Background and Objectives: Primary malignant bone tumors are rare lesions, and their complex treatment can lead to functional impairment. It is important to have a postoperative assessment tool for patients’ functional outcomes to be evaluated and to consequently adapt future treatments in the pursuit of a continuous improvement of their quality of life. The Musculoskeletal Tumor Society Score (MSTS) is a validated specific system score that is used frequently in the follow-up of these patients. We found no information about a valid translated Romanian version of this score neither for the upper limb nor for the lower limb. We proposed in this study to translate the original version of the MSTS Score into Romanian and to perform validation analysis of the Romanian-language MSTS Score. Materials and Methods: We selected 48 patients who underwent limb-salvage surgery after resection of bone sarcomas. Patients were interrogated twice according to the translated Romanian version of the MSTS Score during their follow-up. The translation was performed according to the recommended guidelines. A total number of 96 questionnaires were valid for statistical analysis. Results: Internal consistency and reliability were good for both sets of questionnaires’ analytic measurements, with Cronbach’s alpha values of 0.848 (test) and 0.802 (retest). The test-retest evaluation proved to be statistically strong for reproducibility and validity with Spearman’s rho = 0.9 (p < 0.01, 95% CI). Conclusions: This study permitted the translation of this score and the validation of psychometric data. Our results showed that the Romanian version of the MSTS is a reliable means of assessment of the functional outcome of patients who received limb-salvage surgery for the upper and lower extremities. Full article

Numerous previous studies have shown the effectiveness of music therapy in enhancing cognitive functions in patients with dementia. Despite this, robust evidence in this field, especially concerning the comparison of different music therapy types, is lacking. Therefore, randomized controlled trials (RCTs) focusing on music therapy and cognitive functions in dementia patients, termed by “music” AND “dementia” OR “Alzheimer’s disease” AND “cognitive”, were identified from primary electronic databases to conduct this network meta-analysis (NMA). The primary outcome focused on the impact on cognitive functions, and the secondary outcome was the comparison of dropout rates between the intervention groups and the usual care control groups. Standardized mean difference (SMD) values and the corresponding 95% confidence intervals (CIs) were computed for effect evaluation. This study protocol has been registered in IPLASY (INPLASY202430082). A total of 14 RCTs with 1056 participants were enrolled, examining interventions including Active Music Therapy (AMT), Active Music Therapy with Singing (AMT + Sing), Rhythmic Music Therapy (RMT), Listening to Music (LtM), and Singing (Sing). The results indicated that RMT, AMT + Sing, and AMT all significantly improve cognitive functions in dementia patients, of which the SMD were 0.76 (95% CI = 0.32–1.21), 0.79 (95% CI = 0.03–1.49), and 0.57 (0.18–0.96), respectively. Compared with the control group (usual care), no music therapy type was associated with an increased dropout risk. In conclusion, music therapy can improve cognitive functions in patients with dementia without increasing the risk of dropout, particularly RMT, AMT + Sing, and AMT. Full article

Background: Previous studies demonstrate an association between metabolic factors and Helicobacter pylori-related gastric cancer. However, the association of gastric atrophy or intestinal metaplasia (IM) with these factors remains unknown. Methods: Data on 1603 Helicobacter pylori-positive patients who underwent esophagogastroduodenoscopy between 2001 and 2021 were evaluated. The outcome measures were endoscopic atrophy, IM grade, and the incidence of endoscopically diagnosed and pathologically confirmed gastric neoplasms. Clinical factors associated with these findings were also determined. Results: Advanced age; successful Helicobacter pylori eradication; and comorbidities including diabetes mellitus (DM), hypertension, dyslipidemia, and fib4 index were significantly associated with endoscopic gastric atrophy grade. Male sex; advanced age; and comorbidities including DM, hypertension, dyslipidemia, hyperuricemia, fatty liver, aortic calcification, and fib4 index were also significantly associated with endoscopic IM grade, whereas advanced age, successful Helicobacter pylori eradication, DM, fatty liver, and fib4 index were significantly associated with the incidence of gastric neoplasms. Conclusion: Several metabolic disorders, including DM, hypertension, dyslipidemia, hyperuricemia, and fatty liver disease, are risk factors for advanced-grade gastric atrophy, intestinal metaplasia, and gastric neoplasms. Risk stratification according to these factors, particularly those with metabolic disorders, would affect EGD surveillance for Helicobacter pylori-positive patients. Full article

Due to spectacular gains during periods of rapid price increase and unpredictably large drops, Bitcoin has become a popular emergent asset class over the past few years. In this paper, we are interested in predicting the crashes of Bitcoin market. To tackle this task, we propose a framework for deep learning time series classification based on contrastive learning. The proposed framework is evaluated against six machine learning (ML) and deep learning (DL) baseline models, and outperforms them by 15.8% in balanced accuracy. Thus, we conclude that the contrastive learning strategy significantly enhance the model’s ability of extracting informative representations, and our proposed framework performs well in predicting Bitcoin crashes. Full article

Drainage difficulties in the waterlogged areas of sloping cropland not only impede crop development but also facilitate the formation of erosion gullies, resulting in significant soil and water loss. Investigating the distribution of these waterlogged areas is crucial for comprehending the erosion patterns of sloping cropland and preserving black soil resource. In this study, we built varied models based on two stages (one using only deep learning methods and the other combining object-based image analysis (OBIA) with deep learning methods) to identify waterlogged areas using high-resolution remote sensing data. The results showed that the five deep learning models using original remote sensing imagery achieved precision rates varying from 54.6% to 60.9%. Among these models, the DeepLabV3+-Xception model achieved the highest accuracy, as indicated by an F1-score of 53.4%. The identified imagery demonstrated a significant distinction in the two categories of waterlogged areas: sloping cropland erosion zones and erosion risk areas. The former had obvious borders and fewer misclassifications, exceeding the latter in terms of identification accuracy. Furthermore, the accuracy of the deep learning models was significantly improved when combined with object-oriented image analysis. The DeepLabV3+-MobileNetV2 model achieved the maximum accuracy, with an F1-score of 59%, which was 6% higher than that of the model using only original imagery. Moreover, this advancement mitigated issues related to boundary blurriness and image noise in the identification process. These results will provide scientific assistance in managing and reducing the impact in these places. Full article

In response to the unclear drilling resistance characteristics of rocks in the Ji’yang Depression, low drilling efficiency of PDC drill bits, and difficulties in drill bit selection, this study selected rock samples from different depths in the area for indoor drilling resistance analysis testing. Based on logging data, a prediction model was established for drilling resistance characteristics parameters of the strata in the area, and a graph of drilling resistance characteristic parameters of the rocks in the area was drawn. The study showed that the uniaxial compressive strength of the strata rocks was 50–110 MPa, with a hardness of 500–1300 MPa, a plasticity coefficient ranging from 1 to 2, a rock drillability grade of 8–20, and an abrasiveness index of 5–20. Combining the analysis of on-site drilling bit failures, PDC drill bits adapted to the strata in the area were selected, and the mechanical drilling speed of the selected bits reached 12.58 m/h, successfully drilling through the target layer. The above research results are of guiding significance for understanding the reasons for the difficulty of drilling into the Jiyang Depression strata and for improving mechanical drilling speed and drill bit selection in this area. Full article

Microplasma irradiation is a promising technique for the transdermal delivery of high-molecular-weight drugs. In this technique, microplasma components interact with the skin surface or cell membranes, allowing the drugs to penetrate. For efficient and safe drug delivery, it is crucial to understand these interactions. To this end, this study investigated the effects of microplasma irradiation on cellular lipids, particularly those associated with cell membranes. Rat intestinal epithelial cells were treated with microplasma irradiation at two different voltages (4.0 kV or 4.5 kV). An untargeted lipidomic was conducted using liquid chromatography–mass spectrometry (LC/MS) technique. The results revealed that microplasma irradiation at 4.0 kV induces a significant increase in cell membrane lipids within 10 min post-irradiation. All major cell membrane lipids, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin, exhibited increases of over 25% within this short timeframe. Notably, this effect is transient, as lipid levels return to their baseline after 12 h. Furthermore, no significant differences in live and apoptotic cell percentages were observed between the control and 12 h post-irradiated cells. In contrast, irradiation at 4.5 kV did not elicit significant changes in cell membrane lipids, correlating with the absence of drug absorption under this condition. Hence, our study unveiled a correlation between the rapid increase in cell membrane lipids and enhanced drug absorption in microplasma-irradiated cells. This lipid augmentation potentially enhances membrane fluidity and permeability, thus facilitating drug absorption. Beyond elucidating the mechanisms and safety of microplasma-based drug delivery, our research provides valuable insights for advancing various microplasma-based biomedical technologies. Full article

Given the renewed interest in boron neutron capture therapy (BNCT) and the intensified search for improved boron carriers, as well as the difficulties of coherently comparing the carriers described so far, it seems necessary to define a basic set of assays and standardized methods to be used in the early stages of boron carrier development in vitro. The selection of assays and corresponding methods is based on the practical experience of the authors and is certainly not exhaustive, but open to discussion. The proposed tests/characteristics: Solubility, lipophilicity, stability, cytotoxicity, and cellular uptake apply to both low molecular weight (up to 500 Da) and high molecular weight (5000 Da and more) boron carriers. However, the specific methods have been selected primarily for low molecular weight boron carriers; in the case of high molecular weight compounds, some of the methods may need to be adapted. Full article

Salt stress poses a serious threat to tomato production. Red to far-red light ratio (R/FR) is actively involved in the regulation of tomato growth and development; however, it is still uncertain whether and how R/FR improves fruit quality under salt stress. Thus, we conducted metabolomic analysis of tomato fruits under four treatments, including R/FR = 7 (CK), R/FR = 0.7 (L), R/FR = 7 and 100 mmol·L⁻¹ NaCl (Na), and R/FR = 0.7 and 100 mmol·L⁻¹ NaCl (Na+L). Metabolomic analysis indicated that both low R/FR and salt stress enhanced organic acids and phenols accumulation; however, additional low R/FR mainly improved carbohydrates, organic acids, phenols and amino acids accumulation in salt-stressed tomato fruit. Physiological studies were consistent with the above results and further revealed that additional low R/FR drastically promoted plant growth, soluble sugar, total phenol and flavonoid contents, improved osmotic pressure balance and antioxidant capacity, and notably relieved the salt stress-induced suppressions. This study proved the importance of applying light quality regulation in salt-resistant tomato production. Full article

This research examines the structural behavior of the central vault of the Matriz church that collapsed during the 1949 earthquake in Ambato, Ecuador. Following the disaster, the church and Episcopal Palace were demolished. The central vault lacked buttresses and had large cracks two years before the collapse. A study was conducted using graphic restitution and the theory of limit analysis of structures to analyze the mechanical behavior of the central vault. The aim was to provide a technical explanation for the cause of the collapse beyond the impact of the earthquake. The limit analysis of structures is a tool that determines the technical stability conditions of a masonry structure using graphic statics. In this case, the respective checks of the structural behavior could be made, concluding that the structural ensemble of the central vault was unstable and could have collapsed at any moment, not necessarily due to an earthquake. The article is based on the research project “Architectural analysis of the central nucleus of Ambato between 1895 and 1949: styles, types, techniques, losses, and continuities”, which was conducted at the Universidad Técnica de Ambato, Ecuador, from 2021 to 2023. Full article

The 2021 WHO classification of CNS tumors is a challenge for neuroradiologists due to the central role of the molecular profile of tumors. The potential of novel data analysis tools in neuroimaging must be harnessed to maintain its role in predicting tumor subgroups. We performed a scoping review to determine current evidence and research gaps. A comprehensive literature search was conducted regarding glioma subgroups according to the 2021 WHO classification and the use of MRI, radiomics, machine learning, and deep learning algorithms. Sixty-two original articles were included and analyzed by extracting data on the study design and results. Only 8% of the studies included pediatric patients. Low-grade gliomas and diffuse midline gliomas were represented in one-third of the research papers. Public datasets were utilized in 22% of the studies. Conventional imaging sequences prevailed; data on functional MRI (DWI, PWI, CEST, etc.) are underrepresented. Multiparametric MRI yielded the best prediction results. IDH mutation and 1p/19q codeletion status prediction remain in focus with limited data on other molecular subgroups. Reported AUC values range from 0.6 to 0.98. Studies designed to assess generalizability are scarce. Performance is worse for smaller subgroups (e.g., 1p/19q codeleted or IDH1/2 mutated gliomas). More high-quality study designs with diversity in the analyzed population and techniques are needed. Full article

This study evaluates the propagation impact of three risk categories (hazard and exposure, socio-economic vulnerability, and lack of coping capacity) and their associated factors on vaccination uptake policy decisions in Pakistan. This study proposed Bayesian influence diagrams using expert elicitation and data-driven approaches. The Bayesian network (BN) approach uses the best policy algorithm to determine the expected utility of decisions. The study found that the government’s firm vaccine uptake decisions had a positive effect in Pakistan. The findings on hazard and exposure-related factors show that people living in rural areas were more susceptible to COVID-19 than people living in urban areas. Among socio-economic vulnerability factors, household characteristics were affected due to household economic situations, fear of using health facilities due to the spread of COVID-19, lack of public transportation services, food insecurity, a temporary halt in education, and weak governance, which affected the vaccination uptake decision. The factors linked with coping capacity show that the government’s financial assistance and development of digital platforms raised digital health literacy and increased vaccine uptake decision utility. The proposed methodology and results of this study can be used to develop contingency planning for any future potential pandemic situations. Full article

In response to the need for improvement in the utilization of ammonium-rich solutions after the electrochemical reduction of nitrate (NO₃⁻–RR), this study combined phosphorus-containing wastewater and adopted the electrochemical precipitation method for the preparation of struvite (MAP) to simultaneously recover nitrogen and phosphorus resources. At a current density of 5 mA·cm⁻² and an initial solution pH of 7.0, the recovery efficiencies for nitrogen and phosphorus can reach 47.15% and 88.66%, respectively. Under various experimental conditions, the generated struvite (MgNH₄PO₄·6H₂O) exhibits a typical long prismatic structure. In solutions containing nitrate and nitrite, the coexisting ions have no significant effect on the final product, struvite. Finally, the characterization of the precipitate product by X-ray diffraction (XRD) revealed that its main component is struvite, with a high purity reaching 93.24%. Overall, this system can effectively recover ammonium nitrogen from the NO₃⁻–RR solution system after nitrate reduction, with certain application prospects for the recovery of ammonium nitrogen and phosphate. Full article

The carbon-to-nitrogen (C/N) ratio in the cultivation medium significantly influences the growth rate, vigor of mycelium, yield of fruiting bodies, and their nutritional composition. Recently, agricultural and forestry wastes have been increasingly used in cultivating Flammulina velutipes. However, systematic research on how these materials affect the nutritional and functional properties of the fruiting bodies is lacking. This study investigated the effects of different C/N ratios on F. velutipes cultivation. We evaluated the agronomic traits, nutritional composition, and flavor compounds of the fruiting bodies. Our findings reveal that an optimal C/N ratio of 27:1 in the composted substrates enhances the total yield of fruiting bodies, with 25.1% soybean straw as the primary raw material. This ratio also significantly increases the levels of crude protein, total amino acids, and essential amino acids in the fruiting bodies (p < 0.05). Fruiting bodies from the high-nitrogen (HN) treatment showed the highest content of umami amino acids and equivalent umami concentration value. Additionally, we employed an untargeted liquid chromatography–mass spectrometry (LC-MS)-based metabolomics approach to analyze the metabolite profiles of fruiting bodies cultivated in high-nitrogen (HN), medium-nitrogen (MN), and low-nitrogen (LN) substrates. We found that the carbon–nitrogen ratio can affect the flavor and quality of fruiting bodies by regulating amino acid biosynthesis and metabolism and other related pathways. Our results suggest that a C/N ratio of 27:1 offers numerous benefits for the cultivation of F. velutipes with comprehensive analyses and has promising application prospects. Full article

The aim of this study was to evaluate outcomes of transarterial radioembolization (TARE) for hepatocellular carcinoma (HCC) in patients previously treated with transarterial embolization (TAE). In this retrospective study, all HCC patients who received TARE from 1/2012 to 12/2022 for treatment of residual or recurrent disease after TAE were identified. Overall survival (OS) was estimated using the Kaplan–Meier method. Univariate Cox regression was performed to determine significant predictors of OS after TARE. Twenty-one patients (median age 73.4 years, 18 male, 3 female) were included. Median dose to the perfused liver volume was 121 Gy (112–444, range), and 18/21 (85.7%) patients received 112–140 Gy. Median OS from time of HCC diagnosis was 32.9 months (19.4–61.4, 95% CI). Median OS after first TAE was 29.3 months (15.3–58.9, 95% CI). Median OS after first TARE was 10.6 months (6.8–27.0, 95% CI). ECOG performance status of 0 (p = 0.038), index tumor diameter < 4 cm (p = 0.022), and hepatic tumor burden < 25% (p = 0.018) were significant predictors of longer OS after TARE. TARE may provide a survival benefit for appropriately selected patients with HCC who have been previously treated with TAE. Full article

Wheat is a vital crop globally, essential for agriculture, economics, and food security. However, in arid and semi-arid conditions, wheat production faces significant challenges due to low water availability, uneven rainfall distribution, and high soil salinity. The germination and early seedling stages are particularly vulnerable to these stresses. Therefore, this study assessed 15 wheat genotypes for their tolerance to salinity stress during early growth stages, using a hydroponic system with four salt stress levels (0, 50, 100, and 150 mM NaCl). Significant differences were observed for genotype and salinity main effects and their interaction on all investigated traits, indicating considerable variability in the response to salt stress among the investigated wheat cultivars. High NaCl concentrations led to substantial reductions in measured parameters across genotypes, with some showing resilience while others exhibited heightened sensitivity. Stress tolerance indices, such as mean productivity (MP), geometric mean productivity (GMP), harmonic mean (HM), stress tolerance index (STI) and yield index (YI), were identified as reliable indicators for selecting salt-tolerant wheat cultivars. Consequently, Sidi Okba (G11), Ziad (G12), Tamezghida (G13) and Zidane (G14) emerged as the most promising, displaying acceptable performance under both non-stress and salt-stress conditions. These genotypes could serve as valuable genetic resources for breeding programs aimed at enhancing wheat’s salinity tolerance, particularly in arid and semi-arid regions. Full article

Sodium p-perfluorous nonenoxybenzene sulfonate (OBS) is one of the key alternatives to perfluoroalkyl substances (PFASs). Its widespread tendency has increased extensive contamination in the aquatic environment. However, the present treatment technology for OBS exhibited insignificant adsorption capacity and long adsorption time. In this study, three proportions (1:5, 3:5, and 10:1) of chitosan-modified amino-driven graphene oxide (CS-GO) were innovated to strengthen the OBS adsorption capacity, compared with graphene oxide (GO) and graphene (GH). Through the characterization of SEM, BET, and FTIR, it was discovered that CS was synthetized on GO surfaces successfully with a low specific surface area. Subsequently, batch single influence factor studies on OBS removal from simulated wastewater were investigated. The optimum removal efficiency of OBS could be achieved up to 95.4% within 2 h when the adsorbent was selected as CS-GO (10:1), the dosage was 2 mg, and the pH was 3. The addition of inorganic ions could promote the adsorption efficiency of OBS. In addition, CS-GO presented the maximum adsorption energy due to additional functional groups of -NH₃, and electrostatic interaction was the foremost motive for improving the adsorption efficiency of OBS. Moreover, OBS exhibited the fastest diffusion coefficient in the CS-GO-OBS solution, which is consistent with the fitting results of adsorption kinetics. Full article

This work analyses the treatment of elements such as biases and their relationship with disinformation in international academic production. The first step in this process was to carry out a search for papers published in academic journals indexed in the main indexing platforms. This was followed by a bibliometric analysis involving an analysis of the production and impact of the selected publications, using social media techniques and a semantic content analysis based on abstracts. The data obtained from Web of Science, Scopus, and Dimensions, relating to health, biases, and fake news as well as post-truth, show how these works have multiplied in the last decade. The question relating to this research is as follows: How have cognitive biases been treated in national and international academic journals? This question is answered with respect to the scientific or research method. The results, which date from 2000 to 2024, show a considerable academic dedication to exploring the relationship between biases and health disinformation. In all these communities we have observed a relationship between production with the field of medicine as a general theme and social media. Furthermore, this connection is always tied to other subjects, such as an aversion to vaccines in Community 10; disinformation about COVID-19 on social media in Community 5; COVID-19 and conspiracy theories in Community 6; and content for the dissemination of health-related subjects on YouTube and the disinformation spread about them. The community analysis carried out shows a common factor in all the analysed communities—that of cognitive bias. Full article

Exosomal biomarker detection holds great importance in the field of in vitro diagnostics, offering a non-invasive and highly sensitive approach for early disease detection and personalized treatment. Here, we proposed an “APPROACH” strategy, combining aptamer-mediated proximity ligation assay (PLA) with rolling circle amplification (RCA) and time-resolved Förster resonance energy transfer (TR-FRET) for the sensitive and semi-homogenous detection of exosomal biomarkers. PLA probes consisted of a cholesterol-conjugated oligonucleotide, which anchored to the membrane of an exosome, and a specific aptamer oligonucleotide that recognized a target protein of the exosome; the proximal binding of pairs of PLA probes to the same exosome positioned the oligonucleotides in the vicinity of each other, guiding the hybridization and ligation of two subsequently added backbone and connector oligonucleotides to form a circular DNA molecule. Circular DNA formed from PLA underwent rolling circle amplification (RCA) for signal amplification, and the resulting RCA products were subsequently quantified by TR-FRET. The limits of detection provided by APPROACH for the exosomal biomarkers CD63, PD-L1, and HER2 were 0.46 ng∙μL⁻¹, 0.77 ng∙μL⁻¹, and 1.1 ng∙μL⁻¹, respectively, demonstrating excellent analytical performance with high sensitivity and quantification accuracy. Furthermore, the strategy afforded sensitive detection of exosomal CD63 with a LOD of 1.56 ng∙μL⁻¹ in complex biological matrices, which underscored its anti-interference capability and potential for in vitro detection. The proposed strategy demonstrates wide-ranging applicability in quantifying diverse exosomal biomarkers while exhibiting robust analytical characteristics, including high sensitivity and accuracy. Full article

Despite the care provided, some newborns, who are perfectly healthy, show functional alterations that impair a good breast attack in the first few days. This situation often leads to the early failure of lactation. We conducted a randomized single-blind controlled trial to evaluate whether four weeks of osteopathic treatment can normalize the sucking score in a group of neonates with impaired lactation ability. Forty-two healthy full-term neonates were enrolled in this study. On the basis of the sucking score and the assessment of the infant’s breastfeeding skills, infants who had intrinsic breastfeeding difficulties were selected. The inclusion criteria were healthy infants born > 37 weeks, a suction score ≤ 6, and any breast milk at enrolment. At the end of the study, the sucking score was significantly greater in the osteopathic group than in the untreated group; the median sucking score in the treated group was in the normal range, while it remained lower in the untreated group. At the end of the follow-up, the percentage of exclusively breastfeeding infants in the treatment group increased by +25%. This pilot study demonstrates the efficacy of early osteopathic intervention to relieve breastfeeding difficulties in newborns in the first few weeks of life. Full article

Background: Metastatic triple-negative breast cancer (TNBC) is aggressive with poor median overall survival (OS) ranging from 8 to 13 months. There exists considerable heterogeneity in survival at the individual patient level. To better understand the survival heterogeneity and improve risk stratification, our study aims to identify the factors influencing survival, utilizing a large patient sample from the National Cancer Database (NCDB). Methods: Women diagnosed with metastatic TNBC from 2010 to 2020 in the NCDB were included. Demographic, clinicopathological, and treatment data and overall survival (OS) outcomes were collected. Kaplan–Meier curves were used to estimate OS. The log-rank test was used to identify OS differences between groups for each variable in the univariate analysis. For the multivariate analysis, the Cox proportional hazard model with backward elimination was used to identify factors affecting OS. Adjusted hazard ratios and 95% confidence intervals are presented. Results: In this sample, 2273 women had a median overall survival of 13.6 months. Factors associated with statistically significantly worse OS included older age, higher comorbidity scores, specific histologies, higher number of metastatic sites, presence of liver or other site metastases in those with only one metastatic site (excluding brain metastases), presence of cranial and extra-cranial metastases, lack of chemotherapy, lack of immunotherapy, lack of surgery to distant sites, lack of radiation to distant sites, and receipt of palliative treatment to alleviate symptoms. In the multivariate analysis, comorbidity score, histology, number of metastatic sites, immunotherapy, and chemotherapy had a statistically significant effect on OS. Conclusions: Through NCDB analysis, we have identified prognostic factors for metastatic TNBC. These findings will help individualize prognostication at diagnosis, optimize treatment strategies, and facilitate patient stratification in future clinical trials. Full article

Objective: Cenobamate is approved by the European Medicine Agency for the treatment of adult patients with epilepsy (PWEs) with ongoing focal-onset seizures despite appropriate treatment with at least two established antiseizure medications. Pivotal trials and post-marketing real-world observational studies suggest high efficacy with unusually high seizure-free rates. The authors sought to investigate the plasma levels of cenobamate under steady-state conditions in seizure-free versus non-responding PWEs, and in PWEs who experienced adverse events versus those who did not. Methods: Blood samples were collected from adult PWEs who were treated with adjunct cenobamate under steady-state conditions. Daily doses, concomitant medications, efficacy, and tolerability were assessed. The plasma cenobamate levels of seizure-free versus non-responding PWEs and between PWEs with and those without clinical adverse events were compared. Results: Samples from 101 PWEs were included. Thirty-six PWEs were seizure-free and 65 were non-responders. In 31 PWEs, adverse events were apparent, whereas in the remaining 70, no tolerability issues were reported. A linear correlation was found between the daily doses (range: 100 mg–400 mg) and the plasma levels (3.8 mg/L–54.6 mg/L). Neither the daily doses nor the plasma levels differed significantly between the investigated subgroups. The main reason for this result was that the individual therapeutic ranges varied widely: seizure freedom and adverse effects were observed alongside low doses and plasma levels in some PWEs. Conversely, there were examples of PWEs who did not respond or who reported no tolerability issues at high doses or plasma levels. Conclusions: To evaluate the individual therapeutic range and to better understand the influence of other drugs in cases where concomitant medications are used, the therapeutic drug monitoring of cenobamate may be useful. A general therapeutic range cannot be defined. Full article