CT-Based Intratumoral and Peritumoral Radiomics Nomograms for the Preoperative Prediction of Spread Through Air Spaces in Clinical Stage IA Non-small Cell Lung Cancer.

The study aims to investigate the value of intratumoral and peritumoral radiomics and clinical-radiological features for predicting spread through air spaces (STAS) in patients with clinical stage IA non-small cell lung cancer (NSCLC). A total of 336 NSCLC patients from our hospital were randomly divided into the training cohort (n = 236) and the internal validation cohort (n = 100) at a ratio of 7:3, and 69 patients from the other two external hospitals were collected as the external validation cohort. Univariate and multivariate analyses were used to select clinical-radiological features and construct a clinical model. The GTV, PTV5, PTV10, PTV15, PTV20, GPTV5, GPTV10, GPTV15, and GPTV20 models were constructed based on intratumoral and peritumoral (5 mm, 10 mm, 15 mm, 20 mm) radiomics features. Additionally, the radscore of the optimal radiomics model and clinical-radiological predictors were used to construct a combined model and plot a nomogram. Lastly, the ROC curve and AUC value were used to evaluate the diagnostic performance of the model. Tumor density type (OR = 6.738) and distal ribbon sign (OR = 5.141) were independent risk factors for the occurrence of STAS. The GPTV10 model outperformed the other radiomics models, and its AUC values were 0.887, 0.876, and 0.868 in the three cohorts. The AUC values of the combined model constructed based on GPTV10 radscore and clinical-radiological predictors were 0.901, 0.875, and 0.878. DeLong test results revealed that the combined model was superior to the clinical model in the three cohorts. The nomogram based on GPTV10 radscore and clinical-radiological features exhibited high predictive efficiency for STAS status in NSCLC.

Anti-Seizure Monotherapy and Early Abortion Under Real-World Conditions.

Background: Most pregnant epilepsy patients need to continue using anti-seizure medications (ASMs) to control epileptic seizures. Objective: This study aimed to evaluate the risk of early abortion in pregnant epilepsy patients exposed to anti-seizure monotherapy. Methods and Material: We prospectively followed up pregnant epilepsy patients treated with anti-seizure monotherapy in our epilepsy center between January 2010 and January 2020 under real-world conditions. Early abortion (spontaneous abortion in the first trimester of pregnancy) was the endpoint. Results: Of 211 pregnancies exposed to monotherapy, including 40% (n = 85) to lamotrigine (LTG), 28% (n = 58) to oxcarbazepine (OXC), 15% (n = 32) to sodium valproate (VPA), 9% (n = 19) to levetiracetam, and 8% (n = 17) to carbamazepine, six ended in early abortion. The overall risk of early abortion in pregnant patients exposed to ASM monotherapy was 2.8% (n = 6) [95% confidence interval (CI) = 0.013-0.073]. The risk of early abortion was 2.4% (n = 2) (95% CI = 0.003-0.082) in women treated with LTG, 3.5% (n = 2) (95% CI = 0.004-0.115) in women treated with OXC, and 6.3% (n = 2) (95% CI = 0.008-0.208) in women treated with VPA. The relative risk of early abortion in the LTG, OXC, and VPA groups did not reach statistical significance. Conclusions: Although the sample size of our study was small, these results indicate that the use of anti-seizure monotherapy in pregnant epilepsy patients may not increase the risk of early miscarriage. Larger prospective studies are needed for sufficient statistical analysis.

New dechlorination products and mechanisms of tris(2-chloroethyl) phosphate by an anaerobic enrichment culture from a vehicle dismantling site.

End-of-life vehicles (ELVs) dismantling sites are the notorious hotspots of chlorinated organophosphate esters (Cl-OPEs). However, the microbial-mediated dechlorination of Cl-OPEs at such sites has not yet been explored. Herein, the dechlorination products, pathways and mechanisms of tris(2-chloroethyl) phosphate (TCEP, a representative Cl-OPE) by an anaerobic enrichment culture (ZNE) from an ELVs dismantling plant were investigated. Our results showed that dechlorination of TCEP can be triggered by reductive transformation to form bis(2-chloroethyl) phosphate (BCEP), mono-chloroethyl phosphate (MCEP) and by hydrolytic dechlorination to form bis(2-chloroethyl) 2-hydroxyethyl phosphate (TCEP-OH), 2-chloroethyl bis(2-hydroxyethyl) phosphate (TCEP-2OH), 2-chloroethyl (2-hydroxyethyl) hydrogen phosphate (BCEP-OH). The combination of 16S rRNA gene amplicon sequencing, quantitative real-time PCR (qPCR) and metagenomics revealed that the Dehalococcoides played an important role in the reductive transformation of TCEP to BCEP and MCEP. A high-quality metagenome-assembled genome (completeness >99% and contamination <1%) of Dehalococcoides was obtained. The sulfate-reducing bacteria harboring haloacid dehalogenase genes (had) may be responsible for the hydrolytic dechlorination of TCEP. These findings provide insights into microbial-mediated anaerobic transformation products and mechanisms of TCEP at ELVs dismantling sites, having implications for the environmental fate and risk assessment of Cl-OPEs at those sites.

Fishery-based adaption to climate change: the case of migratory species flathead grey mullet (Mugil cephalus L.) in Taiwan Strait, Northwestern Pacific.

The flathead gray mullet (Mugil cephalus L.) is a cosmopolitan fish that lives in warm and temperate zones over 42°N-42°S. It is a key fish species for industrial fishing off coastal Taiwan. Gray mullets enter the coastal waters of the southeastern Taiwan Strait (22°N-25°N) to spawn in winter and feed in the coastal and tidal waters of China (25°N-30°N). From 1986 to 2010, the annual catch of gray mullet decreased substantially and remained low. Although the Pacific Decadal Oscillation and El Niño-Southern Oscillation are recognized to affect gray mullet migration, the increase in sea surface temperature may be the main cause of the aforementioned decrease. We explored how weather changes affect fishing conditions and patterns at the gray mullet fishing grounds in Taiwan's coastal areas. Because of the decrease in gray mullet catches, the most common method for catching gray mullet in Taiwan's coastal areas between 1990 and 2010 was the use of drift or trawl nets instead of two-boat purse-seiner fleets. Since 2012, purse-seiner fleets have become the most common method for catching gray mullet. This trend indicates that the local fishing industry is adapting to changing environmental conditions.

MWCNTs dispersion adopting GA and its application towards copper tailings-based cementitious materials.

Hydrophobic carbon nanotubes are hardly to disperse in water and prone to agglomerate when poured with Copper Tailing-Based Cementitious Material (CTCM). Multi-walled carbon nanotubes (MWCNTs) + Arabic Gum (GA) dispersions were prepared by a novel method of synergistic optimization of concentration, controlling low-frequency ultrasonic time and setting the ambient temperature with non-toxic anionic surfactant GA as surfactant. The results of UV-Vis spectroscopy showed that the high stability MWCNTs + GA dispersion with low aggregation area (< 1.2%) and low aggregation beam size (< 219 nm) have been prepared by using 1.7 mmol/l GA. The effects of highly stable MWCNTs dispersion on the mechanical properties, microstructure and durability of CTCM were studied. The 28 days compressive strength increased by 21.5%, and the flexural strength increased by 20.5%, almost reaching the mechanical level of the control group. The results of SEM, XRD and EDS showed that GA significantly enhanced the dispersion of MWCNT in aqueous solution at a suitable concentration (mass ratio of GA:CNTs = 1:1). The microstructure of the prepared CTCM by high stability MWCNTs dispersion was optimized obviously, and the mechanical properties and durability were improved significantly. This method solves the dual problem of MWCNTs not being fully dispersed in aqueous solution and being easily re-agglomerated in cementitious materials, as well as finding a breakthrough for the low cost and industrialization of tailings cement-based composite cementitious materials.

Nomogram based on clinical characteristics and radiological features for the preoperative prediction of spread through air spaces in patients with clinical stage IA non-small cell lung cancer: a multicenter study.

PURPOSE: To investigate the value of clinical characteristics and radiological features for predicting spread through air spaces (STAS) in patients with clinical stage IA non-small cell lung cancer (NSCLC). METHODS: A total of 336 patients with NSCLC from our hospital were randomly divided into two groups, i.e., the training cohort (n = 236) and the internal validation cohort (n = 100) (7:3 ratio). Furthermore, 69 patients from two other hospitals were collected as the external validation cohort. Eight clinical patient characteristics were recorded, and 20 tumor radiological features were quantitatively measured and qualitatively analyzed. In the training cohort, the differences in clinical characteristics and radiological features were compared using univariate and multivariate analysis. A nomogram was created, and the predictive efficacy of the model was evaluated in the validation cohorts. The receiver operating characteristic curve and area under the curve (AUC) value were used to evaluate the discriminative ability of the model. In addition, the Hosmer-Lemeshow test and calibration curve were used to evaluate the goodness-of-fit of the model, and the decision curve was used to analyze the model's clinical application value. RESULTS: The best predictors included gender, the carcinoembryonic antigen (CEA), consolidation-to-tumor ratio (CTR), density type, and distal ribbon sign. Among these, the tumor density type [odds ratio (OR): 6.738] and distal ribbon sign (OR: 5.141) were independent risk factors for predicting the STAS status. Moreover, three different STAS prediction models were constructed, i.e., a clinical, radiological, and combined model. The clinical model comprised gender and the CEA, the radiological model included the CTR, density type, and distal ribbon sign, and the combined model comprised the above two models. A DeLong test results revealed that the combined model was superior to the clinical model in all three cohorts and superior to the radiological model in the external validation cohort; the cohort AUC values were 0.874, 0.822, and 0.810, respectively. The results also showed that the combined model had the highest diagnostic efficacy among the models. The Hosmer-Lemeshow test showed that the combined model showed a good fit in all three cohorts, and the calibration curve showed that the predicted probability value of the combined model was in good agreement with the actual STAS status. Finally, the decision curve showed that the combined model had a better clinical application value than the clinical and radiological models. CONCLUSION: The nomogram created in this study, based on clinical characteristics and radiological features, has a high diagnostic efficiency for predicting the STAS status in patients with clinical stage IA NSCLC and may support the creation of personalized treatment strategies before surgery.

Understanding unmet medical needs through medical crowdfunding in China.

OBJECTIVES: Online medical crowdfunding has gained popularity in recent years in China. The objective of this study was to identify unmet medical needs in the public healthcare system through analysis of Chinese medical crowdfunding data. STUDY DESIGN: Text information extraction and statistical analysis based on large-scale data. METHODS: From 19 June 2011 to 15 March 2020, data from 30,704 medical crowdfunding projects were collected from Tencent GongYi, which is one of the largest Chinese medical crowdfunding platforms. Text mining methods were used to extract data on the medical conditions and locations of the applicants of medical crowdfunding. In addition, 125 medical crowdfunding projects initiated by leukaemia patients in Chongqing and Nanyang were further investigated through manual data extraction, and the factors impacting the fundraising goals were explored using a generalised linear model. RESULTS: The most common conditions using medical crowdfunding to raise funds were as follows: cancer (31.87%), chronic conditions (18.14%), accidental injury (7.80%) and blood system-related conditions (7.75%). Treatments for cancer and blood system-related conditions are expensive and have serious long-term impacts on the lives of patients. Results showed that the cities of Nanyang and Chongqing had the largest number of crowdfunding projects. CONCLUSIONS: This study found that the medical conditions that prompted individuals to apply for crowdfunding were those with long treatment cycles, complexities and expensive medical or non-medical costs. Furthermore, discrepancies in health insurance policies between different regions and residents seeking treatments outside their insurance locations were also important factors that triggered medical crowdfunding applications. Adjusting health insurance policies accordingly may improve the efficiency of utilising health insurance resources and reduce the financial burden on patients.

Discovery of two ent-atisane diterpenoid lactones with AChE inhibitory activity from the roots of Euphorbia fischeriana.

Euphorlactone A (1), a rare rearranged ent-atisane norditerpenoid with an undescribed 3-nor-2,4-olide-ent-atisane scaffold, and euphorlactone B (2), a new ent-atisane diterpenoid with an unprecedented seven-membered lactone ring C, were isolated from the roots of Euphorbia fischeriana. Their planar structures with absolute configurations were extensively elucidated by analysis of 1D and 2D NMR data, electronic circular dichroism (ECD) calculations, Rh2(OCOCF3)4-induced ECD curves, and single-crystal X-ray diffraction. Euphorlactone A (ELA) showed a remarkable AChE (acetylcholinesterase) inhibitory activity (IC50 = 2.13 ± 0.06 µM and Ki = 0.058 µM), which was five times stronger than that of the positive control (rivastigmine, IC50 = 12.46 ± 0.82 µM), and further in vitro enzyme inhibition kinetic analysis and molecular docking studies were performed to investigate the AChE inhibitory mechanism.

The Apelin/APJ system modulates seizure activity and endocytosis of the NMDA receptor GluN2B subunit.

In the central nervous system (CNS), the apelin/APJ system is broadly expressed. According to some studies, activation of this system protects against excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors and exerts neuroprotective effects. However, the role of this system in epilepsy remains unclear. In the present study, immunofluorescence staining and western blotting were used to assess APJ localization and expression in the brains of mice with recurrent spontaneous seizures induced by kainic acid (KA). Behavior and local field potentials (LFPs) were assessed in mice with KA-induced seizures. Susceptibility to seizures was assessed in a pentylenetetrazole (PTZ)-induced seizure model. Whole-cell patch-clamp recordings were used to evaluate the role of the apelin/APJ system in regulating synaptic transmission in brain slices from mice in which Mg2+-free medium was used to induce seizures. NMDA receptor GluN2B subunit expression and phosphorylation of GluN2B at Ser1480 were measured in the mouse hippocampus. APJ was primarily localized in neurons, and its expression was upregulated in the epileptic brain. APJ activation after KA-induced status epilepticus (SE) reduced epileptic activity, whereas APJ inhibition aggravated epileptic activity. In the PTZ model, APJ activation reduced and APJ inhibition increased susceptibility to seizures. The apelin/APJ system affected NMDA receptor-mediated postsynaptic currents in patch-clamp recordings. Moreover, APJ regulated the levels of GluN2B phosphorylated at Ser1480 and the abundance of cell-surface GluN2B in neurons. Furthermore, endocytosis of the NMDA receptor GluN2B subunit was regulated by the apelin/APJ system. Together, our findings indicate that the apelin/APJ system modulates seizure activity and may be a novel therapeutic target for epilepsy.

Targeting CDK12 obviates the malignant phenotypes of colorectal cancer through the Wnt/ß-catenin signaling pathway.

Colorectal cancer (CRC) is the second most common cause of cancer-related mortality and lies third in terms of morbidity due to the limited number of effective druggable targets. Since cancer stem cells (CSCs) are considered to be one of the roots of tumorigenesis, outgrowth and metastasis, targeting CSCs may be a promising strategy to reverse the malignant phenotypes of CRC. Cyclin-dependent kinase 12 (CDK12) has been reported to be involved in the self-renewal of CSCs in various cancers, rendering it an attractive potential target against CSCs to consequently limit the malignant phenotypes in CRC. In the present study, we aimed to investigate whether CDK12 can be a potential therapeutic target for patients with CRC and clarify its underlying mechanism. We found that CDK12, but not CDK13 is required for CRC survival. CDK12 was found to drive tumor initiation according to the colitis-associated colorectal cancer mouse model. In addition, CDK12 promoted CRC outgrowth and hepatic metastasis in the subcutaneous allograft and liver metastasis mouse models, respectively. In particular, CDK12 was able to induce the self-renewal of CRC CSCs. Mechanistically, the activation of Wnt/ß-catenin signaling mediated by CDK12 was implicated in stemness regulation and malignant phenotype maintenance. These findings indicate that CDK12 is a candidate druggable target in CRC. Therefore, the CDK12 inhibitor SR-4835 warrants clinical trial testing in patients with CRC.

Syntaxin 7 modulates seizure activity in epilepsy.

The exact pathogenesis of epilepsy, one of the most common and devastating diseases of the nervous system, is not fully understood. Syntaxin7 (STX7) is a member of the SNARE superfamily, which mediates membrane fusion events in all cells. However, the role STX7 plays in epilepsy remains unclear. Therefore, this study investigates the role of STX7 in epilepsy. Our study found that the expression of STX7 was reduced in the epileptic brain and that overexpression of STX7 decreased the susceptibility to epileptic seizures and alleviated epileptic activity in a kainic acid-induced model and pentylenetetrazole-induced kindling model of epilepsy, whereas the downregulation of STX7 showed opposite effects. Whole-cell patch-clamp recordings showed that STX7 does not affect the intrinsic excitability of neurons, but rather the excitation/inhibition ratio mediated by affecting the release of presynaptic γ-aminobutyric acid neurotransmitters. Transmission electron microscopy results showed that STX7 did not affect the density of inhibitory synapses but could affect the density of inhibitory vesicles. Taken together, these results reveal a previously unknown function of STX7 in epilepsy and suggest that STX7 may serve as a novel target for epilepsy therapy.

Identification of hub genes and pathways in lung metastatic colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent types of malignant tumours. Metastasis is the leading cause of cancer-related mortality, with lung metastases accounting for 32.9% of all metastatic CRCs. However, since the biological mechanism of lung metastatic CRC is poorly understood, limited therapeutic targets are available. In the present study, we aimed to identify the key genes and molecular processes involved in CRC lung metastasis. METHODS: The differentially expressed genes (DEGs) between primary and lung metastatic CRC patients were obtained from the Gene Expression Omnibus (GEO) database via the GEO2R tool. The enriched biological processes and pathways modulated by the DEGs were determined with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome Gene Sets analyses. The search tool Retrieval of Interacting Genes (STRING) and Cytoscape were used to construct a protein-protein interaction (PPI) network among DEGs. RESULTS: The DEGs were enriched in surfactant metabolism, cell-cell communication and chemokine signaling pathways. The defined hub genes were included CLU, SFTPD, CCL18, SPP1, APOE, BGN and MMP3. Among them, CLU, SFTPD and CCL18 might be associated with the specific lung tropism metastasis in CRC. In addition, the expression and prognostic values of the hub genes in CRC patients were verified in database of The Cancer Genome Atlas (TCGA) and GEO. Moreover, the protein levels of the hub genes were detected in primary and lung metastatic CRC cells, serum or tissues. Furthermore, SFTPD was confirmed to facilitate cellular proliferation and lung metastasis in CRC. CONCLUSION: This bioinformatics study may provide a better understanding of the candidate therapeutic targets and molecular mechanisms for CRC lung metastasis.

Stable Isotopic and Metagenomic Analyses Reveal Microbial-Mediated Effects of Microplastics on Sulfur Cycling in Coastal Sediments.

Microplastics are readily accumulated in coastal sediments, where active sulfur (S) cycling takes place. However, the effects of microplastics on S cycling in coastal sediments and their underlying mechanisms remain poorly understood. In this study, the transformation patterns of different S species in mangrove sediments amended with different microplastics and their associated microbial communities were investigated using stable isotopic analysis and metagenomic sequencing. Biodegradable poly(lactic acid) (PLA) microplastics treatment increased sulfate (SO42-) reduction to yield more acid-volatile S and elementary S, which were subsequently transformed to chromium-reducible S (CRS). The S isotope fractionation between SO42- and CRS in PLA treatment increased by 9.1‰ from days 0 to 20, which was greater than 6.8‰ in the control. In contrast, recalcitrant petroleum-based poly(ethylene terephthalate) (PET) and polyvinyl chloride (PVC) microplastics had less impact on the sulfate reduction, resulting in 7.6 and 7.7‰ of S isotope fractionation between SO42- and CRS from days 0 to 20, respectively. The pronounced S isotope fractionation in PLA treatment was associated with increased relative abundance of Desulfovibrio-related sulfate-reducing bacteria, which contributed a large proportion of the microbial genes responsible for dissimilatory sulfate reduction. Overall, these findings provide insights into the potential impacts of microplastics exposure on the biogeochemical S cycle in coastal sediments.

Dissociating the Multiple Psychological Processes in Everyday Moral Decision-Making with the CAN Algorithm.

In previous research frameworks, researchers used an everyday dilemma to test people's altruistic versus egoistic inclination. However, there are at least three different psychological processes that could induce altruistic over egoistic decisions, i.e., stronger altruistic sensitivity, weaker egoistic sensitivity, and stronger overall action versus inaction preference. To dissociate these different psychological processes, we developed new materials and applied the CAN algorithm from traditional moral dilemma research in two studies. In Study 1, we designed scenarios varying with a 2 (egoistic/non-egoistic) × 2 (non-altruistic/altruistic) structure. Then, we recruited 209 participants to validate the scenarios and filtered six scene frameworks with 24 scenarios in total. In Study 2, we recruited 747 participants to judge whether they would conduct behavior that is simultaneously altruistic (or non-altruistic) and egoistic (or non-egoistic) in the filtered scenarios obtained from Study 1. They also filled in the Social Isolation Scale, Distress Disclosure Scale, and some other demographic information. As we dissociated the psychological processes using the CAN algorithm, significant correlations between social isolation and distress disclosure and three parameters (i.e., altruistic tendency, egoistic tendency, and overall action/inaction preference) underlying the altruistic choice were revealed to varying degrees. Other individual differences in the psychological processes in everyday moral decision-making were further demonstrated. Our study provided materials and methodological protocols to dissociate the multiple psychological processes in everyday moral decision-making. It promotes our insights on everyday moral decisions from a differential psychological processes perspective.

CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer.

BACKGROUND: Hepatic metastasis is the primary and direct cause of death in individuals with colorectal cancer (CRC) attribute to lack of effective therapeutic targets. The present study aimed to identify potential druggable candidate targets for patients with liver metastatic CRC. METHODS: The transcriptional profiles of super-enhancers (SEs) in primary and liver metastatic CRC were evaluated in publicly accessible CRC datasets. Immunohistochemistry of human CRC tissues was conducted to determine the expression level of CDK12. Cellular proliferation, survival and stemness were examined upon CDK12 inhibition by shCDK12 or a selective CDK12 inhibitor named SR-4835 with multiple in vitro and in vivo assays. RNA sequencing and bioinformatics analyses were carried out to investigate the mechanisms of CDK12 inhibition in CRC cells. RESULTS: We identified CDK12 as a driver gene for direct hepatic metastasis in CRC. Suppression of CDK12 led to robust inhibition of proliferation, survival and stemness. Mechanistically, CDK12 intervention preferentially repressed the transcription of SE-associated genes. Integration of the SE landscape and RNA sequencing, BCL2L1 and CCDC137 were identified as SE-associated oncogenic genes to strengthen the abilities of cellular survival, proliferation and stemness, eventually increasing liver metastasis of CRC. CONCLUSIONS: Our data highlight the potential of CDK12 and SE-associated oncogenic transcripts as therapeutic targets for patients with liver metastatic CRC.

The Application Effect of Evidence-Based Care in Gastrointestinal Surgical Pipeline Nursing.

With the improvement of the higher nursing education system, the overall quality and work ability of clinical nurses have also been significantly improved. Most nursing staff have a positive attitude towards evidence-based nursing medicine but lacking of the knowledge and skills about evidence-based nursing. Clinical nurses are still short of the ability to evaluate relevant research data, which is one of the cause of interference for the clinical nurses to use the latest research results reasonably and effectively at present. The purpose of this paper is to explore the application effect of evidence-based nursing in gastrointestinal surgical pipeline nursing and to clarify the impact of evaluation ability on nurses in clinical practice, investigate, and discuss the application effect of evidence-based nursing in gastrointestinal surgical pipeline nursing. This paper selects the clinical nurses of the three top three hospitals in a province as the research object, using the ways of general data questionnaire, the general individual performance sensitivity scale, the evidence-based nursing application behavior questionnaire, the evidence-based nursing application behavior willingness questionnaire, and the evaluation ability training needs questionnaire to collect data for 100 cases of gastrointestinal surgery clinical nurses. Analyze nurses' awareness level of evidence-based nursing, the willingness of evidence-based nursing behavior, and the relevance of evidence-based nursing behaviors. Use multiple regression analysis methods to explore its influencing factors, and use data statistics to analyze the role and effect of evidence-based nursing in the gastrointestinal surgery pipeline. The research results show that the evaluation ability has a significant promotion effect on clinical nursing application, and it is one of the important factors for clinical nurses to use evidence-based nursing. Clinical nurses have a higher demand for evaluation ability training, and basically here, the application effect of evidence-based nursing in the gastrointestinal surgical pipeline nursing is relatively good.

Development and Validation of a Deep Learning Model for Predicting Treatment Response in Patients With Newly Diagnosed Epilepsy.

Importance: Selection of antiseizure medications (ASMs) for epilepsy remains largely a trial-and-error approach. Under this approach, many patients have to endure sequential trials of ineffective treatments until the "right drugs" are prescribed. Objective: To develop and validate a deep learning model using readily available clinical information to predict treatment success with the first ASM for individual patients. Design, Setting, and Participants: This cohort study developed and validated a prognostic model. Patients were treated between 1982 and 2020. All patients were followed up for a minimum of 1 year or until failure of the first ASM. A total of 2404 adults with epilepsy newly treated at specialist clinics in Scotland, Malaysia, Australia, and China between 1982 and 2020 were considered for inclusion, of whom 606 (25.2%) were excluded from the final cohort because of missing information in 1 or more variables. Exposures: One of 7 antiseizure medications. Main Outcomes and Measures: With the use of the transformer model architecture on 16 clinical factors and ASM information, this cohort study first pooled all cohorts for model training and testing. The model was trained again using the largest cohort and externally validated on the other 4 cohorts. The area under the receiver operating characteristic curve (AUROC), weighted balanced accuracy, sensitivity, and specificity of the model were all assessed for predicting treatment success based on the optimal probability cutoff. Treatment success was defined as complete seizure freedom for the first year of treatment while taking the first ASM. Performance of the transformer model was compared with other machine learning models. Results: The final pooled cohort included 1798 adults (54.5% female; median age, 34 years [IQR, 24-50 years]). The transformer model that was trained using the pooled cohort had an AUROC of 0.65 (95% CI, 0.63-0.67) and a weighted balanced accuracy of 0.62 (95% CI, 0.60-0.64) on the test set. The model that was trained using the largest cohort only had AUROCs ranging from 0.52 to 0.60 and a weighted balanced accuracy ranging from 0.51 to 0.62 in the external validation cohorts. Number of pretreatment seizures, presence of psychiatric disorders, electroencephalography, and brain imaging findings were the most important clinical variables for predicted outcomes in both models. The transformer model that was developed using the pooled cohort outperformed 2 of the 5 other models tested in terms of AUROC. Conclusions and Relevance: In this cohort study, a deep learning model showed the feasibility of personalized prediction of response to ASMs based on clinical information. With improvement of performance, such as by incorporating genetic and imaging data, this model may potentially assist clinicians in selecting the right drug at the first trial.

Beclin1 Deficiency Suppresses Epileptic Seizures.

Epilepsy is a common disease of the nervous system. Autophagy is a degradation process involved in epilepsy, and in turn, seizures can activate autophagy. Beclin1 plays a critical role in autophagy and participates in numerous physiological and pathological processes. However, the mechanism underlying the effect of Beclin1 on epilepsy remains unclear. In this study, we detected increased expression of Beclin1 in brain tissues from patients with temporal lobe epilepsy (TLE). Heterozygous disruption of beclin1 decreased susceptibility to epilepsy and suppressed seizure activity in two mouse epilepsy models. We further illustrated for the first time that heterozygous disruption of beclin1 suppresses excitatory synaptic transmission, which may be caused by a decreased dendritic spine density. These findings suggest for the first time that the regulation of Beclin1 may serve as a strategy for antiepileptic therapy. In addition, Beclin1 participates in synaptic transmission, and the development of dendritic spines may be a biological function of Beclin1 independent of its role in autophagy.

SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities.

Aberrantly synchronized neuronal discharges in the brain lead to epilepsy, a devastating neurological disease whose pathogenesis and mechanism are unclear. SAPAP3, a cytoskeletal protein expressed at high levels in the postsynaptic density (PSD) of excitatory synapses, has been well studied in the striatum, but the role of SAPAP3 in epilepsy remains elusive. In this study, we sought to investigate the molecular, cellular, electrophysiological and behavioral consequences of SAPAP3 perturbations in the mouse hippocampus. We identified a significant increase in the SAPAP3 levels in patients with temporal lobe epilepsy (TLE) and in mouse models of epilepsy. In addition, behavioral studies showed that the downregulation of SAPAP3 by shRNA decreased the seizure severity and that the overexpression of SAPAP3 by recombinant SAPAP3 yielded the opposite effect. Moreover, SAPAP3 affected action potentials (APs), miniature excitatory postsynaptic currents (mEPSCs) and N-methyl-D-aspartate receptor (NMDAR)-mediated currents in the CA1 region, which indicated that SAPAP3 plays an important role in excitatory synaptic transmission. Additionally, the levels of the GluN2A protein, which is involved in synaptic function, were perturbed in the hippocampal PSD, and this perturbation was accompanied by ultrastructural morphological changes. These results revealed a previously unknown function of SAPAP3 in epileptogenesis and showed that SAPAP3 may represent a novel target for the treatment of epilepsy.

Effects of antiseizure medications on alternative psychosis and strategies for their application.

Forced normalization (FN) is a unique phenomenon that is often seen in the treatment of epilepsy. FN is characterized by abnormal mental behavior and disordered emotions in epilepsy patients despite a significantly improved electroencephalogram and successful seizure control; the occurrence of FN seriously affects patients' quality of life. The causes of FN include antiseizure medications (ASMs), epilepsy surgery and vagus nerve stimulation, with ASMs being the most common cause. However, with the timely reduction or discontinuation of ASMs and the use of antipsychotic drugs, the overall prognosis is good. Here, we perform an extensive review of the literature pertaining to FN, including its epidemiology, possible mechanisms, clinical features, treatment and prognosis.