that HLA molecules of both glioblastoma tissues and tumour cell lines present bacteria-specific peptides. This finding prompted us to examine whether tumour-infiltrating lymphocytes (TILs) recognize tumour-derived bacterial peptides. Bacterial peptides eluted from HLA class II molecules are recognized by TILs, albeit very weakly. Using an unbiased antigen discovery approach to probe the specificity of a TIL CD4 + T cell clone, we show that it recognizes a broad spectrum of peptides from pathogenic bacteria, commensal gut microbiota and also glioblastoma-related tumour antigens. These peptides were also strongly stimulatory for bulk TILs and peripheral blood memory cells, which then respond to tumour-derived target peptides. Our data hint at how bacterial pathogens and bacterial gut microbiota can be involved in specific immune recognition of tumour antigens. The unbiased identification of microbial target antigens for TILs holds promise for future personalized tumour vaccination approaches. Tumour-infiltrating lymphocytes from glioblastoma can recognize bacterial and gut microbial peptides.

Air-sea and air-sea-ice fluxes in the Southern Ocean play a critical role in global climate through their impact on the overturning circulation and oceanic heat and carbon uptake. The challenging conditions in the Southern Ocean have led to sparse spatial and temporal coverage of observations. This has led to a ‘knowledge gap’ that increases uncertainty in atmosphere and ocean dynamics and boundary-layer thermodynamic processes, impeding improvements in weather and climate models. Improvements will require both process-based research to understand the mechanisms governing air-sea exchange and a significant expansion of the observing system. This will improve flux parameterizations and reduce uncertainty associated with bulk formulae and satellite observations. Improved estimates spanning the full Southern Ocean will need to take advantage of ships, surface moorings, and the growing capabilities of autonomous platforms with robust and miniaturized sensors. A key challenge is to identify observing system sampling requirements. This requires models, Observing System Simulation Experiments (OSSEs), and assessments of the specific spatial-temporal accuracy and resolution required for priority science and assessment of observational uncertainties of the mean state and direct flux measurements. Year-round, high-quality, quasi-continuous in situ flux measurements and observations of extreme events are needed to validate, improve and characterize uncertainties in blended reanalysis products and satellite data as well as to improve parameterizations. Building a robust observing system will require community consensus on observational methodologies, observational priorities, and effective strategies for data management and discovery.

DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1–3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of NF2 inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the HOXD gene cluster in this MC, which, together with general upregulation of HOX genes in the malignant MC, indicates a role of HOX genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target.

Purpose Multimodal therapies have significantly improved prognosis in glioma. However, in particular radiotherapy may induce long-term neurotoxicity compromising patients’ neurocognition and quality of life. The present prospective multicenter study aimed to evaluate associations of multimodal treatment with neurocognition with a particular focus on hippocampal irradiation. Methods Seventy-one glioma patients (WHO grade 1–4) were serially evaluated with neurocognitive testing and quality of life questionnaires. Prior to (baseline) and following further treatment (median 7.1 years [range 4.6–11.0] after baseline) a standardized computerized neurocognitive test battery (NeuroCog FX) was applied to gauge psychomotor speed and inhibition, verbal short-term memory, working memory, verbal and non-verbal memory as well as verbal fluency. Mean ipsilateral hippocampal radiation dose was determined in a subgroup of 27 patients who received radiotherapy according to radiotherapy plans to evaluate its association with neurocognition. Results Between baseline and follow-up mean performance in none of the cognitive domains significantly declined in any treatment modality (radiotherapy, chemotherapy, combined radio-chemotherapy, watchful-waiting), except for selective attention in patients receiving chemotherapy alone. Apart from one subtest (inhibition), mean ipsilateral hippocampal radiation dose > 50 Gy (Dmean) as compared to < 10 Gy showed no associations with long-term cognitive functioning. However, patients with Dmean < 10 Gy showed stable or improved performance in all cognitive domains, while patients with > 50 Gy numerically deteriorated in 4/8 domains. Conclusions Multimodal glioma therapy seems to affect neurocognition less than generally assumed. Even patients with unilateral hippocampal irradiation with > 50 Gy showed no profound cognitive decline in this series.

This study presents a survey on pesticide use, pesticide storage and pesticide disposal among 100 residents near a former pesticide store in rural Georgia using a standardized paper questionnaire. More than one quarter of the participants responded that the age of the pesticides they use is higher than 20 years. Based on this finding, it cannot be excluded that persistent organic pollutants like Dichloro-diphenyl-trichloroethane and hexachlorocyclohexanes still are released to the environment. Knowledge about active ingredients of pesticides is lacking among farmers: More than two thirds state that they know the active ingredients, while less than 10% mention an active ingredient matching the brand name they report. Purchasing pesticides in containers without labels appears to be common practice. Information about the pesticides is mainly obtained from the pesticide retailer, while the label is less important as a source of information. More than 95% of the participants store the pesticides in a separate store, but appropriate possibilities of hazardous waste disposal seem to be insufficient in rural areas in the region. The finding that pesticides are purchased and stored in repacked secondary containers, poses direct risks and hampers communication of risks to users. Improving (implementation of) regulations for pesticide handling and strengthening local knowledge through better vocational training can improve soil and groundwater protection and sustainable use of resources. Article highlights One of the main findings is that residents report using the pesticides for a long time. Not only are the pesticides used way longer than they may remain suitable for use, but also the pesticides could be dating from before international legislation entered into force which was set up to protect from long-lived organic pollutants (the Stockholm Convention). Our results show that often pesticides are repacked and stored in alternative containers such as plastic containers for detergents. This means users cannot find important information on how to use pesticides safely on these alternative containers. The label cannot be used as a source of information for example regarding health risks. This may lead to poisoning of users. In Georgia, the transition process results in poor implementation of environmental regulations such as laws about waste management. The results show that educational level has a positive influence on choosing safe storage options such as a separate store. The results indicate that especially in rural areas possibilities of proper disposal of old pesticides or other dangerous chemicals are poor. This has implications for the health of residents. Efforts to better implement environmental regulations should be strengthened especially in rural areas to overcome the legacy of long-lived pesticides which are now banned. Old pesticides might still be in use because they are difficult to dispose of safely.